CN1894000A

CN1894000A - Blood glucose level control

Info

Publication number: CN1894000A
Application number: CN200480032636.9A
Authority: CN
Inventors: 塔米·哈雷尔; 谢·波利克; 拉德温·卡沃尔德; 尤瓦尔·米卡; 奥弗·格拉斯伯格; 阿哈伦·格罗斯曼
Original assignee: Impulse Dynamics NV
Current assignee: Impulse Dynamics NV; Metacure NV
Priority date: 2003-09-04
Filing date: 2004-09-05
Publication date: 2007-01-10

Abstract

A method of glucose level control comprising, providing at least one electrode adapted to apply an electric field to a pancreas; and applying an electric field to the pancreas using said at least one electrode such that blood glucose levels are significantly reduced and blood insulin levels are not significantly increased compared to a regular insulin response in a same person.

Description

The control of blood sugar level

Related application

The application is the USSN 10/804 that submitted on March 18th, 2004, the part continuity application of the PCT application PCT/IL03/00736 of 560 and 2003 on JIUYUE submission in 4,, the latter is the U. S. application 10/237 of JIUYUE in 2002 submission on the 5th, 263 part continuity application, U. S. application 10/237,263 is the part continuity application of the PCT application PCT/IL00/00566 (now being disclosed as WO01/66183) of JIUYUE in 2000 submission on the 13rd, and it specifies the U.S..The application also is that the PCT that submitted on March 5th, 2000 applies for that the part of PCT/IL00/00132 continues application, and it specifies the U.S., now is the U. S. application of submitting on January 24th, 2,002 09/914,889.The application requires the rights and interests of the U.S. Provisional Application 60/123,532 of submission on March 5th, 1999 based on 35U.S.C. § 119 (e).The application also requires the rights and interests of the U.S. Provisional Application 60/488,964 of submission on July 21st, 2003 based on 35U.S.C. § 119 (e).The application also relates to the disclosed WO 99/03533 of PCT.The disclosed content of all these applications all is incorporated herein by reference at this.

Invention field

The present invention relates to control the field of serum level of glucose, specifically is that electric field (electric field) is applied on the pancreas, with the output of control insulin.

Background of invention

The control secretion of insulin is very important, because the pancreas cisco unity malfunction of many diabetics.In the diabetes of some types, total insulin level is reduced to and is kept under the required level of euglycemia level.In other type, can produce required insulin, but only just produce in one period unacceptable period of delay after blood sugar level increases.In other type, because some factors, health is resisted the effect of insulin.

Though need continuous control blood sugar level (as avoiding dangerous rising sharply and plunge), at present some patients also do not realized.

The secretion of insulin process is as follows: glucose level is relevant with β-islet cells depolarization rate in the pancreas in the blood.Suppose that when glucose level is higher ATP/ADP ratio in the beta cell is higher, and this can close potassium channel, cause the depolarization of beta cell.When the beta cell depolarization, calcium level in the cell raises, and the calcium level that raises causes Proinsulin (pro-insulin) to be converted into insulin, and causes the emiocytosis insulin.

Beta cell is arranged in islets of langerhans, and in the zone of reasonableness of blood sugar level, the action potential in the islets of langerhans (action potential) increases.Usually, the electrical activity of beta cell is an explosion type in the islets of langerhans, and each outburst comprises a large amount of little action potentials.

Propose among the disclosed WO 99/03533 of the PCT that is hereby incorporated by: use a non-irritating electric field to reduce the output of pancreas.

Propose among the disclosed WO 98/57701 of the PCT that Medtronic is hereby incorporated by: provide the zest electric pulse to islets of langerhans, cause outburst to begin as early as possible, thereby improve the outburst frequency and increase insulin secretion.

Medtronic proposes in above-mentioned PCT publication: provide irritability pulse (as more than threshold of stimulation) at burst period, to end outburst and to reduce insulin secretion.Also propose the different parts of stimulating pancreas successively in this publication, thereby make not stimulation location rest.

Yet, a limitation in the method described in the PCT of the Medtronic publication is: improve outburst speed and can increase intracellular Ca2+ level in the beta cell for a long time, and the interval (intra-burst interval) in outburst, this level does not allow to reduce.This increase can cause various cell death mechanism to be activated and/or also upset the normal equilibrium of beta cell, final killer cell.In addition, so high calcium level can cause the beta cell hyperpolarization, thereby reduces insulin secretion and suppress the action potential increment.Up to now, also effectively not electrical pancreas control device.

As the interaction of the various hormones that generate in the pancreas described among the Diabetologia that is hereby incorporated by (1992) 35:1035-1041.Insulin promotes the utilization of glucose, thereby reduces blood sugar level.Insulin also stimulates the secretion of glucagon, and this causes the hepatic secretion glucose, to increase blood sugar level.Somat reduces the secretion of insulin and glucagon.This publication has also been described the experiment that stimulates sympathetic nerve to cause the Somat secretion to increase.Propose in this paper: a healthy people's normal glucose level can be maintained by the secretion of glucagon.

Summary of the invention

Specific embodiment more of the present invention relate to and reduce glucose level and not obvious increase insulin level, are no more than a small amount of increase and/or in a short time and/or Comparatively speaking like this with the popular response among the same experimenter at least.In a typical specific embodiment of the present invention, an electric field is applied on the pancreas, reducing blood sugar level, but the insulin level that significantly do not raise, or even reduce described insulin level.In a typical specific embodiment of the present invention, reduce glucose level and raise to suppress insulin level.This can produce useful influence to pancreas by being avoided depleted.In a typical specific embodiment of the present invention, insulin raises and to be no more than 20%, 15%, 10%, 5% or still less, even reduces 5%, 10% or more.The persistent period that insulin raises is restricted to and is less than 10 minutes, is less than 5 minutes or is less than 1 minute.

In a typical specific embodiment of the present invention, increase though see tangible insulin, this increase is to be caused by the glucose level that increases, and therefore is starkly lower than desired increase under the situation of taking in the same amount glucose.For example, in glucose incident (glucose event) process, in accepting situation about stimulating, cumulative insulin secretion is compared with reference examples can reduce by 20%, 40%, 60% or more.

In a typical specific embodiment of the present invention, the minimizing of glucose and, in some embodiments, the minimizing of insulin realizes by an electric field is applied on the pancreas.In specific embodiment more of the present invention, electric field directly or indirectly reduces glucagon secretion.Alternatively or in addition, electric field other non-insulin factor of causing reducing blood sugar level in the blood and/or glucose uptake discharges.In specific embodiment more of the present invention, electric field or other control method are used to postpone gastric emptying, to reduce the utilizability (availability) of glucose.

In specific embodiment more of the present invention, glucose level also stimulates by the identical or different part to pancreas and reduces, and described stimulation causes glucose level to reduce by insulin secretion.

The aspect of some embodiments of the present invention relates to electricity irritation or by other means electric field is applied to pancreas, and wherein electrode and pancreas have certain distance.In an exemplary embodiment of the present invention embodiment, described electrode is positioned near the pancreas place, makes the electric field that electrode applied have higher value at the pancreas place or near the pancreas place.Optional, the electrode that the electric field utilization is positioned at stomach two offsides applies, and makes main pathway between the electrode (its can not by the cavity of stomach) get around stomach and by part pancreas.Optional, electric field does not almost have other organ such as stomach or not influence.Optional, electric field has useful influence (for example reducing glucose) to one or more peripheral organs.Place the possible advantage on Weishang to be that stomach is relatively stable and to damaging immunity is arranged relatively at electrode.Particularly, the problem of pancreas perforation or infection can be avoided.

Relate to regularly glucose control therapy in some specific embodiment of invention, to avoid or to reduce the initial rising of blood sugar level when having a meal.In a typical specific embodiment of the present invention, Therapeutic Method as electric field is applied on the pancreas, regularly reduce the glucagon level fast, so food digestion can not produce high glucose peak.Alternatively or in addition, control pancreas produces insulin with quick bolus (bolus) form.Alternatively or in addition, postpone gastric emptying, reduce and/or postpone glucose peak as controlling by electricity or medicine.It is generally acknowledged, concerning some patients, suitably reduce or postpone this peak value and can reduce insulin output peak, and can avoid the spike (overshooting) of pancreas.Can be with detecting diet automatically as the movable induction apparatus of stomach.Selectively, supply with the medicine gastric emptying that slows down as drug efflux pump.Alternatively, diet can manually detect, as utilizes a kind of magnetic program " rod (wand) ".

In the typical specific embodiment of the present invention, because the glucose peaks due to the diet postpones at least 5,10,15 or 20 minutes.Alternatively or in addition, the amplitude of this peak value (amplitude) (with respect to baseline value) is reduced by at least 10%, 20%, 30%, 50%, 60% or more.Alternatively or in addition, the persistent period of this peak value (surpassing baseline greater than persistent period of 40%) shortens at least 10%, 20%, 30%, 50%, 60% or more.Alternatively or in addition, because the glucose level that increases due to the diet has reduced 10%, 20%, 30%, 50%, 60% or more at least.

In the typical specific embodiment of the present invention, because the insulin peak due to the diet postpones at least 5,10,15 or 20 minutes.Alternatively or in addition, the amplitude of this peak value reduces (with respect to baseline value) at least 10%, 20%, 30%, 50%, 60% or more.Alternatively or in addition, the persistent period of this peak value (surpassing baseline greater than persistent period of 40%) shortens at least 10%, 20%, 30%, 50%, 60% or more.Alternatively or in addition, because the insulin level that increases due to the diet has reduced 10%, 20%, 30%, 50%, 60% or more at least.

In exemplary of the present invention, these differences were measured in the corresponding time period that body reacts to glucose absorption incident, for example about 60 minutes of described time period.In the exemplary of the present invention, the shortage of these reductions or obviously increase is not for controlling (for example after meal) desired increase.In some embodiments and/or situation, lacking increases for base line condition

Alternatively or in addition, the blood insulin value keeps relative low value, as every

milliliter

30,20, below 15 or 10 micro-units.

Specific embodiment more of the present invention relate to the method that the pancreas that has a built-in safety effect (built-insafety effect) by electricity irritation is controlled glucose.In the typical specific embodiment of the present invention, in case reach glucose baseline level, used electric field just substantially no longer reduces glucose level.Alternatively or in addition, use electric field, as several days or can significantly not disturb the viability (viability) of exocrine pancreas function and/or pancreas several week in the effective time section.In the typical specific embodiment of the present invention, the decline of glucose level below baseline is no more than 30%, 20%, 10% or littler percentage ratio.In the specific embodiment of the invention, glucose level no longer further significantly reduces, and the degree of reduction is less than baseline Fructus Vitis viniferae level above 40%, 30%, 20% or still less.

Specific embodiment more of the present invention relate to be selected and/or Comprehensive Control generates and influence the various hormones of blood sugar level by pancreas, with glucose level control.Control can be used pure electricity irritation, maybe can use one or more medicines and/or other molecule to combine with electricity irritation in required mode and reach.Medicine can suppress pancreatic cell and produce and/or secreting hormone.Alternatively, medicine can the inhibitory hormone activity, as by the blocking-up receptor or make the hormone inactivation.Alternatively or in addition, hormone can be from external or provide with insulin pump as insulin, Somat or glucagon.In specific embodiment more of the present invention, control right and wrong excitatoty (non-excitatory) (being defined as follows).In other specific embodiment of the present invention, control is the combination of irritability or irritability and the control of non-irritability.

In typical specific embodiment more of the present invention, not only glucose level control is also controlled required hormonal readiness, reaching gratifying physiologic effect, rather than only prevents the symptom of undesired blood sugar level.As for to reach required short run effect, or alternatively or in addition for to reach required long-term effect, can implement such control.Effective control types of two parameters should with only come blood sugar control to distinguish mutually by changing insulin level.This simple control can not reach required blood sugar level and insulin level, can cause the pancreas excessive secretion perhaps.

Have a kind of hypothesis think a unsuccessful possible factor in some prior aries be for the control glucose to take neural of pancreas or directly to stimulate be non-selective stimulations excitatoty and to some different hormone secretions, reduced the effectiveness and/or the pancreas of hormone secretion and excessively worked.

In the typical specific embodiment of the present invention, the secretion of antergic hormone (as glucagon or insulin) is suppressed, and to prevent feedback effect, the secretion of its hormone that hits (as insulin or glucagon) increases the retroaction hormone secretion.

Alternatively or in addition, the stimulation of target hormone secretion is remained on enough low level, do not cause a large amount of secretions of retroaction hormone.The secretion time can prolong, so the hormone total amount is enough to the result that reaches required.

Alternatively or in addition, the stimulation of target hormone secretion is controlled at the outbreak period (in burst), the curtailment of its time is to stimulate a large amount of secretions of retroaction hormone.Alternatively, can keep secretion, to reach secretion that on purpose causes the retroaction hormone and/or the retroaction hormone that produces capacity.

Alternatively or in addition, the secretion of targeting hormone maintains sufficiently high level to overcome retroaction.

Alternatively or in addition, stimulation to the targeting hormone secretion maintains the secretion (as Somat) of sufficiently high level with the restricted hormone of generation effective dose, its secretion suppresses the secretion of retroaction hormone, discharges the targeting hormone but be not enough to suppress stimulation.

Alternatively or in addition, the secretion of some pancreatic hormones is suppressed by the pancreas hyperpolarization.This hyperpolarization is charged in natural product or chemical drugs.As, diazoxide causes hyperpolarization and reduces the activity of pancreas.

Alternatively or in addition, beta cell (as insulin secretion) is suppressed the response of hyperglycemia level, rather than blocking-up, be in order to prevent hypoglycemia.Alternatively or in addition, no matter whether glucose uptake reduces when still keeping high insulin levels, the secretion glucagon prevents hyperglycemia.In some cases, avoid causing excess (overshoot) with insulin response decay and/or glucagon supply, as, by postponing manually operated response to pancreas.In some cases, using and/or cancelling gradually increases or reduces insulin (or other hormone) pulse (as considering effect or instantaneous frequency), to prevent this excess.Alternatively or in addition, use a kind of method of active, as antagonist hormonal is provided.

In the typical specific embodiment of the present invention, when stimulation caused a large amount of insulin secretion, glucose level also increased, to avoid hypoglycemia.In an example, this is provided by glucose pump.In another example, this is that release by direct stimulation glucagon provides.In other example, insulin secretion is in a large number or fast, so it directly or indirectly causes glucagon secretion.In an example, secretion of insulin is faster than its speed of being removed (as natural or minimizing artificially) by blood flow, causes the very high insulin level in part (to pancreas), and this can stimulate the generation of glucagon.Alternatively or in addition, the general enough height of intravital insulin level (and/or raising enough soon) produce to stimulate glucagon.In other possible specific embodiment of the present invention, keep insulin slowly to increase, avoiding the secretion of glucose in the body and/or various hormones, as, the habituation (habitation) by promoting relevant physiological mechanisms and/or avoid triggering rate sensitivity mechanism.

Specific embodiment more of the present invention relate to by the control glucagon secretion and realize control to insulin and/or glucose blood level.In the typical specific embodiment of the present invention, increase glucagon secretion and be used to increase blood sugar level, rather than reduce insulin secretion or extra increasing.Selectively, the secretion of restriction glucagon can not cause the full consumption of glucose in the liver.Alternatively or in addition, glucagon secretion increases stimulates secretion of insulin.In the typical specific embodiment of the present invention,, can reach the required gentle required insulin level of G/W simultaneously by suitable control glucagon secretion.Alternatively or in addition, do not stimulate glucagon secretion, to avoid producing unusual high-level insulin.In some cases, promote the deposit of glucose in the liver, or exhaust this deposit with glucagon with secretion of insulin.

In typical specific embodiment more of the present invention, control effect rather than the blood sugar level of the gentle insulin level of G/W, as influence gluconeogenesis, ketogenesis, fat storage, the glycogen formation of lipid metabolism, liver with the control insulin.

Alternatively or in addition, liver can be controlled by glucose and/or insulin, and do not have relevant hyperglycemia, so that forcing supplying fully and/or avoiding the liver of glucose to absorb of glycogen reserves after a while.

Alternatively or in addition, insulin level can reduce, make that the glycogen that stores is less in liver.This may excessively store in disorder and/or other the excessive storage disorder useful at von Gierke.

Specific embodiment more of the present invention relate to active response of map (mapping) pancreas and/or feedback.This map can be used for, as a given patient, and/or a kind of patient and/or pancreatic diseases.

In a kind of typical specific embodiment of the present invention, measure following one or more characteristics of pancreas:

(a) interaction between two or more hormones, comprise one or more gains (amplificationgain) (plus or minus), a kind of hormone short-term and the long-term influence that continues to change to another kind of hormone, the time delay of the another kind of hormone of a kind of hormonal effects, and/or the active native sequences of hormone;

(b) response of hormone secretion and/or produce various stimulations and suppress effect is as electric field, medicine and/or nerve stimulation;

(c) influence of glucose level, the early stage stimulation of pancreas and/or levels of drugs are to the interactional influence of hormone with to stimulating and response and/or other physiologic parameters of other pancreatic hormone level, as the digestive enzyme level;

(d) the outburst ability comprises, as intercellular hormones and prohormone storage capacity and/or time constant generating the hormone ability;

(e) the pancreas different parts is different movable; With

(f) electrical activity of all or part of pancreas.

In some embodiments, map is also determined the effect of non-pancreatic hormone, as the hormone of hypophysis, thyroid and kidney.Some hormones can directly act on increases or reduces blood sugar level on the liver.

In the typical specific embodiment of the present invention, the direct measurement of absolute or relative hormonal readiness and/or the measurement of glucose level and/or other physiologic parameters are used for determining the effect of various stimulations.This measurement can be online or off line.In the typical specific embodiment of the present invention, chemical optical fibre induction apparatus (fiber-optic chemical sensor) is used to analyze hormonal readiness.Alternatively or in addition, use the antibody basic test.In the typical specific embodiment of the present invention, controller comprises port or the lead that is connected to pancreas and/or Portal circulation system.Perhaps, for approaching easily, port or lead pass from health, only extend under the skin and/or lead to body cavity.Such port or lead can be used for control lead (catheter), to remove the blood that is full of hormone in the pancreas.In case the mapping stage finishes, and can remove conduit and/or lead.Alternatively or in addition, port is used to handle endoscope, to implant and/or to reappose induction apparatus and/or electrode.

Alternatively or in addition, interact, also will measure pancreas various physiological conditions procedure of adaptation and/or health procedure of adaptation and/or blood hormonal readiness to various pancreas states in order to measure in the pancreas.This mensuration can be finished in laboratory.Alternatively or in addition, revocable or implanting device is provided by patent, be used to measure the activity in time of above-mentioned pancreas.

In the typical specific embodiment of the present invention, the above-mentioned activity that measures is as the parameter of the movable forecasting model of pancreas.Alternatively or in addition, new model is as producing neural netted system type model from measure.This model may be used to predict therapeutic effect and/or make one's options between selectable Therapeutic Method.In the typical specific embodiment of the present invention, this model is used to select a kind of Therapeutic Method that reduces glucose level, and this method increases insulin secretion, but does not increase glucagon secretion.

Typical specific embodiment more of the present invention relate to the blood that flows into pancreas by control, control pancreas activity indirectly, influence the generation and the secretion of hormone, and/or flow out the blood of pancreas, influence that hormone in the pancreas distributes and/or the local horizontal of hormone by control.In the typical specific embodiment of the present invention, use the non-irritating electric field, selectivity shrinks or diastole some or all of tremulous pulsies and/or vein in pancreas or the pancreas, with the control blood flow.

A typical specific embodiment of the present invention relates to when avoiding producing not satisfied calcium level curve, increases a kind of method of insulin secretion.In the typical specific embodiment of the present invention, insulin output is by in the suitable interval that keeps between the outburst, and the prolongation explosion time increases, thereby calcium level was decayed in interval.Alternatively or in addition, insulin output is by increasing the usefulness of burst period calcium input, may not change that outburst frequency and/or working cycle increase.Alternatively, in two kinds of methods, when reaching higher insulin output level or keeping identical output level, the outburst frequency may reduce and/or increase interval.

In the typical specific embodiment of the present invention, by to adopt non-irritability pulse to influence insulin secretion to small part pancreas.Term used herein " non-irritating " is used to describe and does not produce new action potential, but can change the pulse of existing or later current potential.This activity can be the result of pulse, amplitude, frequency or pulse envelope (pulse envelope), and also relies on commutator pulse usually.Known single pulse can have irritability and non-irritability part.As 100ms pacemaker impulse (pacingpulse), can stop obtaining in pace-making effect behind the 20ms (pacing effect) and the real non-irritability effect behind 40ms.

In the typical specific embodiment of the present invention, when the used pulse typical specific embodiment according to the invention, its increases outburst amplitude (burst amplitude), and its effect may continue for some time.Selectively, pulse ceaselessly breaks out.May break out also and be extended.It is generally acknowledged that increasing the outburst amplitude can increase insulin generation and/or secretion.

Pulse can with local electrical activity, as with the outburst or synchronous with the individual part current potential.Alternatively or in addition, pulse may with the period of change of insulin level in the blood (being typically 12 minute cycle of healthy people) synchronously.Alternatively, pulse can be asynchronous with part or whole pancreas electrical activity.Alternatively, use pulse can cause in the pancreas most of islets of langerhans synchronous, as by exciting an outburst.Two parts pulse (two part pulse) can be provided, and a part is synchronous, and a part provides the non-excitable activity of pulse.Though use term " pulse ", known used electric field can have to be longer than action potential (action potential) or even persistent period of being longer than outburst.

Typical specific embodiment more of the present invention relate to the calcium level that reduces β-islet cells.In the typical specific embodiment of the present invention,, a kind of oral drugs reduce this level by being provided.Alternatively, reduce this level by the interval that increases between the outburst.Can increase at interval, as outburst, as using irritability or non-irritability pulse by inhibitory action voltage.Alternatively, a kind of electric physiology medicine that is used for this purpose is provided, example hydrochloric acid procainamide and quinidine sulfate are the sodium channel antagonisies, minoxidil (Minoxidil) and pinacidil (Pinacidil) are potassium channel activators, and amiloride (Amiloride) hydrochlorate is the antagonist of sodium channel and epithelium.Other known drug in the prior art, described as receptor classification RBI handbook, and can obtain from RBI Inc..Can reduce calcium level to reduce the response of pancreas to glucose level in the blood.Alternatively or in addition, this minimizing is used for offseting the passive side effect of medicine or other Therapeutic Method and/or makes to small part pancreas and has a rest.Alternatively or in addition, this minimizing can be offseted by the usefulness that increases insulin secretion.

Typical specific embodiment more of the present invention relate to the pace-making (pacing) of small part pancreas and, use non-irritability pulse the period of delay behind pace-making.Can provide non-irritability pulse to strengthen or suppress insulin secretion or for other reason.In the typical specific embodiment of the present invention, this pacemaker impulse provides synchronously, so in the basic identical phase place of its action potential, non-irritability pulse can contact most cells.Then, according to the anticipated impact of non-irritability pulse, can provide further excitement or non-excitatoty pulse to action potential.

In the typical specific embodiment of the present invention, be used for influencing insulinogenic boost pulse and also be used to produce stride.In an example, pulse resets the electrical activity of pancreas, can be in a kind of similar mode that is used for the defibrillation pulse of heart.Alternatively or in addition, boost pulse may cause the generation of outburst immediately, and the pulsion phase after causing is the pulse automatically delaying hereto.In the typical specific embodiment of the present invention, no matter synchronous actual cause use boost pulse, and causing after pulse, had the short delay of several seconds before the outburst of new (nominal at least) conventional length produces.

Typical specific embodiment more of the present invention relate to medicine and the electric control that pancreas is provided simultaneously.In the typical specific embodiment of the present invention, the negative influence of medicine is offset in electric control.Alternatively or in addition, medicine is offset the negative influence of electric control.Alternatively or in addition, electric control and medicine replenish mutually, as, drug influence insulin generting machanism and electric control influence insulin secretion mechanism.Electric control and/or medicine control can be used for controlling the active various aspects of pancreatic endocrine, comprise one or more: glucose level induction (sensing), insulin generation, insulin secretion, cell regeneration, healing and cultivation mechanism and/or action potential increment.In the typical specific embodiment of the present invention, electricity and/or medicine mechanism are used for replacing or support the pancreas mechanism that operation is bad, stop insulinogenic feedback mechanism as replacing when reaching required blood sugar level.Can be used to influence pancreas with the synergistic medicine of the controller of pancreas.Alternatively, they can influence the other parts of health, as affect the nerves system or cardiovascular system.

Typical specific embodiment more of the present invention relate in the various activation schemes and activate pancreatic cell, as to realize cultivating (training), regeneration, treatment (healing) and/or optimum utilization.In the typical specific embodiment of the present invention, this activation comprises one or more irritability pulses, non-irritability pulse and uses medicine and/or glucose.If expect that ill cell can not deal with normal load and use this load, ill cell can be degenerated.Yet, by time normality load is provided, these cells energy continuous firing and can curing after utilizing self treatment mechanism.Especially, expect certain diseased cells, under the stimulation of minimum at least activation levels, can fully recover, rather than decline.Alternatively or in addition, expection by certain intensity make cellular stress, compensation mechanism, as the response speed and curve (profile), cell usefulness and/or the cell quantity that increase cell size, glucose level can prove effective, thereby cause the increase of insulin generative capacity, insulin response time and/or other required pancreas parameter.Need suitable activation curve to determine patient's tolerance basis.Perhaps, the different activation curve of a part of test pancreas, and if they work as expected, just can be applicable to the other parts of pancreas.The other parts of these pancreas can be suppressed at test period, so that avoid excessively stress (stressing).Alternatively, can be as by electric control or medicine or insulin control they being maintained to think the level of activation of " safety ".

Typical specific embodiment more of the present invention relate to electrical influence and preferably control the insulin generation, influence insulin secretion alternatively or additionally.In the typical specific embodiment of the present invention, strengthen insulin from beta cell " (milking) that extrude " insulin and generate, the supply that makes insulin is subaverage (under par) always.Alternatively or in addition, this cell is extruded deficiency (under-milking) (as secretion inhibitor), insulin generates and reduces.Some patients may produce adverse consequences, excessively extrude (over-milking) and can cause insulin to generate minimizing, and/or extrude not enough can the generation by the increase insulin.Alternatively, suppress the insulin generation, therefore cause a large amount of insulins to be stayed in the cell by suppressing emiocytosis insulin (as by suppressing depolarization), and may, the further generation of insulin suppressed.Ending insulinogenic this mechanism is found in pancreatic cell.

In the typical specific embodiment of the present invention, when a large amount of insulin of needs,, store a large amount of insulins by causing cell as hyperglycemia disease, can reach response time faster.Cell can be by depolarization systematically to produce stocking of insulin then.Perhaps, regularly stock a large amount of (at different time identical or different) pancreatic cell, so that the outburst of insulin to be provided.

Alternatively or in addition, in therapeutic process, suppress insulin output, with the prevention hypoglycemia.Alternatively or in addition, the inhibition or the enhancing of insulin output are used to make the tumor cell of pancreas excessively to work, and therefore, because insulin excessively generates or overstock, cause death of neoplastic cells.In some cases, by the cell transition work due to the circulation demand can be used as a kind of make that cell dies down stress (stress) form and with other stress be in conjunction with, cell killing.Alternatively or in addition, suppress the activity that insulin output is used to reduce the pancreas or the part pancreas of implantation, help to overcome and transplant shock.

Typical specific embodiment more of the present invention relate to other parameter of action potential in the increment of control action current potential and/or the control islet cells, alternatively or in addition with the parameter of control outburst activity (burstactivity).In the typical specific embodiment of the present invention, pulse selectable select synchronous with the respective action current potential of islets of langerhans, be used for the control action current potential, as increasing or reduce the persistent period of plateau.Alternatively or in addition, offset minimizing, be easy to excitement more as obtaining required frequency by pacemaker cell or making it to become in the terminal action potential frequency of outburst.

In the typical specific embodiment of the present invention, use chemistry and/or electrotherapy, by the beta cell in selectivity sensitization (sensitizing) or desensitization (desensitizing) islets of langerhans, the increment of control action voltage is as strengthening or blocking-up.Strengthening action potential is useful to the production rate that increases insulin, if especially in some cells the conveyer mechanism of glucose be compromised.Suppress the action potential increment to the generation of avoiding insulin and/or to force its rest be useful.

Typical specific embodiment more of the present invention relate to by changing the response parameter of pancreas, as response time that increases glucose level and the response gain (response gain) that increases glucose level, the activity of remote-effects pancreas.Therefore, pancreas that can the non-response of sensitization causes glucose level to have little change can cause that also insulin flows out.Alternatively, pancreas weak or excessively response may be desensitized, so do not need to generate (a large amount of) insulin for each minor swing of blood sugar level.Known two kinds of therapies can be applicable to the different piece of single pancreas simultaneously.

Typical specific embodiment more of the present invention relate to the synchronously movable of pancreas different piece.This form that can take to activate all different pieces synchronously.Alternatively, when the other parts that suppress pancreas (or making it keep inactivation), comprise an activation part (or making its activation) synchronously.In the typical specific embodiment of the present invention, be used to force the different piece of pancreas to have a rest synchronously.Alternatively or in addition, synchronously with the quick response part of selectivity activation pancreas or the slow response part of pancreas.

In the typical specific embodiment of the present invention, between the islets of langerhans or in islets of langerhans synchronously by medicine is provided, as Connexin, reduce impedance (gap resistance) at interval and strengthen.This medicine can be as oral administration, through local blood systematically or local, and as giving through bile duct.In the typical specific embodiment of the present invention, this medicine passes through to change the pancreatic cell gene, as uses genetic engineering method to provide.

Typical specific embodiment more of the present invention relate to implant electrode in pancreas (and/or induction apparatus).In the typical specific embodiment of the present invention, electrode provides through bile duct.Perhaps, the controller that is attached on the electrode also provides through bile duct.In the typical specific embodiment of the present invention, implantation process does not need general anesthesia, and uses endoscope.Alternatively, electrode provides through intestinal.Perhaps, the device of control electrode energising also provides through intestinal.In the typical specific embodiment of the present invention, when electrode through intestinal with enter near the pancreas or in the pancreas time, device is stayed in the intestinal, perhaps at the folded part of intestinal.Alternatively, electrode can provide through blood vessel, as portal vein.In the typical specific embodiment of the present invention, electrode is along electrode independence or independently the prolongation electrode of contact point in a large number to be arranged.Electrode can be straight or curved.In the typical specific embodiment of the present invention, electrode is entered in the pancreas, in curved mode as guiding, so electrode covers required pancreas surface or whole by endoscope.Calibration phase in that labelling is implanted can pass through image, or detects by the electric field that electrode sends, and guarantees accurate covering.

Typical specific embodiment more of the present invention relate to and are suitable for adopting above-mentioned one or more the pancreas controller of method.In the typical specific embodiment of the present invention, in the implanted body of controller.One or more electrodes that the typical control device comprises are given the power supply of electrifying electrodes and the control circuit of control energising.Selectively, glucose or other induction apparatus are used for feedback control.

Therefore,, provide this pancreas controller, comprising according to the typical specific embodiment of the present invention:

The glucose induction apparatus is with the level of glucose in the perception serum or insulin;

At least one electrode is to insulin cellulation or cell mass energising;

Give the power supply of described at least one electrifying electrodes, its pulse can not excite the action potential in the described cell and the effect that increases insulin secretion is arranged; With

Controller receives sensation level and the described power supply of described at least one electrifying electrodes is given in control, to be created in the desired effects on the described level.Selectively, contiguous pancreas of described insulin cellulation and wherein said electrode are suitable for being positioned over contiguous described pancreas.Alternatively or in addition, described controller comprises the shell (casing) that is suitable for implanting for a long time.Alternatively or in addition, described electrode is suitable for contacting with bile for a long time.Alternatively or in addition, device comprises that the electrical activity induction apparatus and the wherein said power supply of the electrical activity of the described cell of perception give described electrode with the frequency energising higher than sensed described cell depolarization frequency, thereby causes described cell with higher frequency depolarization.

In the typical specific embodiment of the present invention, design described pulse with persistent period of the plateau that prolongs described action potentials of cells, flow in the cell thereby make in more calcium.Selectively, design described pulse reducing the action potential frequency of described cell, and do not reduce excretory insulin from described cell.

In the typical specific embodiment of the present invention, design described pulse and break out the active persistent period to prolong described cell.

In the typical specific embodiment of the present invention, described pulse has enough amplitudes to raise the cell of not participating in insulin secretion in the described cell mass.

In the typical specific embodiment of the present invention, described device comprises second electrode to the vicinity of second cell mass energising of insulin secretory cell at least, wherein said controller is given described second electrifying electrodes, and second electrode has second pulse that is different from described first electrode.Selectively, design described second pulse to suppress insulin secretion.Selectively, work out the program of described controller, giving described second electrifying electrodes in after a while time, thereby force the described insulin of secretion, described insulin is suppressed secretion in early days.Alternatively, design described second pulse, make the described second cell hyperpolarization.

In the typical specific embodiment of the present invention, described controller is given described at least one electrifying electrodes, its pacemaker impulse (pacing pulse) has enough amplitudes so that the pith depolarization of described cell, thereby harmonizes the cell work voltage relevant with non-irritability pulse.

In the typical specific embodiment of the present invention, for the outburst activity of described cell, described controller and described electrifying electrodes are synchronous.

In the typical specific embodiment of the present invention, for the individual part current potential of described cell, described controller and described electrifying electrodes are synchronous.

In the typical specific embodiment of the present invention, to the electrical activity of described cell, described controller is asynchronous with described electrifying electrodes.

In the typical specific embodiment of the present invention, to each action potential of described cell, described controller does not use described pulse.

In the typical specific embodiment of the present invention, to each outburst activity of described cell, described controller does not use described pulse.

In the typical specific embodiment of the present invention, the persistent period of described pulse is less than the single action current potential of described cell.Selectively, the persistent period of described pulse is less than the persistent period of the plateau of described cell.

In the typical specific embodiment of the present invention, the single action current potential that lasts longer than described cell of described pulse.

In the typical specific embodiment of the present invention, the described cell that lasts longer than of described pulse breaks out the active persistent period.

In the typical specific embodiment of the present invention, described controller is determined the response of described energising to the Drug therapy that acts on cell.Selectively, described Drug therapy comprises the pancreas treatment.Alternatively or in addition, described controller is used described pulse to offset the retroaction of described Drug therapy.

In the typical specific embodiment of the present invention, described controller is used described pulse, with described Drug therapy synergism.Alternatively, described controller is used the retroaction of described pulse with the pacing stimulation (pacing stimulation) of offsetting described cell.

In the typical specific embodiment of the present invention, described device comprises alarm.Selectively, if described glucose level is reduced to below the threshold level, described controller excites described alarm.Alternatively or in addition, if described glucose level more than threshold value, described controller excites described alarm.

Also provide a kind of method of controlling insulin secretion according to the typical specific embodiment of the present invention, comprising:

Electrode is added at least a portion pancreas;

On at least a portion pancreas, this pulse increases secretion of insulin with non-irritability pulse application.Selectively, this method comprises that the irritability pulse combines application with described non-irritability pulse.Alternatively or in addition, this method comprises and uses minimizing excretory non-irritability (the secretion reducing non-excitatory) pulse relevant with described non-irritability pulse.

In the typical specific embodiment of the present invention, this method comprises with the order that designs uses a plurality of pulses, to reach the required effect of described at least a portion pancreas.

Therefore, provide a kind of pancreas controller, comprising according to the typical specific embodiment of the present invention:

Be suitable for being given at least one electrode of small part pancreas energising; With

The setting program controller is given described electrifying electrodes, for the effect of at least two aspects below the positive control at least: the level of blood sugar level, blood insulin levels and another hormone of pancreas.Selectively, control comprises described at least two aspects of change simultaneously.Alternatively or in addition, when reducing influencing each other between described two aspects at least, control comprises one of described at least two aspects of selectively changing.Alternatively or in addition, control comprises and is retained to less one of described level in required physiology's scope.Alternatively or in addition, described at least two aspects comprise the gentle insulin level of G/W.Selectively, control comprises adjustment and the irrelevant described insulin action of carbohydrate metabolism.

In the typical specific embodiment of the present invention, one of described at least two compositions comprise glucagon.Selectively, control comprises the increase glucagon secretion, to reduce the effect of insulin.Alternatively or in addition, control comprises the increase glucagon secretion, to reach higher blood sugar level.Alternatively or in addition, control comprises when insulin secretion increases, the secretion of minimizing glucagon.

In the typical specific embodiment of the present invention, one of described at least two aspects comprise Somat.Alternatively or in addition, one of described at least aspect comprises glucose level.Selectively, described controller is optionally being controlled the therapy of selecting the described glucose level of a kind of minimum upset between the therapy.

In the typical specific embodiment of the present invention, described controller uses the described aspect of electric field controls separately.

In the typical specific embodiment of the present invention, described controller is considered intravital molecule is carried out described control.Selectively, described molecule need not described controller control.Alternatively, described molecule is under the control of described controller.

In the typical specific embodiment of the present invention, at least a pancreatic hormone secretion of described molecules in inhibiting.Alternatively or in addition, the effect of at least a pancreatic hormone of wherein said molecules in inhibiting.Alternatively or in addition, described molecule improves at least a pancreatic hormone secretion.Alternatively or in addition, described molecule improves the effect of at least a pancreatic hormone.

In the typical specific embodiment of the present invention, control a kind of hormone composition and comprise the secretion that suppresses antagonist hormonal.Alternatively or in addition, control hormone composition comprises the secretion that improves antagonist hormonal.

In the typical specific embodiment of the present invention, described controller comprises the interactional learning and memory module of the feedback of collecting described pancreas.Selectively, the interaction of described feedback is included in the interaction between the hormonal readiness.Alternatively or in addition, the interaction of described feedback is included in the interaction between the hormonal readiness.Alternatively or in addition, the interaction of described feedback depends on blood sugar level.Alternatively or in addition, the interaction of described feedback is determined by the activity of following the trail of described pancreas by described controller.Selectively, described controller actively changes the hormonal readiness of the gentle pancreas of at least a G/W, to collect the interaction data of feedback.

In the typical specific embodiment of the present invention, this controller comprises the induction apparatus of the level of the described controlled composition of perception.Alternatively or in addition, this controller is included as the estimator of the level of estimating described controlled composition.Alternatively or in addition, described electrode is used non-irritability pulse and reached described control.Alternatively, the pulse of described electrode application irritability reaches control.

In the typical specific embodiment of the present invention, described electrode changes the blood flow relevant with described pancreas to reach described control.Selectively, the blood flow of described change comprises the blood flow of the hormone cellulation of described pancreas.Alternatively, the blood flow of described change comprises the blood flow from described pancreas.

In the typical specific embodiment of the present invention, the blood flow of described change comprises the blood flow from the hormone cellulation of described pancreas.

In the typical specific embodiment of the present invention, described at least one electrode comprises at least two electrodes of selectivity to the different piece energising of described pancreas, to reach the required control to described at least two aspects.

In the typical specific embodiment of the present invention, control comprises the control secretion.

In the typical specific embodiment of the present invention, control comprises that control generates.Alternatively or in addition, control comprises the control physiological activity.

Also provide a kind of active method of pancreas of describing according to the typical specific embodiment of the present invention, comprising:

Be determined at the activity of pancreas under first group of situation;

Be determined at the activity of pancreas under second group of situation; With

Analyze the movable of pancreas and analyze several groups of situations, to determine the model of action of pancreas.Selectively, described model of action is included in the mutual relation between two kinds of hormones of described pancreas.Alternatively or in addition, described several groups of situation spontaneous generationes.Alternatively or in addition, described several groups of situations to small part by the artificial induction.

In the typical specific embodiment of the present invention, this method comprises that the described pancreas of control is to the active response of described mensuration.Selectively, control comprises control use medicine.Alternatively, control comprises control use electric field.

Also provide a kind of control pancreas to break out active method according to the typical specific embodiment of the present invention, comprising:

Electric field is applied to small part pancreas, makes and after the described application several seconds, excite the outburst activity; With

Repeat described applied several times, make all outburst activities of described pancreas part synchronous with described application and repeated application during described application.Selectively, this method comprises that the repetitive rate that changes described application is to control the outburst rate (burst rate) of described at least part pancreas.

Also provide a kind of control pancreas active method according to the typical specific embodiment of the present invention, comprising:

The power supply of electric field is provided; With

Make the energising of described power supply so that electric field is applied to small part pancreas, make used electric field increase the amplitude of at least one outburst after the described application.Selectively, used electric field does not cause new outburst.Alternatively or in addition, used electric field does not change the outburst rate of described pancreas in fact.Alternatively or in addition, described increase amplitude outburst increases with normal amplitude and breaks out relevant insulin level.Alternatively or in addition, this method comprises described energising and the described sequence synchronization of outburst naturally to small part pancreas.

Also provide a kind of method of controlling glucose level according to the typical specific embodiment of the present invention, comprising:

Provide and be fit to electric field is applied at least one electrode on the pancreas; With

Use described at least one electrode that electric field is applied on the pancreas, make with same experimenter in insulin regular reacting phase ratio, blood sugar level significantly reduces and blood insulin levels does not significantly improve.Selectively, this method comprises subsequently second electric field is applied to described pancreas that second electric field increases insulin level.

Optional, described electric field is effective to reducing glucagon secretion.

Optional, described electric field is effective to the glucose secretion that reduces liver relevant with described pancreas on the physiology.

Optional, it is effective that described electric field increases glucose uptake to the somatic cell that comprises described pancreas.

Alternatively, described electric field is effective to the nervous tissue that influences described pancreas.

Optional, described electric field right and wrong excitatoty (non-excitatory), it does not cause the active new outburst of islets of langerhans of described pancreas basically.

Optional, described electric field is used as the electric field (biphasic andcharge balanced time varying field) with the change of charge balance time of two-phase.Optional, each short time period of described electric field uses.Selectively, the frequency of utilization of described period is 1Hz-15Hz.Optional or in addition, the frequency of utilization of described period is about 5Hz.Optional or in addition, the described period is less than 30ms.Optional or in addition, about 10ms of described period.

Optional, described electric field repeats in less than 30 minutes period.

Optional, described electric field repeated in 30-180 minute period.

Optional, described electric field is used for all periods basically of glucose absorption incident.

Optional, described electric field was used before the glucose uptake incident of expection.

Optional, this method comprises with the described electric field of glucose uptake activity-triggered.

Optional, do not consider the picked-up incident, use described electric field.

Optional, do not consider blood sugar level, using described electric field in the part-time at least.

Optional, constantly used described electric field at least 24 hours.

Optional, do not use described electric field under the situation of its effect of perception at least 15 minutes.

Optional, described electric field has a certain size and time range, so it does not significantly change blood insulin and glucose level basically when not absorbing incident.

Optional, described electric field reduces blood sugar level, at least 20% of the glucose level rise of minimizing more than fasting baseline glucose level.

Optional, shown in the meansigma methods of measuring among five minutes, described electric field increases blood insulin levels no more than 20%.

Optional, described electric field reduces blood insulin levels, and as what measure by the cumulative amount of glucose uptake incident, described blood insulin levels is compared with described experimenter's popular response situation to have reduced and surpassed 20%.

Optional, this method comprises by stomach is treated and postpones gastric emptying.

Optional, described electric field is effective to postponing glucose peak between its operating period at least.

Optional, described electric field effectively postpones glucose peak at least 10 minutes.

Optional, described electric field effectively postpones insulin peak at least 10 minutes.

Optional, described electric field effectively reduces insulin spikes.

Optional, described electric field effectively reduces glucose peaks.

Optional, described electrode is not attached to pancreas.

Optional, described electrodes is in pancreas.

Provide at least one to be fit to (adapted to) electric field is applied to electrode on the pancreas; With

If blood sugar level raises, the electric field that effectively reduces the blood sugar level that raises is applied on the pancreas, and if glucose level do not improve basically then obviously do not reduce this level in sharp mode.Selectively, described electric field reduces the glucose level at least 20% that improves.Alternatively, described electric field not extremely (acutely) reduce the glucose level that is not enhanced and surpass 10%.Alternatively, described electric field does not damage the exocrine function of described pancreas.

Also provide a kind of glycemic control device according to the typical specific embodiment of the present invention, comprising:

Be fit to electric field is applied at least one electrode on the pancreas; With

The suitable circuit of giving described at least one electrifying electrodes and utilizing non-excitated type electric field to dispose to described electrifying electrodes in the mode that compensates the sharp loss that responds of described pancreas.Selectively, described circuit compensates by the insulin secretion that causes bolus form (bolus).

Alternatively, described circuit compensates by the glucose level that reduces the non-insulin form.Alternatively, described circuit compensates by reducing glucagon secretion.

Alternatively, described circuit reduces or suppresses the substantial increase of insulin secretion between the described amortization period.

Alternatively, the picked-up incident at least 20%, described circuit only uses the acumen control of insulin level.Selectively, described device comes setting program by the insulin treatment based on the long response time chemistry (slow acting chemical-based insulin therapy) to described pancreas.

Alternatively, this device comprises that automatic detection absorbs active automatic picked-up induction apparatus.

Alternatively, this device comprises the automatic glucose induction apparatus of the sharp responsive status of automatic detection needs.

Alternatively, this device comprises the automatic glucose induction apparatus of the insulin response situation that automatic detection needs are sharp.

Alternatively, described response is sharp insulin response.

Alternatively, described electrode is suitable for being connected in pancreas.

Alternatively, described electrode is suitable for being connected in muscular organ.

At least one is fit to electric field is applied to electrode on the pancreas; With

The mode of the blood sugar level of be fit to giving at least one described electrifying electrodes and improving with remarkable minimizing is to the circuit (circuitry) of the configuration of described electrifying electrodes, and the circuit of described configuration does not use described electric field yet when glucose level improves.Selectively, described circuit is a closed-loop system, comprises induced electrified effect and wherein under doubt situation, sets overstimulation (over-stimulate) for described circuit.

Alternatively, described circuit is semi-open circuit system, wherein uses long relatively stimulation series and feedback not.

Alternatively, described circuit is an open loop system, and wherein response excites but uses when not feeding back stimulates series (stimulation series).

Be fit to electric field is applied at least one electrode on the pancreatic tissue; With

Be fit to give described at least one electrifying electrodes and switch on for described electrode as follows and the circuit that disposes, this mode is for when glucose level improves, the minimizing glucose level, but do not improve above the insulin level more than the baseline value basically.Selectively, described circuit is a closed-loop system, comprises induced electrified effect, wherein under doubt situation, gives and states circuit setting overstimulation.

Alternatively, described circuit is to use the stimulation series of growing relatively and the semi-open circuit system that does not feed back.

Alternatively, described circuit is an open loop system, wherein uses response to excite and do not have the stimulation series of feedback.

Alternatively, the constant voltage electric field of described circuit application.

Selectively, described circuit application constant current electric field.

Selectively, described pancreatic tissue comprises pancreas in the body.

Alternatively, described pancreatic tissue comprises the pancreatic tissue of implantation.

Alternatively, described baseline is to use the experimenter's of described device baseline insulin response.

Also follow according to illustrative embodiments of the present invention the insulin level control method be provided, comprising:

Provide at least one to be fit to electric field is applied to electrode on the pancreas; With

Utilizing described at least one electrode that electric field is put on pancreas makes not obvious increase of blood sugar level and blood insulin levels obviously reduce.

Exemplary also according to the present invention provide electric field is used for pancreas or on function and position the tissue relevant with pancreas, comprising:

With at least one electrodes in tissue except described pancreas; With

Make to described electrifying electrodes tangible electric field is added on described pancreas or linked groups with at least one level in control pancreatic secretion level and the blood sugar level.Optional, described method comprises also utilizes described at least one electrode custom of keeping on a diet.

Exemplary also according to the present invention provide electric field put on pancreas or on function and position the device of the tissue relevant with pancreas, comprising:

At least one is suitable for being attached to the electrode of the tissue except described pancreas; With

Give the equipment of described electrifying electrodes, make tangible electric field is put on described pancreas or linked groups with at least one level in control pancreatic secretion and the blood sugar level.

The accompanying drawing summary

Preferred embodiment of the present invention wherein appears at the analog structure, composition or the part that surpass in the accompanying drawing and marks with identical or similar numbering in institute's drawings attached that they occur with reference to the description of the typical specific embodiment of following band accompanying drawing:

Fig. 1 is the structure chart according to the pancreas controller of the typical specific embodiment of the present invention;

Fig. 2 is the typical electrical activity figure of the single beta cell implemented at ordinary times at the G/W that improves slightly;

Fig. 3 A is the flow chart according to the typical control logical scheme of the typical specific embodiment of the present invention;

Fig. 3 B is the flow chart according to another typical control logical scheme of the typical specific embodiment of the present invention;

Fig. 4 A-4D sets forth the suitable different type electrodes to the pancreas energising according to the typical specific embodiment of the present invention;

Fig. 4 E sets forth an electrode according to the typical specific embodiment of the present invention, and wherein the controller main body among Fig. 1 is as at least one electrode;

Fig. 5 sets forth according to the typical specific embodiment of the present invention, and pancreas is subdivided into a plurality of control zones, and each zone is by different electrifying electrodes;

Fig. 6 A and 6B are the flow charts according to the method for implantation of the typical specific embodiment of the present invention;

Fig. 6 C is the abdominal cavity sketch map according to the typical specific embodiment of the present invention, shows the position that electrode is placed near the Weishang pancreas.

Fig. 7 is according to the typical specific embodiment of the present invention, the flow chart of the typical method of controller implantation and setting program;

Fig. 8 A is presented in six animals, and electricity irritation is to the influence of insulin level;

Fig. 8 B-8D is the lab diagram of pancreas original position, shows according to the typical specific embodiment of the present invention, the increase of insulin secretion;

Fig. 9 shows the effect of electricity irritation to blood sugar level, and the increase of glucose is than only suppressing desired fast of insulin secretion in experiment;

Figure 10 A-10B is respectively lab diagram and pulse diagram, shows as result-glucose level of using electric pulse according to the typical specific embodiment of the present invention to descend;

Figure 11 A-11B is respectively lab diagram and pulse diagram, shows as result-glucose level of using electric pulse according to the typical specific embodiment of the present invention to descend;

Figure 12 A-12B is respectively lab diagram and pulse diagram, shows as result-glucose level of using electric pulse according to the typical specific embodiment of the present invention to descend;

Figure 13 A-13B is respectively lab diagram and pulse diagram, shows as result-glucose level of using electric pulse according to the typical specific embodiment of the present invention to descend;

Figure 14 display application boost pulse increases the experiment that breaks out amplitude but do not cause new outburst;

Figure 15 A-15C is lab diagram and two enlarged drawings, shows that boost pulse and outburst activity are synchronous, does not perhaps produce new outburst at once;

Figure 16 A-16C is lab diagram and two enlarged drawings, shows to induce new outburst with boost pulse;

Figure 17 is a lab diagram, is presented at the intermediary stimulation of outburst and can not stops outburst (burst);

Figure 18 A and 18B show obviously the variation of the insulin level that is caused by stimulation;

Figure 19 shows when not stimulating, metastable glucose level in a rat pancreas that is poured;

Figure 20 A shows and when not stimulating, the variation of the insulin level in the piglets of the work of a feeding Cube sugar;

Figure 20 B is corresponding with Figure 20 A, is presented at the relation between the gentle insulin level of G/W under the incentive condition;

Figure 20 C is corresponding with Figure 20 A, is presented under the non-incentive condition relation between glucose and the insulin level;

Figure 21 A shows and when not stimulating, and gives the variation of insulin level of the piglets feeding of a work;

Figure 21 B is corresponding with Figure 21 A, shows blood sugar level;

Figure 22 A shows according to the typical specific embodiment of the present invention, in a series of experiments, gives under the situation of first pig stimulation the delay of glucose peak and the decline of level;

Figure 22 B shows according to the typical specific embodiment of the present invention, in a series of experiments, gives under the situation of first pig stimulation the delay of insulin peak and the decline of level;

Figure 22 C shows according to the typical specific embodiment of the present invention, as using the result-glucagon that stimulates to reduce;

Figure 23 shows according to the typical specific embodiment of the present invention, in a series of experiments, gives under the situation of second pig stimulation the minimizing of glucose level;

Figure 24 shows according to the typical specific embodiment of the present invention in a series of experiments,, give under the situation that the 3rd pig stimulate the minimizing of glucose level;

Figure 25 sets forth according to the typical specific embodiment of the present invention, and onset under the condition of (IV hyperglycemic clamping) is fixed in the stimulation that reduces glucose in the IV hyperglycemia;

Figure 26 shows according to the typical specific embodiment of the present invention on normal glucose level, do not have the danger effect that stimulates;

Figure 27 shows stimulates the influence to people's glucose level according to the typical specific embodiment of the present invention;

Figure 28 shows stimulates the influence to people's insulin level according to the typical specific embodiment of the present invention;

Figure 29 shows stimulates the influence to people's c-peptide level according to the typical specific embodiment of the present invention;

Figure 30 A and 30B show according to the typical specific embodiment of the present invention there not be the danger effect of stimulation, to the influence of the people's of fasting glucose level;

Figure 31 A and 31B show according to the typical specific embodiment of the present invention there not be the danger effect of stimulation, to the influence of the people's of fasting insulin level;

Figure 32 A and 32B show that according to the typical specific embodiment of the present invention, glucose in the pig and insulin reduce;

The accumulation of glucose and insulin level in the pig among Figure 32 C and 32D displayed map 32A and the 32B.

Figure 33 A and 33B show according to the typical specific embodiment of the present invention, the glucose in the another pig and the reduction of insulin.

The glucose of pig among Figure 33 C and 33D displayed map 33A and the 33B and the accumulation level of insulin.

Figure 34 shows according to the typical specific embodiment of the present invention, under various electric field applying conditions, and the accumulation level of glucose.

Figure 35 A and 35B show that according to the typical specific embodiment of the present invention, glucose in the another pig and insulin reduce.

The glucose in the pig of Figure 35 C and 35D displayed map 35A and 35B and the accumulation level of insulin.

Figure 36 shows that according to the typical specific embodiment of the present invention, the glucose level in the another pig reduces.

Figure 37 A and 37B show according to the typical specific embodiment of the present invention, the glucose in the Canis familiaris L. and the reduction of insulin.

Figure 38 A and 38B show according to the typical specific embodiment of the present invention, and the glucose in two Canis familiaris L.s reduces, and wherein electrode places the Weishang.

Figure 38 C shows that according to the typical specific embodiment of the present invention interruption gives the test of Canis familiaris L. signal and gives the different-effect of the test of Canis familiaris L. signal continuously.

Figure 38 D is the sketch map that shows the relative position of pancreas lobus dexter stomach function regulating in the Canis familiaris L..

Figure 39 A and 39B show according to the typical specific embodiment of the present invention, and the glucose in two Canis familiaris L.s reduces, and wherein electrode places the Weishang.

Detailed Description Of The Invention

General introduction

Fig. 1 is a sketch map according to the pancreas controller 102 of the specific embodiment of the invention.In specific embodiments of the invention, device 102 is used for providing the control current impulse to pancreas 100.This control impuls comprises excited boost pulse and non-excited boost pulse.Especially, this pulse can comprise pacemaker impulse and action potential change pulse.

In specific embodiments of the invention, control impuls is used for controlling patient's glucose and insulin level.And can reach the glucose and/or the insulin level of special expection.Can also control the secretion of other hormone of pancreas in addition.Other application of controller 102 will be expressed in the following description, and its application can for example comprise the damage of cultivating, curing (healing) and prevention pancreatic cell.

Can adopt the concrete of the metabolic disorder of following proper method treatment and/or hormone disturbance to comprise non-insulin-dependent diabetes mellitus, insulin dependent diabetes mellitus (IDDM) and hyperinsulinemia with non-localized example.

Below description comprise that many kinds can be used for obtaining the different pulse of required effect, also cladding system of the scope of Miao Shuing clearly, as be programmed and be used to the controller 102 that uses pulse and/or process to feed back.It should also be noted that the various combinations that can adopt following pulse realize expected effect with two kinds of different orders.The special pulse combined that is applicable to particular patient should be that the basis is determined with patient, and this special combination also may change over time.Yet concrete pulse and order are as described below.

The device example

The controller 102 of pancreas generally includes a field source by the generation electric field of control circuit 106 controls, and this electric field passes pancreas 100 or its part.At random, power supply 108 provides power supply for field source 104 and control circuit 106.Use the multi-electrode inductance, for example common electrode 110 and many single electrodes 112.Can use other electrode scheme in addition, for example a plurality of electrode pairs.

Can also provide the electricity with other pick off with the input controller 106.Though electrode also can be used as electric transducer,, in a specific embodiment of the present invention, use the pick off 114 of pick off independently such as pancreas or be positioned at blood glucose sensor 118 on the blood vessel wall 120.The extracellular pick off of measuring glucose level in the cell also can use.Controller 102 can also comprise an external unit 116, for example is used for transmitting electric energy or programming Control circuit 106 and/or power supply 108.Selectively or additionally, external unit can be used to provide the indication from patient and/or sensor information.Selectively or additionally, external unit can propose alarm to the patient, for example under the situation of the unusual control of glucose level.Selectively or other, this alarm can be provided by human body inside, for example, uses lower frequency sounds or by nerve of electricity irritation, muscle or intestinal.

Be the supplemental instruction of this embodiment and other additional embodiment below.Yet, the ordinary construction of controller 102 can utilize parts and the design principle that is used for other electric physiology controller, for example in PCT document WO 97/25098, WO98/10831, WO98/10832 and US patent application 09/260,769, described in, patent 6292693 disclosed contents are incorporated herein by reference.Yet, it should be noted that pulse in the pancreas frequency, power level and persistent period may be used for different as heart.Especially, power level may be lower.In addition, except the probability that causes the tissue injury that patient disease increases the weight of, can not resemble and implement life-threatening the similar error that pulse produces in the heart implementing immediate effect that the error in the pulse process causes to pancreas.

Use the tissue of controller

What the present invention mainly described is about pancreatic tissue.This tissue can be positioned in the middle of the pancreas or the part of graft, may be positioned at other position of health, and perhaps or even in the shell of controller itself, that graft comprises is for example homologous, from tissue body or allogenic.Selectively or additionally, graft produces insulin through genetic modification usually.Different piece that it should be noted that pancreas has different secretion behaviors and/or the response different to electrical field stimulation.

Electrical activity in the pancreas

Fig. 2 is under the slight glucose level that raises, the sketch of the typical electrical activeness of single beta cell.In high range Figure 130, the activity of individual cells is shown as and contains a plurality of outbreak period 132, and the outbreak period 132 comprises a plurality of respective action current potentials, and is separated by a plurality of interval 134, does not have action potential in interval basically.As amplify shown in Figure 140, each outburst comprises a plurality of depolarization incidents 142, each process of depolarization heel is with a repolarization phase 144.The intracellular Ca2+ level increased during the outbreak period 132, reduced in interval 134.

The beta cell of pancreas is arranged in the islets of langerhans, and each such islets of langerhans when glucose level is enough high, will be propagated action potential as an one zone of action in this zone.Therefore, cumulative action potential is multiple average action potential in the islets of langerhans, and its frequency is for example 1Hz, depends on the propagation time of action potential by islets of langerhans usually.During interval 134, if there are enough beta cells to participate in interval, whole islets of langerhans keeps tranquillization or has only depolarization takes place once in a while usually.Individual cells can turn round under higher frequency, for example 5-20Hz.Selectively or additionally, slow wave can per minute around the about 3-5 circle of adventitia.It should be noted that synchronization between the cell and/or the interrelated slit connection of depending between beta cell and other cell in the islets of langerhans.According to embodiments of the invention, resistance or this slit join dependency also may be by glucose and/or hormonal readiness decision or control in the level of glucose and/or hormone.Selectively or additionally, the synchronicity level between islets of langerhans and/or the islets of langerhans can be used as the indicator of glucose and/or hormonal readiness.The nearest synchronicity that studies show that the pancreas different piece is mediated by nervous pathway.In specific embodiments of the invention, in order to achieve desired results, using electric field and/or medicine irritation and/or block this nervous pathway.The example of this research is at Porksen N, Hollingdal M, Juhl C, " " Pulsatile insulin secretion:detection that Butler P, Veldhuis JD, SchmitzO deliver, regulation, and role indiabetes ", Diabetes.2002 April; 51 increase 1:S245-54, Denmark, Aarhus, hospital of Aarhus University endocrine and metabolism system " in describe to some extent, the disclosed content of this document is incorporated herein by reference.

Insulin secretion increases

Secretion of insulin is different from the generation of insulin, and it can be strengthened by number of ways according to specific embodiments of the invention.Below method can in conjunction with or use separately.The all right topical application of these methods, the several portions of selection pancreas, perhaps overall applicability acts on whole pancreas.

In first method, the persistent period of outburst 132 has prolonged, and allows more calcium to enter beta cell thus.The level that the it is believed that intracellular Ca2+ directly quantity with the insulin of cell release is relevant.Adaptable a kind of pulse pattern is a pacemaker impulse, forces the cell depolarization in the islets of langerhans.Such pulse is used arbitrarily, and its frequency is identical with individual actions current potential frequency, for example 10Hz.Yet, needn't start each action potential, the pacing signal of one-period is enough to produce successive process of depolarization.Cardiac pacing technology as is well known, many kinds of technology can be used for increasing the probability of capturing pacing signal, for example dual pace-making, pulse shape (pulse shape) and persistent period.Through suitable modification, these methods also can be used for the pace-making of pancreas.The another kind of method that increases outburst length is to increase beta cell to unpolarized sensitivity, for example, and by the subthreshold value pulse.The method of another kind of sensitized cell and/or increase action potential duration is a hyperpolarization before passive or normal unpolarizing.May be by preventing normal reduction in outburst depolarization in latter stage frequency, can obtain higher insulin output to realize the outburst of equal length.

Another kind method kind, insulin secretion are to increase by the efficient that flows in the calcium that increases the individual part current potential.In specific embodiments of the invention, realize by the length that increases plateau 144, for example in the process of repolarization that connects each process of depolarization 142, make the pulse of electricity consumption.If providing the calcium channel that flows in the calcium to use such pulse as early as possible before closing in the repolarization phase of an action potential, these passages will be opened the longer time and stream in the more calcium will be provided.It should be noted that beta cell starts (firing) frequency and will reduce.

In some cells, stream is more effective in depolarizing phase calcium.In these cells, depolarizing phase 142 prolongs arbitrarily, for example uses an additional depolarization pulse at depolarizing phase or in blink thereafter.Selectively or additionally, can use the medicine that strengthens repolarization, so that make the time of repolarization shorter, the time of outbreak period 132 is more in the polarization incident.Selectively or additionally, can plateau use one suitably pulse shorten plateau.In one embodiment, closing the back at calcium channel uses a pulse expection to shorten the repolarization ground time.Selectively or additionally, the individual part current potential is with than glucose level highland ratio pace-making more just often.This pace-making can be crossed repolarization ground terminal point, and forcing more continually, unpolarizing takes place.Notably be to be compared to that spontaneous generation can obtain quite high pacing rate by pace-making under the identical physiological condition.Pacing rate may be higher than islets of langerhans physiological normal condition under any glucose level.

In another approach, islet secretion increases secretion of insulin by the outburst (with respect to above-mentioned higher action potential frequency) of pace-making islets of langerhans higher frequency.The shortening of the interval 134 of Chan Shenging as a result of has ill effect, for example keeps the long time of high calcium level in the cell.In a specific embodiment of the present invention, this potential drawback can overcome with the time that do to increase interval, for example, used a hyperpolarization pulse in interval, allowed calcium to leak out beta cell thus.Yet, it should be noted that in some cases the calcium level of the rising that continues is required, in these cases, shortened interval artificially.By way of compensation, the effectiveness that causes the outburst of insulin secretion has reduced.

The potential advantage of pace-making is that pacing signal can cause raising of depolarization and associated beta cell, otherwise it can not be participated in the activity of pancreas.Expection is because the intracellular Ca2+ level increases (or other control mechanism), and some cells will stop to participate in bioelectric.By using pacemaker impulse, expect that some cells will be forced to participate in also therefore continue excreting insulin.

The potential advantage of another of pace-making is relevant with the synchronicity problem.The control impuls that is appreciated that some kinds must be used in the specific period of action potentials of cells.In an action potential of propagating, be difficult to provide the pulse of one-period and all cells coupling, particularly because the increase of depolarization frequency.Yet, be forced to depolarization simultaneously by whole islets of langerhans, each stage is synchronized, the pulse period of easier formation expectation.Yet it should be noted that even without pace-making, for example, can in for islets of langerhans, all effectively constantly use some pulses by most of cell in order to prolong the plateau of an action potential.

In the typical method that some insulin secretions increase, the unpolarized amplitude of islets of langerhans obviously strengthens.For example, by raising other non-participation cell, perhaps because cell synchronization makes signal of telecommunication stack.

Alternatively or in addition, except the carrier transportation of calcium mediation, in a specific embodiment of the present invention, electric field is direct uelralante from the REP of cell and/or other organelle the cell also.

Insulin secretion suppresses

For example in some cases, if the level of glucose is low excessively, the inhibition of insulin secretion is expected.Also have, following method can be used together or separately.In addition, as mentioned above, diverse ways can be used for the different part of islets of langerhans, and for example, the electrode 112 among difference energising Fig. 1 is secreted the enhanced while when the part of islets of langerhans thus and reduced in different part secretion of insulin.Insulin suppresses expect in another situation, and this is in order to prevent the out of control of feedback circuit, and secretion of insulin causes the secretion of glucagon in this feedback circuit, subsequently the more glucose of release from liver.

In the first method that insulin secretion reduces, make the beta cell hyperpolarization as using the DC pulse.Therefore, cell can not made response to the glucose level that raises by depolarization and insulin secretion.It should be noted that apply pulse does not need to make bioelectric synchronous.Be desirably in the end-of-pulsing after-hyperpolarization and continue a moment.May have only prolong interval, and not exclusively stop the outburst activity.

In the second approach, dump the insulin deposit of (dump) pancreas so that in the time afterwards, the insulin that cell does not have obviously to measure is used for secretion.For example in order to prevent untoward reaction, this hectare unload can be for example by providing glucose or insulin antagonist to finish simultaneously.Insulin resistance agent described herein, glucose or other medicines can be provided by multiple mode.Yet in a specific embodiment of the present invention, they can provide by the pump (not indicating) of external unit 116 or controller 102 inside.

In the third method, shortened plateau 144, for example super pace-making (over-pacing) insulin cell is not so that there is time enough to make stream in the calcium.Perhaps, by during the repolarization or calcium channel make the cell hyperpolarization prolong inner depolarizing phase after closing (or force them to close by hyperpolarization).This hyperpolarization will postpone next unpolarized initial, therefore, reduce in total calcium in a period of time and will flow.

Selectively or additionally, in the process of outburst, can use the hyperpolarization pulse and shorten outburst.

Influencing insulin produces

It is believed that various feedback mechanism produces relevant with the electrical activity and the insulin of beta cell.In a specific embodiment of the present invention, handle the generation that these mechanism increase or reduce insulin, perhaps or in addition directly control secretion of insulin.

In a specific embodiment of the present invention, pulse hinders the beta cell excreting insulin as hyperpolarization in application.Therefore, it is full that intracellular spares keeps, and produces less insulin (therefore, having less insulin to enter blood flow).

In a specific embodiment of the present invention, beta cell is stimulated uelralante.For cell, if a cell, expects that it can be very tired by overstimulation, need considerable time to recover, inner cell can not produce insulin during this period.If a cell is under the stimulation, expect that it is incited somebody to action loss in time and secretes insulin less and less, because it has adapted to news.If a cell is accepted enough stimulations, it will be with at utmost continual generation insulin so.

Pancreas response control

In a specific embodiment of the present invention, pancreas can change for the parameter of different G/W flat responses, rather than directly controls the level of insulin secretion.A variable parameter is a response time.Another parameter is the gain (gain) (amplification) of response.In some cases, these two parameters can not be separated mutually.Yet, it should be noted that controller 102 can directly provide many different response modes by controlling pancreas fully.

In specific embodiments of the invention, have patient fast and the slow-response part for pancreas, blocking-up or startup pancreas fast-response part will increase or reduce the response time of pancreas.For example partially or completely hyperpolarization will realize blocking-up.For example just using the subthreshold value pulse before depolarization will realize starting.The potential advantage of this subthreshold value pulse is that energy that it uses than other pulse still less.

By as blocking-up or start the part of pancreas, control participates in the total amount of the pancreatic tissue of response, gain that can control response.It should be noted that startup " slow-response " cell causes it to serve as the fast-response cell, increases the gain of fast-response thus.In some cases, starting and/or blocking to need periodic repetition, to keep the sensitivity of described pancreas.

Selectively or additionally, by supporting the propagation of (or preventing) action potential, as give suitable medicine, may strengthen the sensitivity of (or weakening) pancreas.Octonal and Heptonal are the examples of the medicine that is connected of decoupling (decouple) slit.

In another embodiment of the present invention, will change the secretion of part or all of pancreas and/or the ability of generation insulin by the blood flow of controlling inflow and/or outflow pancreas.

According to conjecture, reduce generation rate and/or secretion rate that the blood flow that flows into pancreas will reduce multiple pancreatic hormone.

Selectively or additionally, leave pancreas, the local concentration of multiple hormone is raise, demonstrate the stronger enhancing of other hormone secretion effect or suppress effect (some situation can be like this) by the blood that stops the load hormone.

It should be noted that for type ii diabetes pancreas is the level that increases insulin to the response of the glucose level of increase.Yet therefore this operating lag increases value (magnitude).As a result, perhaps owing to different mechanism, body reduces and/or delay the response of insulin, forces just more insulin to be discharged.In a specific embodiment of the present invention, the control of pancreas response is used to prevent the generation of this feedback circuit.In a specific embodiment of the present invention, prevent to secrete the insulin of recruitment.Selectively or additionally, the secretion of (as the sign before taking food) glucagon reduces when glucose level increases or before increasing, and prevents that (or minimizing) occurs because the concentration of glucose that feed causes reaches the peak fast.Selectively or additionally, for example electricity consumption or medicine postpone the emptying of stomach.

In a specific embodiment of the present invention, when feeling or predict the exception response of pancreas, should carry out following one or two schemes: (a) suppress the response of pancreas; (b) quicker than usual and/or increase the response (reducing) of pancreas more as insulin secretion and/or glucagon, be turned back to physiological situation thereby eliminate exception response fast.And according to specific embodiments more of the present invention, optionally hormone control allows for the patient provides optionally hormone ratio, for example provides than (or lower) glucagon higher under the situation that does not have electricity irritation and the ratio of discharging insulin.Should be appreciated that in some cases, it is impossible controlling hormone and/or glucose level separately owing to biological coupling.Yet, use method described here, it is possible reaching relative control by the reduction coupling.

In some cases, the overreaction that expection reduces pancreas can make pancreas be restored, reduce or get rid of to other or the needs of successive treatment.Randomly, do not use its control or reduce control degree, controller 102 is periodically tested this probability and is determined whether the pancreas response is normal.

Non-insulin control

Except that the control secretion of insulin with producing, also can control the secretion and/or the generation of other pancreatic hormone.The polypeptide (poly-peptide) that the example of this hormone comprises glucagon, somatostatin and pancreas (PP).When also controlling insulin level or directly do not controlling level and the curve (profile) that to control these hormones when insulin level allows it to change.Therefore, in some embodiments of the invention, described hormone can not rely on insulin and part control.

Should be noted that in some cases the level of the control insulin that the factor of control except that insulin can be indirect.For example, the level of reduction glucose causes the reduction of the level of insulin usually.Similarly, the hormone of some pancreas interacts by biological feedback mechanism, for example, increases glucagon and also increases insulin.These interactions can be represented with a set of equations.In other embodiments, use neutral net.In an embodiment of the present invention, the fact of generation is that the feedback equation is non-linear.Alternately, described equation typically comprises the different gains that time delay is relevant with different hormonal readinesses.And physiological mechanism can depend on the active and/or multiple Digestion hormone of glucose level, nerve stimulation, pancreas formerly.The special equation of particular patient and/or equation parameter need to measure, for example by control experiment (following the tracks of it to other functions of hormones as the level that changes a hormone) or observation.

In case equation is known, basically for other hormone individually (perhaps interdependently less) control a hormone be possible.For example, insulin roll up level with the rising glucagon, yet within a very long time more a spot of increase insulin and the secretion (this will obscure the reduction glucose effect of (confound) insulin) that do not start glucagon can have similar effect to blood glucose.Selectively or additionally, the increase of glucagon (or, on the contrary, insulin or other pancreatic hormone) can be used as a series of short outburst, and rest period is arranged between the outburst.Therefore, even excretory hormone is brought into play its activity, it can not be accumulated in blood and/or in the cell and be able to cause the obvious excretory level of antagonist hormonal.As the less multilevel example that relies on each other, when specific physiological status (as glucose level), ratio between the hormone secretion level can raise or reduce at least 10%, 20%, 30%, 40% or more, with initial higher level as denominator.

Alternatively or in addition, medicine can be used for reducing the sensitivity (or increasing sensitivity) of a certain cell for other cell category, therefore, changes the feedback equation and also allows to occur in the hormone Selective Control some errors.Perhaps, the response of cell can be by medicament adjusting, so all cell categories produce response in a kind of consistent more mode.The example that selectivity influences the medicine of pancreas reaction comprises streptozotocin and alloxan, and they can reduce the discharge of insulin from beta cell, and multiple medicine is used for the treatment of diabetes.

Alternatively or in addition, the receptor of employed medicine blocking-up hormone makes its invalid by selectivity.Alternatively or in addition, medicine, for example antibody makes the hormone in the blood flow invalid.

The example of medicine is for example being put down in writing J Biol Chem February 11 in 2000 in the following document; 275 (6): 3827-37, Acta Crystallogr D Biol Crystallogr in May, 2000; 56 (Pt 5): 573-80, Metabolism 1999 Jun; 48 (6); 716-24, Am J Physiol in January, 1999; 276 (1Pt1): E19-24, Endocrinology in November, 1998; 139 (11): 4448-54, FEBS Lett 2000May 12; 473 (2): 207-11, Am J Physiol in August, 1999; 277 (2 Pt 1): E283-90, CurPharm Des in April, 1999; 5 (4): 255-63 and J Clin Invest on April 1st, 1998; 101 (7): 1421-30, the disclosed content of these documents is incorporated herein by reference.

Alternatively or in addition, because the ratio difference of each cellular type of pancreas different piece, therefore optionally a certain specific part of stimulating pancreas and/or the activity of optionally blocking some part of pancreas can make a kind of hormone with respect to other hormone different changes take place.

Alternatively or in addition, different cell types are different to the response of identical electrical field stimulation, therefore allow different hormones is carried out different control.

Control hormonal readiness and control cause that the difference between the level of glucose of hormone secretion merits attention.The level of control glucose can prevent that at least too high or too low glucose level from damaging human body, can not guarantee that but body cell can utilize glucose.On the other hand, keep the level of hormone, can not only keep glucose in the scope of an expectation, can also guarantee that available insulin reaches enough levels, make body cell can assimilate glucose in expection.In addition, hormone causes the human body effect of multiple expection, as controls fat and proteinic metabolism, prevents insulin resistant.

It should be noted that in some cases what expectation obtained is ratio or a temporary transient hormone pattern of a hormone, rather than a simple hormone value.Effect by control can realize as temporary transient change hormone.

In a specific embodiment of the present invention, the reduction of glucose level can realize by activating the non-insulin-dependent glucose transporter indirectly.These effects can by direct local excitation import in the pancreas (or contiguous pancreas) nervous pathway or by realizing by the enhanced pancreas activeness of these local nervus centripetalis perception (by stimulating generation).Included nerve signal can strengthen the activity that the non-insulin of human body in organizing relies on GLUT at a distance, strengthen glucose uptake thus and do not rely on insulin and blood sugar lowering or with pancreas in increase low, temporary transient or partial insulin parallel.The hormone approach also is possible.Nearest article shows that the cell in the cardiac stimulus can cause the increase of cellular uptake glucose.The existence of the nervous pathway of irritation cell (as the cell of heart) also is known.Article is " Contraction-Induced Fatty Acid Translocase/CD36 Translocation inRat Cardiac Myocytes Is Mediated Through AMP-Activated Protein KinaseSignaling ", Diabetes in July, 2003; 52 (7): 1627-34, Luiken JJ, CoortSL, Willems J, Coumans WA, Bonen A, Van Der Vusse GJ, Glatz JF, the physiology system of cardiovascular research institute of Universiteit Van Maastricht of Dutch Maas Te Lihete and the motion function system of University of Waterloo (CA) Waterloo, Ontario, N2L3GI Canada of Canadian Waterloo, the disclosed content of this article is incorporated herein by reference.

Indirect insulin control

In a specific embodiment of the present invention, control the level of insulin indirectly by reducing glucose level.In a specific embodiment of the present invention, glucose level reduces by following electricity irritation.As a result, insulin level reduces and/or not obvious increasing.In a specific embodiment of the present invention, electricity irritation reduces the level of glucagon.Alternatively, when also descending, the level of insulin level decline glucagon uses some other path.In a specific embodiment of the present invention, the level of prerequisite hyperinsulinism and/or reduce the level of glucagon on the feed is not so that feed can cause the unexpected fast peak that reaches of glucose level.

The example of control method

Fig. 3 is the flow chart according to the control method 200 of the specific embodiment of the invention.In this figure, pancreas activity intensity (with the danger of following) increases along with the increase of glucose level.Above or following more specifically the description strengthen and weaken pancreas activity ground several different methods.Randomly at ordinary times the patient is carried out early warning at ultimate G/W.And, the error that this method causes may be partial to hyperglycemia some because the untoward reaction of hyperglycemia is serious unlike the untoward reaction of hypoglycemia, the untoward reaction of hypoglycemia takes place at once.The logic (logic) of the automatic control glucose level of once developing before it should be noted that is used for insulin pump also can be used for controller 102.The additional functionality of controller 102 is to suppress body self to produce insulin.Randomly the extra restriction of controller 102 needs considerations is to avoid the damage of stimulation oversaturation to pancreas.

In step 202, measure the level of glucose.Many kinds of methods can be used for measuring the level of glucose.In a specific embodiment of the present invention, suppose it is hyperglycemia, before begin treatment, measure several times repeatedly.Suppose it is hypoglycemia, before treatment, measure several times repeatedly or do not measure.The treatment circulation repeated once in randomly per two to five minutes.Perhaps, in case of emergency, as under the hypoglycemia situation, circulation repeats more continually.

If glucose level under 60 (mg/dl) (steps 204), further produces insulin and randomly is suppressed (206), and randomly, to patient give a warning (208).

If glucose level is (210) between 60 to 150, do not operate, because these are normal glucose levels.

If glucose level is (212) between 150 to 200, depend on the operation and the previous glucose level of measuring that had before carried out and operate.For example previous glucose level is higher, just keeps or reduces the insulin secretion activity.On the other hand, if glucose level is lower, then increase the insulin secretion level.For example, if now glucose level has reduced than the previous value of measuring, then using ratio between modified outburst and the not modified outburst is 1: 3 pulse application ratio (pulseapplication ratio) (214).Be appreciated that the gentle pulse parameter of definite G/W that is used for particular patient not only depends on patient's medical history certainly, also depends on the specific response of patient to employed pulse parameter.Some patients may not resemble and produce response other patients, should use stronger pancreas activity change of plan.

If glucose level is (216) between 200 to 250, the operation of formerly carrying out is depended in the measure of taking, as the pulse application ratio between 1: 1 and 1: 2 that uses.Alternatively or in addition, the degree of variation, the direction of variation and/or the rate of change of glucose level are depended in the operation of taking.Randomly, the pattern of insulin secretion, digestion and/or the effect of blood sugar level is used for estimating the significance that glucose level changes.

If glucose level is (220) between 250 to 300, use higher pulse application ratio, as 1: 1 (222).

It is breakneck that glucose level is higher than 300.Therefore, if determine so high level, should use and break out pacing rate or individual part current potential (individual action potentials) pacing rate (224) faster.Alternatively or in addition, secretagogue non-irritability pulse also is used at least some pacemaker impulses.

If glucose level surpasses 400 (226), use biphasic (bi-phasic) pacemaker impulse for the individual part current potential.Expect that first of this pulse induces depolarization mutually, second extends plateau mutually makes that stream increases in the calcium.Alternatively or in addition, if use in advance, can adopt the control in many pancreas district to be used for more total part of the pancreas of excreting insulin with increase.

If glucose level is higher than 500 (230), need stringent effort, for example warn patient or its doctor (232), inclining all available insulins (234) in the pancreas.Only in these situations, the standby of available insulin can be retained in pancreas or install in 102 (or the insulin pumps that link to each other).

It should be noted that said method only is an example.For example, each operation of determining can be changed, because operation can be the combination that postpones before multiple operation, pulse parameter and the change operation.

This control method is utilized sluggish closed hoop control loop.Perhaps, can be used in and the conventional similar open loop of glucose level processing.In such ring, the amount that insulin is discharged from a specific pulse is known, and the insulin of discharge is used for the measurement of rare glucose level is made a response, and described measuring method is as using blood testing.Periodic glucose level test can be used for detecting the control (failed control) of inefficacy.Intermediary control loop (Intermediate controlloop) has the control loop (having open loop and closed hoop) of the control loop of less delay and combination, can be used in another specific embodiment of the present invention.

The investigation of long-term and short-term

When adopting the inductance pulse according to specific embodiments of the invention, short-term and secular effect are all optional to be needed to investigate.Shortterm effect for example comprises the effect to insulin secretion and generation.Secular effect comprises as the effect to organization survival ability and electrode polarization ability.

As described below, long term may be negative, as cell death, or positively charged, cure as treatment or acceleration.

Polarization of electrode and crust (encrustation) can be avoided by randomly using ion electrode and equalizing pulse (using the positive and negative charge of equivalent basically).Alternatively, can use special bag, as those electrodes with yttrium oxide or titanium nitride coating by electrode.Alternatively or in addition, can use big relatively electrode.Balance can also can extend to several pulses on each pulse basis.

In a specific embodiment of the present invention, controller 102 is kept in the internal memory with the effect of the picked-up electricity of its (not having to show) record glucose level, use and/or controlled delivery of pharmaceutical agents, food and/or control pancreas electrical activity and/or to the effect of blood sugar level.

It should be noted that owing to disease develops in time the cell of particular types such as β cell can fade away, thus distinct methods/or therapeutic scheme design be suitable for the different phase of disease.For example, strengthen secretion of insulin at the initial period of disease, disease than the secretion that reduces glucagon latter stage.Other therapeutic scheme for example, activates non-insulin and relies on GLUT seldom owing to advancing of disease exerts an influence.

The cell training

In a specific embodiment of the present invention, use inductance and/or dosage regimen and train the reaction of (training) islet cells, be exactly to train cell to make it adapt to specific situation in essence.Expection is executed slightly and stress will be caused that cell is compensatory the β cell, for example enlarges or produces new β cell.The existence of known such regenerative system, as document " ' Amelioration of Diabetes Mellitus in partiallyDepancreatized Rats by poly (ADP-ribose) synthetase inhibitors.Evidence ofIslet B-cell Regeneration '; people such as Y Yonemura, Diabetes; 33 (4): 401-404, in April, 1984 " record to some extent in, the disclosed content of the document is incorporated in this as a reference.Stress be excessively with cell killing.Therefore, at every patient, strengthen the cell service ability stress size need pass through try and error method (trail and error) and measure.In a specific embodiment of the present invention, try and error method is carried out in the different piece of pancreas, and optionally being partial to stress be not enough rather than stress be excessive.In a specific embodiment of the present invention, remarkable reduction of discharging by insulin or electricity reduction or unusual react to measure excessively stress.

Alternatively or in addition, can make the insensitive pancreatic cells of glucose level such as centering by frequent stimulation and/or in the repeatedly stimulation of the glucose level that raises a little, be adjusted to lower glucose level is produced responsive.

In a specific embodiment of the present invention, this training pulse (training pulse) is used in combination with medicine, and purpose is to cause regeneration or cures.

It should be noted that the be complementary profile of the cell that can also be used for keeping the patient who temporarily takes insulin of training and activation scheme, perhaps support from noxious substance or diabetes outbreak, to be able to restorative cell.

Electricity irritation may increase the level of intracellular Ca2+, and the result increases genomic activity in the cell.This will strengthen reparation.Yet strengthen and excessively can cause cell death because of number of mechanisms.Therefore in some embodiments of the invention, provide the time of loosening (relaxation time), calcium level is minimized to pancreatic cell.In other embodiment and/or situation, there be not this loosening.

Other example logic

Fig. 3 B is the flow chart according to another control logic scheme 240 of the specific embodiment of the invention.Fig. 3 B is similar to Fig. 3 A, yet, in order clearly to describe, shown the difference between the littler glucose level among Fig. 3 B.Base value among Fig. 3 B is 40, greater than the respective element among Fig. 3 A.

Fig. 3 B shows the control hormonal readiness, increases glucagon secretion and selects therapeutic scheme and parameter based on the effect to pancreatic hormone rather than insulin.

Corresponding to the perception (242) of glucose level, if level is low, represent hypoglycemia, secretion of insulin is optional is suppressed (246).Alternatively or in addition, the secretion of glucagon be enhanced (245).

If glucose level normal (250) at random carries out extra test, normally whether the hormones tested level (251).In a specific embodiment of the present invention, directly use suitable sensor determination hormonal readiness (for example level of insulin and/or glucagon), for example with fiber optic sensor or by applied chemistry determination sensor restrictedly.Optional or in addition, can estimate the level of hormone based on blood sugar level with the different of pancreas electrical activity.If hormonal readiness is low excessively, just increase its level (253).If hormonal readiness is too high, stop and/or even inhibition (not showing) stimulation.Control logic can start by the perception hormonal readiness like a kind of and Fig. 3 A and Fig. 3 category-B.

Cross element 252 to 258 (identical with Fig. 3 A), if the glucose level height, expectation is response fast, and which is preferred (260) then to test numerous available Therapeutic Method and/or treatment parameter.A problem is the secretion that any Therapeutic Method will cause glucagon, and any secretion can influence the glucose reduction effect of expectation.

In any case if after a reasonable time postpones, glucose level does not reduce (266), will use more violent treatment.

Artificial gain method

Fig. 3 A and Fig. 3 B especially show a kind of scheme that increases progressively, and wherein, along with the continuous rising of glucose level, will use more and more violent Therapeutic Method.For some diseases, the response that pancreas perhaps can be correct, however pancreas does not have enough sensitivity in detection, to such an extent as to its response is delayed and/or can bring into play less than it and to change the responsiveness that blood sugar level and/or Digestion should possess.In the other disease, pancreas can also produce second slower response (as increase the level of insulin fully after dozens of minutes) except that producing initial response (as increasing insulin within several minutes fast).In a specific embodiment of the present invention, controller 102 is used for guaranteeing that pancreas responds (as follows) with enough intensity and/or minimum delay.

In a specific embodiment of the present invention, the activity of controller 102 perception stomaches is differentiated its digestion behavior or is differentiated the release of food from stomach, so stimulating pancreas is secreted a large amount of insulins and/or reduced glucose in other mode.Alternatively or in addition, stimulate the threshold value that reduces pancreas sensitivity, to such an extent as to it can produce reaction rightly to natural stimulus object, i.e. excessively response.Alternatively or in addition, when the natural response of pancreas is crossed when low, stimulation can strengthen its response to the glucose level that raises.

By inference, initial a large amount of insulin is non-linear to the effect of body, for example, causes that the secretion of hepatic glucose stops fast, perhaps stops pancreas and discharges glucagon.Nonlinear effect can be depending on for example total amount and/or its quick generation of insulin.In addition, total effect of the insulin of this bolus form will reduce the actual amount of the insulin of pancreatic secretion.At random, this agglomerate insulin before ingesting (as ingesting preceding 5,10 or 20 minutes) is used, and for example can realize at first that (preemptively) stops liver secretion glucose.

Notably be, normal pancreas will produce response rapidly to feeding activity, and its reaction is to produce a large amount of glucoses to cause the secretion of liver glucose to stop (though sluggish for some time).

The drawback of some Drug therapys is that insulin and glucose may reach the peak in the daytime.In a specific embodiment of the present invention, application controller 102 stops and/or reduces many such peaks.For example, have at least 20%, 40%, 60%, 80% or more peak reduced by 50%, 70% or more with respect to the datum line value.

The logic of open loop

For at least some stimulations according to the specific embodiment of the invention, the side effect that overstimulation causes is lacked than the harm that stimulates the not enough side effect that causes and/or is little.In some embodiments of the invention, the reduction of this side effect is used to design the control scheme, i.e. open loop and part open loop control, and this control scheme is partial to overstimulation one side more rather than is stimulated not enough.The part open loop be meant based on the decision of multiple factor whether periodically (as after ten minutes, after half an hour, after one hour or more hours) use the train of impulses.Anybody, in case decision like this, the impulse action feedback that is intended to adjust with regard to not adopting more detailed assay method to provide.In case this a series of finishing will be made the decision of whether using new stimulation series.Mean with fixed scheme by open loop and not examine or check its effect and to use the train of impulses.Especially, some trains of impulses that describe below do not need the synchronization of pancreas electrical activity, do not need to measure the electrical activity of pancreas yet, are at least during using the train of impulses.

In the example of a comparatively safe train of impulses, as described below, the electricity irritation of some kinds reduces high glucose level, but does not reduce normal glucose level basically.In another example, to the secretion that generally suppresses to prevent insulin and/or glucagon of pancreas, this secretion will cause balance not normal when glucose level during near normal value (perhaps under the certain situation even at lift-off value time).

In a specific embodiment of the present invention, the both open loop stimulation is used for reducing glucose level before food digestion and/or between the period of digestion.In the another one example, the open loop stimulation is used for periodically or semi-continuously reducing glucose level.In some specific embodiments, using series of pulses as described below stimulates, and this impulse stimulation does not influence normal glucose level basically.

In a specific embodiment of the present invention, the user has a peripheral control unit, for example a magnetic or the RF control rod, it can exchange with controller 102 feed situation.Randomly, signal (for example reducing the secretion of glucagon) before sends on the feed, needs the cost dozens of minutes because stop hepatic secretion glucose (as result or other mechanism that increases as glucagon).

Another stimulation according to the safety of some embodiments of the invention is the stimulation that the exocrine function of the endocrine function of survival ability, pancreas to any pancreas and pancreas does not have the prolongation of apparent side effect.

Impulse form and parameter

The non-constant width of scope of the frequent impulse form of using.Must be noted that the different cells of different patient's cells or same patient all are significantly different for the response of identical pulse, its reason is genetics and morbid state for example.In addition, the conduction of the signal of telecommunication is subjected to the influence of the erratic geometry of pancreas and the fat deposit around it near pancreas.Independently layer need the application amplitude higher than expection for these.

It is also noted that at least for some embodiment, the application of pulse is for specific part that influences pancreas rather than whole pancreas.

Owing to lack the significantly conduction of action potential, therefore need act on the zone of a relative homogeneous in the part pancreas from an islets of langerhans of pancreas to another islets of langerhans.Yet do not need fully uniformly zone, owing to only have that the islets of langerhans of medium electric field intensity comprises edge effect and/or because expectation cell effect acute variation not, except the threshold level of perhaps determining with the variation of using strength.

And the behavior of beta cell can be depended on glucose level, the cell insulin level of reserve/or cytoactive formerly.Heart cell is typically to turn round under the restriction of its ability and/or oxygen supply continuously, and different with heart cell is that the normal pancreatic cell rest period is longer, and is turning round inferior under the maximum horizontal.

First parameter of pulse is that it is AC or DC.Because pulse can periodically be used, term DC pulse is the pulse that does not change amplitude in once using considerably, and the AC pulse for example has inherent pulse frequency, and the order of magnitude is greater than 1/ impulse duration.In another specific embodiment of the present invention ground, use the DC pulse or have the pulse that each application has the partial circulating number.In this application, if the amplitude of pulse replaces, for example in explosion time, replace ten times, though its frequency in fact is lower than the frequency of action potential, the pulse synchronous with outburst is the AC that is considered.On the contrary, if pulse is the square pulses (square pulse) synchronous with the individual part current potential, then pulse is the DC pulse of being considered, though its actual frequency are higher than the AC pulse.

The example frequency of the AC pulse that is used to break out between 1 and 1000Hz between, the example frequency of AC pulse that is used for action potential is between 20 to 2000Hz.Randomly, the AC frequency is between 50 to 150Hz.

Use the multiple pulse duration.The advantage of DC long duration pulse is not exist may influence the transient state of other tissue (transient) unintentionally.Expect that this pulse is useful for the hyperpolarization of cell, therefore, may continue several seconds or even a few minutes or several hours.Yet randomly, very the pulse of long duration is interrupted, and possible their polarity conversion prevents some side effect, polarizes or the hyperpolarization of target tissue as the tissue of nearly electrode.

The pulse of influence outburst can continue for example between 1ms to 100 second.The example of persistent period is 10ms, 100ms and 0.5 second.Long pulse may continue for example 2 or 20 seconds.The pulse that influences the individual part current potential is suitable weak point usually, as between 10 and 500ms between.The example of persistent period is 20,50 and 100ms.Yet, the longer persistent period as 600 or 6000ms also can use.

In the AC pulse, can use multiple cycle of operation (duty cycle), as 10%, 50%, 90% and 100%.Percent can react the open/close time of pulse or can be reflected at out and interior relative charge density of pass time.For example, use 50% cycle of operation to be meant on average to have 50% pulse maximum charge to flow.

Pulse can be unipolar or bipolar.In a specific embodiment of the present invention, use equalizing pulse with overall zero charge transfer.Yet in a succession of pulse or through one period long period, also can realize this balance in addition.Expection is at least for some impulse actions, and the effect of islets of langerhans does not rely on the polarity of used pulse.Yet polar variation still has the intended effect, and for example produces ion current.

Known different pulse envelope (pulse envelope) acts on cell membrane by different way.Pulse envelope can be as hole shape, triangle, dimetric, exponential decay, biphasic or the S type.Pulse can be symmetric or asymmetric.Randomly, the selection of pulse envelope will be considered in the impedance of using impulse duration inner tissue and/or the simplicity of electronic equipment.

In a specific embodiment of the present invention, control impuls stream for example makes it maintain within the scope.Alternatively or in addition, controlling impulse voltage for example makes it maintain within the scope.Alternatively or in addition, electric current and voltage all are controlled at a specific scope at least in part.But energy impulse is determined by its total electric charge.

Pulse not of the same race usually but be not to have different amplitudes.The different effect of pulse can be the function of cytoactive state also, and cell is for the function of the sensitivity of electric field when particularly using.The example of pulse amplitude is the subthreshold value pulse, and it influences the depolarization state that cell and passage influence pulse.These pulses are infinite examples of non-irritability pulse, because therefore short arc or low relatively amplitude (with respect to cellular sensitivity) completely can not cause the propagation of action potential in the islets of langerhans.The islets of langerhans electric current that shows a 5pA in Medtronic PCT open file is as boost pulse.

Pacemaker impulse causes the action potential of a propagation clearly, unless pacemaker impulse is caught cells all in the islets of langerhans, in the case, action potential can be propagated nowhere.

" defibrillation (defibrillation) pulse " compared with the strong pulse of the pulse of fighting, causes the tranquillization that is subjected to the function cells electriferous state.

Pore-forming pulse (pore forming pulse), for example high-voltage pulse is being subjected to form the hole on the function cells film, allows calcium current to go into or flows out and/or allow the insulin outflow.

Above-mentioned pulse kind is arranged according to the preface that increases of typical amplitude.Amplitude depends on multiple factor, as mentioned above.Yet the example of a pacemaker impulse is between 1 to 2mA.Non-boost pulse is between 1 to 7mA.The subthreshold value pulse may between as 0.1 to 0.5mA between.It should be noted that lacking excitement may be because the time (timing) of pulse application.

Simple impulse form can be combined to form compound impulse type, especially forms train of pulse (pulsetrain).An example of train of pulse is two pacemaker impulses (two pulses are separated by the sluggishness of a 20ms), to guarantee to catch pacing signal.

The example of another train of pulse is a pacemaker impulse at the delay heel of a weak point with a platform extension pulse and/or other action potential control impuls.Therefore, not only may be being higher than the passive pace-making of normal speed, and also the effect of each action potential has increased.Particularly decide by the time limit of opening and closing of different ions passage and pump by the shape of for example action potential for sluggishness between pacemaker impulse and the action potential control impuls.The example that postpones is 10,50,200 and 400ms.

Use graduate pulse in some embodiments of the invention.Blocking-up first of the first cell of pulse is to the response of second portion pulse.This pulse can be used to for example to distinguish different cell categories, has the cell of different stimulated level and/or cell that differentiation has quick response and the cell with slow response.The definite reaction of this pulse and/or suitable parameter can be measured in training period (training stage), as following shown in Figure 7.

The result of experiment of doing in the different phase of different animal species, life shows that under some parameter settings, new outburst (increase secretion of insulin) is induced in the pulse of 20Hz and 100Hz as general rule.The pulse of 5Hz can not induce new outburst at least in position, so right and wrong is excitatoty.Showing as the pulse that reduces glucose and do not increase even reduce the concrete 5Hz of insulin basically is the pulse of two-phase.Each phase 5ms is long, and two independently is 190ms, i.e. 5Hz carrier wave between the pulse.The application of this pulse is not synchronous with the pancreas electrical activity.

Though the train of impulses can be used several minutes continuously, some pulses are but used in short-term, and for example per minute is one second, and can strengthen the effect to pancreas, as cause that pancreas produces more intensive response to there being the glucose level that raises.

In specific embodiments of the invention, be regarded as low frequency wave (as 5Hz) by the pulse of forming with multiple phase shorter workweek of low frequency, cover with high frequency waves (diphasic pulse of 10ms persistent period).In a specific embodiment of the present invention, low frequency is used for effect of electric field is passed to pancreas.High frequency descends by the voltage that produces on the cell wall, is used for the effect of ripple is passed to individual cells.In a specific embodiment of the present invention, select to have and the periodically similar pulse low-frequency component of the type of (normally) pancreatic cell, institute's targeting.Alternatively or in addition, the selection of pulse width (as high-frequency components) is used for special targeting in the cell category of determining, for example β cell, α cell and neurocyte.For example as if but uncertain low frequency (as the 5Hz component) influences the activity of islets of langerhans, high frequency effect nervous pathway.And low-frequency pulse (as even (even) DC) is used for the hyperpolarization of cell.Known in the state of the artly can use multiple optimization and detection technique, especially find most preferred pulse for particular patients '.

The pulse time limit

Not only to consider the kind of pulse, will consider that also the difference in their cycles changes.

At first to consider whether with an irritability and/or non-irritability pulse and pancreas activity synchronization.If pulse is synchronized, what it will be with determined special cells or islets of langerhans is synchronously active.As mentioned above, but to the pacemaker impulse forced synchronismization of pancreas.Pulse can and/or break out active synchronization with the individual part current potential.In an action potential pulse can with the different characteristic synchronization of action potential, the quiescent stage before for example depolarization, plateau, repolarization and the depolarization.Not every action potential all accurately shows these features.

In once breaking out, pulse can be synchronous with the variation on the initial of outburst or ending or the outburst shell, for example remarkable reduction of action potential frequency or amplitude.

Event synchronized being included in the period of delay of taking place with respect to incident herein used, and perhaps (plus or minus delay) used in the period of delay that incident is prepared to take place.This delay can be constantly maybe can change, and for example depends on that action potential or outburst are active.

Pulse application is in each action potential or break out in the synchronous activity.Apply pulse is less than all activities alternatively, and its ratio is as 1: 2,1: 3,1: 10 or 1: 20.Reason that reduces the pulse utilization rate be prevent the β cell stress excessively and cause cell degradation or meticulous adjustment secreting rate.

In some pulses, important parameters is the frequency (frequency that is different from the individual pulse amplitude variations) of the pulse of using.Frequency range such as 0.1Hz depend on the pulse kind to 100Hz.

In a specific embodiment of the present invention, pulse parameter depends on the electricity and/or the physiological state of islets of langerhans or cell.This state can be used as suitable pick off and measure, and perhaps estimates from the overall status of glucose level.

In a specific embodiment of the present invention, pulse is used with a kind of form that produces the insulin secretion of vibration.The vibration of the random natural imitation of this vibration, controller are used to provide swing naturally that produces as healthy pancreas and the variation of swinging.Can increase the amplitude or the frequency of for example vibration in addition, also can reduce the amplitude or the frequency of for example vibrations.Use vibration can for example periodically increase secretion of insulin and/periodically reduce secretion of insulin.Alternatively or in addition vibration can provide by making the synchronized pace-making of pancreas.Randomly under one or more situations, device 102 therapeutical effect that risen are the natural vibration reactions that strengthen pancreas, have for example increased this reaction by understanding which stimulus sequence.

Pick off

Usually multiple sensors can be used for for example comprising for controller 102 provides feedback:

(a) glucose sensor is for example measured actual glucose level, and the feedback of the therapeutic effect of pancreas is provided.Therefore, for example, for the patient that a pancreas response weakens, stimulating pancreas is secreted more insulin when glucose level is too high.Known in the state of the art have multiple glucose sensor can be used for the present invention, comprises optical, chemical, hyperacoustic, heart rate, biological (as the arrange of catching is gone to

) and (the following the trail of the reaction of β cell and/or islets of langerhans electricity) of electricity.These pick offs can be positioned at human body or human body is outside, link to each other with controller 102 by wired or wireless mode, contact with blood and blood vessel outside.

(b) digestion pick off for example is used for detecting ingesting or being about to and ingests, and starts the generation of insulin or increases the sensitivity of cell.Known in the state of the art have many suitable pick offs, for example measures the impedance transducer of stomach impedance, measures the acceleration sensor of gastrointestinal motility and measure the electric transducer of electrical activity.There is inherent problem in the cell of sensation digestion in some embodiments of the invention, if they can not measure the glucose of true picked-up.Randomly, the digestion pick off is used in combination with other pick off, if and/or digestive system activated by feed, as the activation of long activation or facilitating digestion system, digest pick off and use separately.In a specific embodiment of the present invention, between the period of digestion, can stop for the stimulation of pancreas some parts (comprising the part of less islets of langerhans) at least as some, avoid hindering in the pancreas other cell type, produce the cell of Digestive systems as those.Alternatively or in addition, generally speaking, using stimulates the interaction that preferably can reduce with non-β cell, as the α cell.The α cell produces glucagon, and their stimulation can be measured by following the tracks of the serum glucagon level.Propose as the application's other parts, in some cases, the reduction of glucagon is the reaction of an expectation, and expection does not in certain embodiments hinder exocrine function.

(c) pancreas activity pick off, for example with the sub-fraction of whole pancreas, pancreas, one islets of langerhans or islets of langerhans in the link coupled electrode of individual cells.Whether such pick off not only provides the feedback of pancreas activity and employed pulse according to the electrical effect (relative with glucose effect) of expection is arranged, and makes pancreas electrical activity synchronization.The example of such pick off is record to some extent in as WO03/045493, and the disclosed content of the document is incorporated herein by reference.

(d) calcium sensor is positioned at cell interior or outside.Be appreciated that the behavior that intracellular calcium will influence cell of measuring.In a specific embodiment of the present invention, only use one or a few cell example as other cell state.A kind of mode of measuring intracellular Ca2+ be with a kind of calcium sensitive dyestuff with cell dyeing, follow the trail of its optical characteristics.It should be noted that electricity and the excretory activity that will influence the β cell in the cell with extracellular calcium level.

(e) insulin pick off, any kind well known in the prior art can be used for measuring the response of single islets of langerhans, islets of langerhans integral body, and/or measure the level of insulin in the blood.

(f) pick off of other pancreatic hormone, for example glucagon and/or somatostatin.Will mention below, in some cases, the pancreatic hormone that level is different can estimate based on the variation of blood sugar level, and this variation conforms to observed variation during pro-is measured hormonal readiness.

The mensuration of the sensor randomly is used for revising pulse parameter or pulse operational version.Alternatively/or in addition, pick off is used for following the trail of for the response of this method and/or the deficiency of pulse application, or be used for calibration.

Available different aware scheme comprises continuous perception and cycle perception.Some pick offs can provide frequent mensuration, for example every several seconds or a few minutes.Other pick off may be relative slow, as per ten minutes or per hour mensuration is once.If only need periodic mensuration, mensuration can be measure between according to the meansigma methods of time, perhaps meansigma methods or the instantaneous value of measuring within a short period of time.In some cases, need secular comprehensive perception, for example total insulin generation.The chemical perception in past is suitable for this comprehensive perception.

Multiple cognitive method and pick off have been described in the following document, as US 6,600,953, the open WO 01/91854 of PCT, US temporary patent application 60/259,925, US temporary patent application 60/284,497, US temporary patent application 60/334,017, PCT applies for PCT/IL02/00007, on January 3rd, 2002 submitted to, PCT publication number WO 02/082968, open WO 03/045493 of PCT above-mentioned and US patent application serial number 10/296,668, the disclosed content of all documents is incorporated herein by reference.It should be noted that the discloseder method for sensing of these applications can be used to estimate total glucose load, glucose increment rate and/or sluggishness before glucose begins to increase.These information can be used for suitably disposing glucose control therapy to Expected Results, for example by adjusting the part of the stimulus duration and the islets of langerhans that acts on.

Electrode type

The electrode that uses can be single functional electrode, for example only is used for pace-making or only is used for the electrode of non-stimulation pulse.In addition, dissimilar non-stimulation pulses, for example hyperpolarization and plateau, expand pulse, can use dissimilar electrode geometries.As selection, can use the compound electrode that comprises pace-making part and pulse application part.Dissimilar electrodes can have different shapes, for example according to the efficient design pacing electrode, according to field uniformity design pulsed electrode.The function of these two kinds of electrodes can have identical or different leading.As selection, the unitary electrode form can be used for pace-making and non-stimulation pulse.

Accompanying drawing 4A-4D has shown according to the preferred embodiments of the invention, applicable to the dissimilar electrode of pancreas energising.

Accompanying drawing 4A has shown the point electrode 300 that has single electric interface on its top 304 of 302 of leading.

Accompanying drawing 4B has shown to lead on 308 at it to have a plurality of electric wire electrodes 306 of 310 of electrically contacting along major diameter.The advantage of wired point electrode is to be easy to use endoscope and/or other minimum level intrusion technology to implant.In a preferred embodiment of the present invention, implant multi-thread electrode.

Accompanying drawing 4C has shown mesh electrode 312, comprises leading 314 and have a plurality of contact points 318 on the junction point 316 of cross hatch.As selecting or additionally, some line segment between junction point provides electrically contacting of prolonging.

Can make each contact point very little, for example little by little big than an islet cells.Replacedly, can use bigger contact surface.In line electrode, illustrative contact surface length is 0.2,0.5,1,2 or 5mm.In some embodiments of the present invention, because less zone can be enough, also be suitable than being used for the littler contact surface of cardiac pacemaker.

In some embodiments, wish to produce the volume stimulation of pancreas.Accompanying drawing 4D has shown multiple volume stimulation electrode.Plate electrode 320 comprises stimulation large-area dull and stereotyped 322 simultaneously.Ball electrode 324 comprises a spherical contact surface 326, and its radius for example is 2 or 4mm, is used for the tissue around the stimulation ball 326.For example, hollow electrode 328 comprises that for example is the open volume contact surface 330 of tennis shape or goblet shape, and it can be used for the excited tissue that contacts with ball 330 arbitrary portions, comprises and the inner tissue that contacts of ball.Another kind may be a coil electrode.Randomly, these coils have remarkable radius, and for example 2 or 5mm, so that the pancreatic tissue of their close significant.It is pointed out that volume (with other electrodes) electrode can contain little or most of pancreas, thereby or even be placed in the somewhere all pancreas that produce insulin are partly switched on.

Above-mentioned arbitrary electrode can be unipolar or bipolar.In bipolar embodiment, single contact surface can separate, or can show bipolar activity between the contiguous contact point.

In addition, above-mentioned many contact points electrode can make all contact points shorten together.As selection, at least some contact points can separately be switched on, and randomly energising separately of other contact points of same electrode.

Can use electrically contacting between many mode intensifier electrodes and the pancreas, for example use porous electrode, steroid (especially by using steroid eluting electrode) and/or other technology well known in the art.The type of electrode can be those types well known in the art, and especially those are designed for the type of long-term electricity irritation effect.

Accompanying drawing 4E has shown a kind of dissimilar electrode, and the sleeve pipe 332 of its middle controller 102 is as list or multi-electrode.Sleeve pipe 332 can be a spill, convex, or have more complicated geometry.Outer electrode may not used in outside at sleeve pipe 332.Randomly, sleeve pipe 332 is made spill, to receive pancreas.As selection, provide at least a common electrode 226 in the outside of controller 102.As selecting or additionally, the sleeve pipe 332 of controller 102 is as common electrode (common electrode).In embodiment preferred of the present invention, in sleeve pipe 332, form a plurality of electrodes 334.For example, electrode type can be those for example above-mentioned types.Optional and optionally, electrode 334 stretches out sleeve pipe 332.In embodiment preferred of the present invention,, therefore controller 102 is placed and pancreas 100 position contacting because the electric insulation layer of fat holds pancreas usually.Randomly, make the geometry of sleeve pipe 332 consistent with the pancreas shape, thus when guaranteeing with the contacting and implant of pancreas to the minimum damage of pancreas.Randomly, provide a kind of flexible or multipart hinge boot, so that sleeve pipe is more consistent with pancreas.

Can electrode be installed to pancreas with multiple mode, for example comprise and use one or many suture or clip, provide coil or rugosity, use goo or by pegging (impaling) pancreas or near tissue at electrode body.For at pancreas suture or clip being installed, electrode can comprise ring-type, poroid or other structures.It is pointed out that pancreas can not be mobile as heart, therefore can use less bounce-back electrode, material and adherence method lead.

Can in single equipment, use the multiple combination of above-mentioned electrode, for example the combination of the grounding pin electrode of the mesh electrode of pancreas below and pancreas top.Can also nearby organize and insert this ground electrode, for example abdominal muscle.

As described below, can multiple control region (plurality of controlled regions) control pancreas.Can between several zones, share unitary electrode.As selecting or additionally, can be zones of different or even provide a plurality of different electrodes for single area.

Optional, electrode or its tip apply with cortisone or other anti-inflammatory agent, with the inflammatory reaction of the organ that prevents to contact with electrode.

The pancreas control region

Accompanying drawing 5 has shown that pancreas is subdivided into multiple control region 340, makes each zone energising by different electrodes 342.Control region 340 can overlapping (as shown) or is not overlapping.Possibly, whole pancreas for example is used for insulin secretion and suppresses also as a control region.Though can control effective percentage ratio of pancreas arbitrarily, for example 10%, 20%, 40% or 60%, part pancreas still can be uncontrolled, for example as a control region or safety measure.The quantity of control region can be different, and for example 2,3,4,6 or 10, in addition more.Described as following many experiments, estimate that about pancreas of 10% to 30% is activated.

The a kind of of different control regions may be to be brought into play it and do the time spent by stimulation when other parts of pancreas, allows a part of pancreas to have a rest.Another kind of possible purposes is the different therapeutic schemes that are used to test zones of different.Another kind of possible purposes is for the pancreas with different abilities partly provides different control logics, thus those zones of better utilization or avoid the damage of those reasons.For example, can use different pulses to fast response or long response time part.In addition, some greater than other parts of pancreas is easier to be ill.

Randomly, the density and/or the size that are positioned at the electrode (with the independent controllable part of electrode) of pancreas are different, for example depend on the distribution and the density of islet cells in the pancreas.For example, can provide better electric control for the dense position of pancreas.It is pointed out that this distribution can be that original distribution or pancreas are ill, some cell death or impaired after distribution.

As mentioned above, the different piece of pancreas can produce the multiple hormone of dissimilar and/or relative quantity.Therefore, can utilize hormonal readiness and/or the mixture of the three-dimensional control of selectivity to obtain expection.

Method for implantation

The implantation of controller 102 comprises the implantation of electrode and the implantation of controller itself.Randomly, use single program to carry out this two kinds of implantation.Yet, it is to be noted that each implantation has the feature of itself.With being technique known in the small casing implantable gastric, for example use peritoneoscope, open surgery or keyhole surgery (keyhole surgerg) are operated.

It is not a standardization program that the electrode of pancreas is implanted.Randomly, use to prolong electrode, uncoiling electrode or stretching, extension electrode are implanted thereby simplify electrode.

In embodiment preferred of the present invention, use peritoneoscope or endoscopic procedure implant electrode.Randomly, use peritoneoscope or endoscope's implant controller 102.In embodiment preferred of the present invention, the geometry of controller 102 is cylinders, so that it can better pass through endoscope's (flexible, pipe that diameter is relatively little) or peritoneoscope (hard, the pipe that diameter is big relatively).As selection, difference implant controller 102 and electrode.In one embodiment, implant the bound fraction (for example line end) of facile electrode.Make another entry wound, with controller attached to bound fraction.Possibly, the bound fraction of implant electrode at first.As selection, after implant electrode, draw back endoscope, allow bound fraction stay in the body.

Accompanying drawing 6A and accompanying drawing 6B are the method for implantation flow process accompanying drawings of the preferred embodiment of the invention.

Accompanying drawing 6A is the flow process accompanying drawing 400 of bile duct approach.At first, endoscope is put to bile duct, for example by stomach (402).Then, for example use method well known in the art, endoscope enters bile duct (404).As shown, endoscope can feed pancreas along bile duct.As selection, can use splenic artery or catheterization of vein that electrode is provided.As selection, portal vein can insert conduit, for example through the peritoneoscope hole of abdominal part.In pancreas or along the pancreas implant electrode, for example in blood vessel or bile duct, pancreas is the body of gland (406) of an elongation.In embodiment preferred of the present invention, at first endoscope (or its extension) is advanced into the far-end of pancreas, electrodes at pancreas, is drawn back endoscope then, electrode is stayed.As selection, can pass through electrode itself, or use cover hard relatively and/or that easily slide that electrode is released pancreas.Optional but optionally, use imaging technique to follow the tracks of electrode and/or endoscope, imaging technique is light for example, ultrasonic or X ray video picture.Can be from video picture in external or the body, for example from the top of endoscope.

Randomly, in drawing back the process of endoscope/conduit, repair any damage to body structure.As selection, can use other tremulous pulsies and/or vein technology.In some technology, implant controller 102, then along blood vessel or other body structures or at their inner leading electrodes to pancreas.

In bile duct is implanted, on electrode or lead, provide a kind of special coating to make it avoid biliary damage with shield electrode or lead.Can be with the contact portion implanting tissue inside of electrode to avoid the damage of bile fluid to it.

Accompanying drawing 6B is flow process 420 accompanying drawings of another kind of method for implantation.Endoscope is advanced into the other parts (422) of the intestinal of duodenum or contiguous pancreas.Electrode extends to (424) the pancreas from intestinal, and controller 102 is retained in the intestinal.Electrode can also extend along the part direction of enteral portion.Electrode on the pancreas distally can be implanted from the different piece of intestinal, or they pass through pancreas.As selection, the hole that forms by the side at intestinal pushs out controller.As selection, in the intestinal bag, seal controller, the intestinal bag randomly forms by sewing up or clamp with the part intestinal.As selection, controller is attached on the intestinal, for example use clip or use stitching.Can repair any damage (426) then to intestinal.

As above about the description of accompanying drawing 1, controller 102 can be a wireless device, and it has the control circuit system with electrode separation.Electrode can have independently power supply, or they can use line electricity (beamed power) that energy (or recharging) is provided.

In an interchangeable embodiment, controller 102 is many parts devices, for example uses to comprise a plurality of microcontrollers, different pancreas part of each microprocessor controls.Make the synchronously movable of microcontroller by communication between the controller or master controller, for example in monomer, master controller may be outside unit 116.Thereby unit 116 can directly make microcontroller synchronously and/or can provide program that they are taken action in a synchronous manner.A preferred geometries of microcontroller is the shape by two balls of electric wire connection.Each ball is an electrode, and bag draws together power supply and another comprises control loop.For example, the communication between the microcontroller can be used radio wave or ultrasound wave, unlimited electric wave be optional be low-frequency.Randomly, in microcontroller, provide suitable pick off and/or receiving element (not shown).

As the replacement scheme of the controller of implanting, controller can be external, and the electrode percutaneous inserts pancreas, or even be retained in external.As selection, controller and electrode can be by the intestinal tube complete closed.For the temporary transient use of device, these " implantation " methods are preferred sometimes.

In some cases, perhaps right sensors is implanted is controversial, for example pierces through the pick off of single β cell or islets of langerhans.In an optional program, remove part pancreas, connect pick off and/or electrode, the part that will be removed is then implanted and is got back in the body.

Above embodiment has pointed out use electrode or electrode guiding (guide) to pierce through pancreas.In one embodiment of the invention, the careful damage of avoiding main nerve and blood vessel when piercing through.In one embodiment of the invention, near the excitable tissue other has been considered in the implantation of electrode, avoids the careless stimulation to these tissues.

As described below, some test demonstration, utilize above-mentioned parameter that electric field is added on stomach, can cause glucose level to reduce.Be not limited to concrete application, infer and such situation can occur, the electric field that applies by electrode expand in pancreas major part (or electric field has other organ of required influence to it) and/or the pancreas or pancreas near nervous tissue.In people and pig, pancreas is positioned near the stomach.Optional, be used to make the electrode of pancreas energising to be connected in stomach.A kind of possible benefit is the pancreas perforation and/or causes the danger of pancreas inflammation or infection to reduce.Another kind of possible benefit is that stomach is a muscular organ, compares with pancreas, and seam or other method of attachment are easier to be used for stomach usually.This also can allow the use of a large amount of electrodes and/or individually defined thing (specificity).Optional, itself is connected in stomach controller.Use the another kind of possible benefit of stomach to be that the same electrode that is used for to the pancreas energising also can be used for controlling obesity, for example United States Patent (USP) 6,571,127,6,630,123 and 6,600,953, U. S. application 09/734,358 and 10/250,714, and described in the PCT application WO02/082968, described document is included in this paper as a reference.Use the another kind of possible benefit of stomach to be that the big portion of stomach is an insulator, any electric field walking around the stomach usually (pass through thus or via pancreas).Another kind of possible benefit is that the endoscopic surgery to stomach is known.Though electric field has some influences to stomach, optional described influence is less and/or can proofread and correct and offset by the field being added on stomach.

Optional, the pancreas control signal is synchronous with respect to the electrical activity of stomach, for example stomach is had minimum influence.Optional, postpone and/or sequential length (sequence length) by assay optimization, for example be 0,1,2,4,6 or other second number, or be centre or bigger value.Particularly, described pulse can stomach (or other) smooth muscle should (refractory) mutually or application in the depolarization mutually.Optional or in addition, described delay and/or sequence length be variable to make the single influence of unmatchful stomach preponderate (if any).Optional, described delay utilizes local induction electrode (may be identical with stimulating electrode) to calculate in application site.Optional or in addition, consider expection or the soak time of another part of the stomach measured.

According to the tissue location that electrode connected, can adopt various electrode spacings, 1cm for example, 2cm, 3cm, 4cm or littler, middle or bigger value.Be appreciated that distance is big more, the field intensity that is not located immediately at the some place between the electrode usually is just big more.This for example can be used for not being located immediately at situation between the electrode when the energising pancreatic tissue.

In the certain situation, the definite charged level of electrode depends on various factors, electrode spacing for example, types of organization, tissue property and electrode direction.Optional, calibrate to obtain suitable field intensity.In the example, adopt ladder sample electric current and/or voltage in a series of tests, up to measuring positive effect, for example each step can be carried out under different glucose uptake incidents.Optional, described calibration also can be used for measuring the considerably less or non-existent harmful effect that electric field causes the influence of other tissue.The result of described calibration can measure, for example which electrode is used for stimulating, stimulus intensity, stimulate polarity, arrangement of time (for example postponing and/or the persistent period), be used for stimulating or do not stimulate the trigger (trigger) of (for example when colon is not full of, utilizing impedance transducer to detect), and/or which kind of should use in the multiple possibility sequential.

Optional, on electrode, provide insulating support substrate with the auxiliary electric field that instructs.For example, holder can be between the tissue that electrode and its connected, to prevent or to reduce an influence to tissue.In the exemplary of the present invention, described holder comprises the silicone pad of volume 20mm * 40mm.

The exemplary location of Fig. 6 C show electrode on stomach 600 and/or duodenum 604.Show a plurality of electrode position 610-632, many other positions also are possible.Except shown in organ, can be connected in one or more following organ: abdominal muscles, liver, other abdomen organ, the other parts in GI road, such as small intestinal or colon, transverse colon for example, duodenum ligament, blood vessel and/or fatty tissue.Usually, described organ can be 6 of pancreas on main lateral any side.

In the accompanying drawing, solid electrode is positioned on the organ, and the electrode that dotted line shows is positioned at (for example stomach) under the organ.The position of shown exemplary electrode is along duodenal electrode 610-618, electrode 620-624 along the stomach of duodenum offside, near the stomach

middle part electrode

626 and 628, near the stomach top electrode 629, arrange electrodes 630 and 632 along two of stomach distally pancreas generally, the row's electrode 634 that departs from (offset) electrode 630, the row of one between pancreas stomach function regulating electrode 636.Other electrode position also can use, and for example can use any point on the organ surface of common contiguous pancreas, perhaps makes the position of heavy current by pancreas.Optional, electrode will have charging order (electrification sequence), make that the part of Different Organs and/or organ was charged in the pancreas different stimulated stage.

Can use various electrode configurations, for example have two electrodes of opposite polarity, or the overcoat (the casing of the device) of an electrode and this equipment, or opposite polarity pair of electrodes or electrode group, wherein each group has identical polarity.

In addition, should note, may have a mind to only make the charged or selectivity of part pancreas to make different piece charged according to selected electrode.

Another problem that should note is that described accompanying drawing shows point electrode.Though can use point electrode, and netted and area electrodes, in exemplary of the present invention, electrode is a wire electrode.Described wire electrode can be crooked or spiral.But optional, described tinsel is straight basically and has direction.Described direction can be for example for pancreas and/or each other (for example under the situation of electrode pair) be parallel, vertical or tilt.

When the electrode that is used for stimulating pancreas was connected in stomach, described electrode can place the muscle of stomach.But optional, described electrode is sutured in muscle but remains on the outside of stomach (or other organ).A kind of possible benefit is to utilize the insulating property (properties) of the film that covers various organs.Another kind of possible benefit is to reduce the damage of organ and/or the danger of caving in.Optional, the covering of pancreas is removed or reduces, to help pancreatotrophic conductivity.

A kind of exemplary electrode configuration is two arrays of electrodes the same side at pancreas.For example,

electrode

620 and 624 or 610 and 612 can apply electric field between them, and it is also with cover part pancreas.Another example is an electrode 634, and itself and electrode 630 match.In the end in example, not only electrode is positioned at the same side of pancreas, and their direction also makes the overwhelming majority of electric field by pancreas, and this is because pancreas is located immediately between the described electrode without any part or departs from aforementioned location a little.

Another exemplary electrode configuration is to be positioned at the pancreas offside.For example, the electrode of group 630 (or 636) matches with the electrode of group 632.Optional, can be from a plurality of electrodes of every group selection, charged with the different piece selectivity that allows pancreas.Another example is that an electrode is from organizing 636, one electrodes from 610-618 and/or transverse colon (not shown).

Another exemplary electrode configuration is be separated by in pancreas a segment distance, for example an

electrode

626 and 628 of electrode.

Another exemplary electrode configuration is that its electric field will be by the organ electrode of stomach for example.Described stomach is empty, therefore normally good insulator.An example is electrode 636 (or 630-634) and electrode 626 pairings.

Another exemplary electrode configuration is as follows.Four electrodes are connected in or are positioned at the top of pancreas, and alternately the electrode position of arranging is near (with alternate electrode are shorted together), and the electrode of for example left is a negative or positive electrode.In exemplary of the present invention, the electrode distance head of pancreas 2-3cm of left.Below three electrodes be separated by 1-2cm and last electrode distance tail of pancreas 6-7cm.In exemplary of the present invention, described electrode is to be suitable for the needle electrode that peritoneoscope is implanted.In various devices, can use a few or a plurality of described alternate type (alternating) electrodes, and can adopt various electrodes orders (for example the 2-1-2-1-numeral shows the electrode that polarity is identical).In some described orders, the number of the different electrodes of opposed polarity is unequal.Distance between electrodes need not unanimity.Particularly, electrode need not to be positioned on the straight line.But optional, electrode is positioned at the position that is easy to utilize the arrival of minimum invasion property technology.

Calibration and programming

Not only pancreas controller 102 can be after learning the stable disease state, implanted, and the pancreas controller can be in the process of progression of disease, implanted.Under these conditions, even in steady statue, the cell expection of controlled device 102 controls be ill and/or excessively stress, its behavior is unpredictable a bit.Therefore, in embodiment preferred of the present invention, the optimization of pancreas control need be implanted the back to its calibration at controller.Yet, it is pointed out that this calibration is not an essential feature of the present invention, its perhaps or even unnecessary, in the reasonable estimation that before implantation, can determine the pancreas physiological status particularly in this way.

Accompanying drawing 7 is embodiments that exemplify according to the present invention, the flow process accompanying drawing of the implementation method of giving an example of controller implantation and program.Can also use additive method.

Before implantation, optional diagnosis patient (502), the optional expection benefit of determining implantation.Yet it is pointed out that to diagnostic purpose can also use controller 102 this is to obtain measurement result because it had in the long-term time, and has the ability of definite pancreatic cell to the response of different stimulations and condition.

Implant controller is for example aforesaid then, and an initial program (504) is provided.When being in, controller can carry out initial programming when external.Yet, in embodiment preferred of the present invention, the detailed programming of controller energy is for example as described below when being positioned at body, so that controller can be selected one or more different logical scheme and pulse, may be different for one or more control zones.

In information gathering step (506), follow the trail of the behavior of pancreas, do not use the pancreas ACTIVE CONTROL possibly.This information gathering randomly continues to the whole life-span of controller.In embodiment preferred of the present invention,, for example use external unit 116 with the property information cycle ground of acquisition and/or continuously to treatment doctor report.An exemplary report is the main incident of the gentle affecting glucose level of G/W in the body.

As the replacement scheme of independent information gathering, but information gathering use test control sequence also, to determine the response of pancreas to different impulse forms and order.

In embodiment that exemplifies of the present invention, use the information gathering step to determine the physiological and pathological situation, be particularly useful for detecting impaired feedback and/or feed forward mechanism.Controller 102 randomly replenishes, and replaces and/or refuses this mechanism.

As selecting or additionally, enable information gathering and interact with feedback and the feedforward that detects in the pancreas, the especially interaction between hormone, it may depend on glucose level, hormonal readiness and/or stimulation history.Can use this information to provide parameter as the pancreas pre-determined model.As selection, can produce a kind of new model, for example use a kind of neural network procedure.

Possibly, attempt different schemes to determine their effect at little control region.

Information gathering, and calibration subsequently and programming can be on everyone bases, or even on the basis of the part of each islet cells or each pancreas, carry out.Randomly, from other patients, determine the baseline programming with similar conditions.

Randomly, arrange different testing sequences with patient's activity, for example feed, sleep, motion and insulin picked-up are identical.Controller programming also can be adapted to the sleep scheme, regimen or other known every days, weekly or other cyclic activity.

Possibly, increase information gathering by hormones tested level and/or other physiological parameters, the pick off on the pancreas controller can provide maybe cannot provide these parameters.These measurement results can be used for understanding glucose level (or other physiological parameters) and/or change the level that causes by hormonal readiness and change.Therefore, just can determine normal and/or unusual hormonal readiness without sensor special subsequently.

Possibly, additional pick off off-line, for example, the laboratory blood count.As selecting or additionally, for the patient provides revocable monitor, the patient is to the different information of its input.

After forming one section image of how to work about pancreas preferably, can carry out the reprogrammed first time (508).Such master control program can use any method well known in the art, for example magnetic field and electromagnetic wave.

Reprogrammed randomly realizes the part control (510) of pancreas.This part control can be used for avoiding whole pancreas excessively stress.As mentioned above, for example use the hyperpolarization pulse to suppress some controlled part.Yet it is to be noted, because injury of pancreas can not cause life danger usually immediately, and because pancreas is formed by a plurality of independent parts in fact, therefore in the influence of testing control sequence, even in test this order is secular has had considerable error when influencing, for example also have error in the heart as organ at other.

In optional step 512, determine the interaction of medicine or hormone therapy by controller.In the case, it is to be noted that heart and neuroelectricity physiology medicine also can be used for the treatment of disorder of pancreas.As selection, pancreas control is wished to offset this passive side effect that is used for the pharmaceutical preparation of non-metabolic disorder.As selecting or additionally, determine that pharmaceutical preparation is to the pancreatic cell behavior and/or feed back interactional influence.

Repeating step 508-512 repeatedly before determining last programming 514.It is pointed out that even programme at last periodically to revalue (516), revise (518) then, for example, consider that pancreas and/or patient's rest improves or degradation, or use different long term effect control sequence.

In embodiment preferred of the present invention, randomly periodically carry out the controlled of pancreas and/or the not organization survival aptitude tests of controlled part, for example be used for the evaluate patient state, upgrade patient's baseline and estimate the usefulness for the treatment of.The method for optimizing of survival ability test comprises the analysis electrical activity, to the response of glucose level or insulin level, and/or to the response of dissimilar electricity irritation effects.

In embodiment preferred of the present invention, programming, detection and/or the previous Therapeutic Method of attempting (comprising possible Drug therapy) are stored in the memory section of controller 102.As selecting or additionally, programming can comprise the particular order of considering to take pharmaceutical preparation.In embodiment preferred of the present invention, notification controller 102 when the patient takes medicine or insulin, for example by inputing to external unit 116 by hand or importing automatically by medication.If the patient ignores and to take medicine, insulin and/or glucose, a kind of compensation control sequence is provided, may ignore and whether the patient is sounded a warning.

Experiment

In a preferred embodiment, place netted monopolar electrode, stomach wall implant needle electrode thereon at the Pancreas Sus domestica gland.((5Hz, 5mA, 5ms persistent period) 5 minutes caused blood glucose to be reduced to 74mg/dl from 89mg/dl to apply pulse stream.Use the ELISA method to measure, blood glucose rises to 5.37 micro-units/ml from 3.8 micro-units/ml.The gentle insulin level of G/W returns to baseline after 30 minutes.In another kind of animal, use 3Hz, 12mA, the pulse of 5ms persistent period 5 minutes causes insulin to rise to 10.85 micro-units/ml from 8.74 micro-units/ml.

Accompanying drawing 8A has shown in six animals the influence to insulin level electricity irritation effect.Yet should be pointed out that clinically the influence to insulin and glucose level is not very big, because their are near baseline or remain near the baseline, the variation of insulin level will produce relatively little physiological effect.

Accompanying drawing 8B-8D is the original position pancreas experiment accompanying drawing according to a preferred embodiment of the present invention, has shown the growth of insulin secretion.In this experiment, similar with following pancreas in rat experiment, per minute is used 5Hz, one second of diphasic pulse of 5ms.Accompanying drawing 8B has shown the electrical activity of measuring.30-60 minute area applications stimulation.Accompanying drawing 8C has shown the phenomenal growth of insulin during the signal application, and this shows can obtain in real system and for example surpasses 20%, 40%, 60%, 80%, 100%, 200% or more the growth.Accompanying drawing 8D has shown the measurement result in the control experiment that does not have stimulation.

Additional experiment

Accompanying drawing 9 has shown in an experiment influence to the electricity irritation effect of blood sugar level, and wherein with separately insulin secretion is desired to be compared by suppressing, and blood sugar level increases quickly.

In the branch accompanying drawing 904 of accompanying drawing 900, reduce glucose level by application of stimulus pulse S1.In the branch accompanying drawing 902 of accompanying drawing 900, increase glucose level by application of stimulus pulse S2, reduce glucose level once more by apply pulse S1 then.What can suppose is only to reduce hypoinsulinism to explain this quick and huge the increasing of glucose level.But the secretion of glucagon has caused that liver discharges glucose, and blood sugar level has raise.

Accompanying drawing 900 is from an experiment, and this experiment is based on a rat of using pentobarbital (40mg/1Kg) anesthesia.After the fasting, with the speed of 2cc/Hr glucose to rat continuous infusion 5%.Lead to oxygen at experimental session to rat.The example that shows in the accompanying drawing 900 is to analyze the result that per blood of taking from right external jugular vein in 5 minutes is obtained by the Rosche glucometer.S1 and S2 have similar form, and different is that S2 has the amplitude of 2mA and 3.5 minutes persistent period, and S1 has the amplification of 1mA and 5 minutes persistent period.This pulse comprises that initial spike and a succession of peak value of following 150ms to postpone propagate 750% dutycycle (duty cycle) that surpasses 400ms.Repeated whole pulse in per 10 seconds.Initial spike reaches 50ms.Electrode all is the iridium oxide that titanium applies.The geometry of electrode is a coil, length 8mm, and diameter 1.2mm has the line of 100 μ diameter 3fillar.Coil is adhered on the silicon plate with insulation and prevention mechanical wounding.These two kinds of electrodes are placed along pancreas, and one a last infra (when rat is when lying on the back).

Accompanying drawing 10A-10B, 11A-11B, 12A-12B and 13A-13B are paired accompanying drawings, each has shown the flow process and the pulse chart of the additional experiment that similar method is carried out in use and the accompanying drawing 9 to accompanying drawing.

Electrode all is above pancreas in accompanying drawing 10,12 and 13, and signal application 5 minutes.

In accompanying drawing 11, electrode all is below pancreas, and signal application 5 minutes.

Additional experiment in the dabbling pancreas in rat

In dabbling pancreas in rat, carry out a series of experiments.In fact pancreas and any control system (for example blood, nerve) are isolating, but do not separate with peripheral organs with its ligament.In an anesthetized rat, with all the main blood vessel knottings around the pancreas, intubate is inserted descending aorta, at last with the thoracic aorta knotting, allow blood substitute (glucose is arranged) to be circulated to liver by coeliac artery, pancreas and duodenum.Collect infusion liquid from portal vein then and be used for further inspection.This can kill rat really.Generally speaking, select one minute applying frequency once, because its natural outburst rate (natural burst rate) common and pancreas matches.For example, the pulse of some application has the two-phase waveform, and 5Hz, phase duration are 5ms, and per minute is used one second.Generally speaking, the different frequency of a scope on probation.For other biological (for example human) and/or different condition, this frequency can be different.Glucose level generally is controlled at about 10mM.

Accompanying drawing 14 has shown an experiment, wherein the application of stimulus build-up of pulse outburst amplitude but do not induce new outburst.Because the electrical properties of measuring method, boost pulse occurs with wire, and it has crossed over the whole field amplitude of this accompanying drawing.Usually this also is real in other accompanying drawings.For clear, with letter " B " expression outburst, with letter " S " expression boost pulse.As mentioned above, this experiment is carried out in rat original position (in sito), and wherein pulse is the two-phase rectangle equalizing pulse of 5Hz, and pulse length is 10ms, and peak swing is 10mA, used the persistent period in 0.5 second, and per minute is used.When non-explosion time is used, do not induce significant new breaking out on this pulse surface, it has increased the amplitude that breaks out suddenly after impulse duration and/or the pulse.Possibly, break out and take place at impulse duration, but owing to the restriction of measuring system is not detected.In addition, the frequency that breaks out does not change, yet that can believe is to use other parameters and does not just only use direct pace-making, the frequency that the energy electric control breaks out.

Should be pointed out that owing to draw and the resolving power restriction of display packing the accompanying drawing of demonstration electrical activity is a summary, do not show all small details of electric signal measurement method.

Accompanying drawing 18B has shown the measuring method (unit that shows in this accompanying drawing and other accompanying drawings is micro-unit/milliliter) of insulin level.Caused the corresponding growth of insulin level on the stimulation surface.Yet as if in twice initial stimulation, this level does not increase at once or increases during stimulation, and just after pulse end or pulse end.Suppose that pulse may have two kinds of influences to the β cell, a kind of is to start their excreting insulins (for example, promoting to produce), and a kind of is to open beginning or secretion inhibitor.Suppose that (being supported by following other experimental result equally) longer pulse may have the effect that stops insulin secretion by β cell hyperpolarization.Depend on the amount that insulin produces in the degree of hyperpolarization and the cell, and/or may depend on ambient signal (for example glucose level and/or hormonal readiness), even during using, can secrete by irritation cell in electric field, after removing electric field, can freely secrete, or after removing electric field, can stop secretion a period of time.If these stimulations are enough intensive, can stop emiocytosis serial, or extremely can overcome hyperpolarization until its immanent action enough strong (for example stimulating) by inner insulin storage until finishing this stimulation.In this influence and other actual measurement influences, should be noted that when supposing differently when machine-processed, can use discovery effect in certain embodiments of the invention, Biochemical processes and electrophysiology process that even must their back of correct understanding.Therefore, length is that the pulse of 1-40ms can have significantly different physiological effect.This can point out and use length is 0.5,1,2,5,10,15,20,32 and the pulse of 40ms or use the persistent period shorter, and intermediary or longer pulse is to realize different effects.

The behavior of β cell that the explanation of another has been a frequency influence.Therefore, can use different frequencies, 2Hz for example, 5Hz, 10Hz, 15Hz, 20Hz, or use forr a short time, intermediary or bigger frequencies are to realize different effects.

Another kind of combination interpretation be the pulse duration (for example, measure one or both length of each seed pulse in certain embodiments with millisecond, in certain embodiments with the length of total second number and each string (train) of its fraction measurement) and the combination of frequency indicated general total stimulation, wherein at least for some frequency and amplitude, total stimulation can be determined the influence of pulse.

Accompanying drawing 15A-15C is an experiment accompanying drawing and its two amplification accompanying drawings, and it has shown that the stimulation pulse makes the activity of breaking out synchronous, may not produce new breaking out at once.As mentioned above, experiment (in-sito) is in position carried out, and wherein the stimulation parameter-definition is 10mA, 40ms during 20Hz, the two-phase rectangle equalizing pulse of using 500ms.Accompanying drawing 15B and 15C are the amplification accompanying drawings of two stimulation pulses, and it has shown on the surface and to produce at once and break out (unless their short really and sheltered by stimulation).Possibly, if stimulus frequency is quite slow, spontaneous breaking out will be taken place.In embodiment preferred of the present invention, break out frequency to a certain degree (for example, with natural compare high or low) by the pulse control of using the type.

Accompanying drawing 16A-16C is an experiment accompanying drawing and its two amplification accompanying drawings, and it has shown inductive new the breaking out of stimulation pulse.New breaking out had an effect in fact at once.Aforesaid, suppose that the length of stimulation pulse is to determine the degree that postpones and/or postpone takes place whether to have before this breaking out.To this possible a kind of support is not show in the accompanying drawing 16 that break out the second time after about 5 seconds, this make the people believe the type impulse stimulation the single generation that breaks out, in variable delay and/or can be used to postpone the spontaneous beginning that breaks out.In any case, break out for example repolarization and depletion (exhaustion) generation at once of can avoiding next time breaking out of intrinsic mechanism in case produce.

Accompanying drawing 17 is experiment accompanying drawings, and it has shown that in some embodiments of the present invention the intermediary stimulation that breaks out does not stop to break out.Breaking out that the left side shows is used for comparison, so that can observe the influence (for example length) of pulse to breaking out.Not obvious and can be left in the basket to the influence of length and amplitude, or this influence is perhaps very remarkable to length and/or amplitude.As mentioned above, accompanying drawing 14 has shown because the amplitude that this stimulation causes increases.Pulse parameter is 10mA, 2ms, and 20Hz 500ms each minute used.

Accompanying drawing 18A and 18B have shown the surperficial insulin level that is caused by stimulation that goes up.Accompanying drawing 18B more than has been discussed.Accompanying drawing 18A has shown two kinds of dual measuring methods of carrying out on the same sample, is used to guarantee the measuring accuracy of insulin.As observed, for during the stimulation, insulin level increases between stimulation period or after stimulating.The growth that can believe insulin level can be the delayed effect of stimulation, and this effect has caused the generally growth of β cytoactive, and may cause the temporary transient growth of output.Stimulation (using these pulse parameters) has obviously caused the increase of ductile insulin numerical value.Possibly, even the influence of stimulation is to increase, but stimulation time itself does not allow to increase.Separate three minutes between the sample.Pulse parameter is 10mA, 2ms, and 20Hz 500ms each minute repeats.

As reference, accompanying drawing 19 has shown under the situation that does not have stimulation, the metastable insulin level of baseline in the pancreas in rat of inculcating.

Additional experiment in the miniature pig that lives

Two miniature pigs (called after Venus and Shifra) are used for these experiments.Body weight has the electrode that is implanted to their pancreas 35 to 40kg

miniature pig.Implant

4 or 6 electrodes, yet, only utilizing 4 electrodes, 2 electrodes are implanted and shortening together at each end of pancreas.This electrode is that line electrode is arranged, a pair of between apart from 2cm, its insertion depth is 3-5mm, this length can conductivity.Make the pig fasting, feed with feedstuff or Cube sugar (sucrose) then.As described below, use and do not use stimulation that same animal is repeated experiment.After the some months, pig still is alive, the injury of not tested on the surface.

Accompanying drawing 20A has shown after fasting, provides in the miniature pig of the Cube sugar work that (each 30 is 2.5 gram sucrose, gives in a few minutes) feeds, and uses and do not use insulin level when stimulating.Ensuing experiment has shown not obviously difference between nursing sucrose and the nursing glucose, sees technically, and liquid is difficult more for feeding pig.Using two kinds stimulates string, and a kind of 15 minutes, and another kind of 10 minutes.The starting point of timeorigin for feeding.Pulse is 100Hz, 10ms, and length 1 second, per minute, amplitude are 5mA.

As shown, compare with the experiment that does not have to stimulate, the insulin in the stimulation experiment increases faster and more.Possibly, this is a kind of enhancement effect, and it has increased insulin active (response of pancreas) by stimulation.

Accompanying drawing 20B conforms to accompanying drawing 20A, has shown the relation between the gentle insulin level of G/W under the stimulation situation.Aforesaid, in the discussion of Figure 21 A, there is physiological mechanism.If glucagon secretion will increase the glucose secretion when for example insulin level increased.In some embodiments of the present invention, can use less stimulation to reduce this glucose secretion.

Accompanying drawing 20C conforms to accompanying drawing 20A, has shown the relation between the gentle insulin level of G/W under the non-stimulation situation.

Accompanying drawing 21A shown in the miniature pig of work that gives about 700 gram foods after fasting, under the stimulation situation and do not have a variation of insulin level under the stimulation situation.Should be appreciated that provand less is controlled than sugar supply usually.Using two kinds stimulates series (series), and a kind of 15 minutes, and another kind of 10 minutes.The starting point of timeorigin for feeding.Pulse is 100Hz, 10ms, and length 1 second, per minute, amplification is 5mA.The influence to insulin is significant after the stimulation first, but not remarkable for the second time, and this may be because pancreas depletion or LG level (as shown in accompanying drawing 20B).The pulse of supposing application does not at random cause insulin secretion, but enlarges or started existing physiological mechanism.Therefore, when glucose level was low, stimulation did not have to cause that insulin level increases to high level (perhaps being dangerous in the case).Perhaps, this is a kind of direct characteristic of pulse, or can be caused by different physiological mechanisms.Continue if another kind of possible explanation is observation, the insulin level that observes after stimulating for the second time increases and also will continue.Perhaps, the slip of relative delay and/or this growth is because one or more above-mentioned mechanism.

Accompanying drawing 21B conforms to accompanying drawing 21A, and it has shown blood sugar level.Though stimulate the back blood sugar increasing first, be lower than the rising under the control situation and reach peak value very soon.This shows that perhaps pulse has directly or indirectly influenced glucose level.A kind of possible mechanism is that insulin secretion has caused that glucagon secretion or pulse directly induced glucagon secretion.Possibly, if insulin produces with the form of bolus (bolus), this to influence meeting more remarkable, so as in the pancreas and/or intravital insulin level quite greatly and/or accumulation apace.

More than experiment has clearly illustrated that the application of electric field can influence the behavior of pancreas, for example increases or reduce insulin output, be with or without and produce new outburst, and different pulses has different behaviors.Further experiment in the miniature pig that lives.

Below following scheme is used in the experiment in the miniature pig of Huoing.In the pancreas of the miniature pig of female Sinclair of growing up, implant pair of electrodes.After phase, carry out two types operation at the surgery recovery in 2 weeks.In a contrast scheme, when the pig fasting, extract 3 blood samples.Time is 0 o'clock oral 75g glucose.Took a blood sample about 100 minutes altogether in per 5 minutes.The application of stimulus effect at once, stimulation protocol is identical with the control scheme after ingestion of glucose.Pulse parameter is: 5ms two-phase waveform, every 200ms are used each phase (5Hz).Amplification is 6-10mA.In this experiment and following experiment moderate stimulation acting duration is 15 minutes.

Accompanying drawing 22A has shown embodiment preferred according to the present invention, in a series of experiments in first pig, and the reduction of the delay of glucose peak and its level under the stimulation condition.Control value and stimulus value be average out to 9 days separately.Should be pointed out that the glucose peak reduction and postponed 20 minutes, and overtime expansion (spread out).In these tests some also can be carried out described in accompanying drawing 35A and 35B.

Accompanying drawing 22B has shown the reduction of the delay of insulin peak and its level in some experiments of accompanying drawing 22.These results have used 6 contrast days and 7 stimulation days.Should be pointed out that insulin level obviously reduces in most digestion time, the size of total insulin level and peak value also is (but the height of possibility peak value does not reduce in fact) like this.This shows that the non-insulin factor has reduced glucose level.The reduction expection of the gentle insulin level of G/W can reduce the pancreas overwork under some morbid state, for example, reduces the inductive pancreas overstimulation of disease.Should be pointed out that the delay of glucose peak and/or reduction are enough to allow the patient to break away from the demand that medicine or insulin are got involved.As selecting or additionally, by launching peak value, the patient can slowly absorb the insulin that (only) absorb rather than absorb insulin fast, therefore may simplify therapeutic scheme and/or prevention and absorb the relevant hypoglycemia of insulin fast.Further, can reduce the injury of over-drastic insulin and/or glucose level by reducing peak value to the patient body system.As selecting or additionally, use the frequency of glucose monitoring to reduce, for example once a day or even still less, rather than one day several times.In embodiment preferred of the present invention, therapeutic scheme comprises reduction and/or delay glucose peak, and the treatment of carrying out is slowed down, and for example injects " slow " insulin or suitable medicine every day.

As observed, even after the stimulation train of impulses stopped, glucose failed to reach and peak the same under collating condition with insulin level.Perhaps, this is a kind of direct effect or inhibition indirect effect of stimulation, for example, because the minimizing of glucose rate of change.As follows, in human experimentation, used the longer stimulation time.Should be understood that, as mentioned above, in some therapeutic schemes, wish to stop stimulation between the period of digestion at glucose, for example, for the response of observing pancreas and/or allow its to have a rest.

Accompanying drawing 23 shown according to an embodiment preferred of the present invention, under the condition identical with the stimulation of accompanying drawing 22, and the reduction of glucose level in a series of tests of second pig.The result is the average of 3 contrast days and 4 stimulation days.

Accompanying drawing 24 shown according to an embodiment preferred of the present invention, under the condition identical with the stimulation of accompanying drawing 22 and 23, and the reduction of glucose level in a series of tests of the 3rd pig.The result is the average of 5 contrast days and 12 stimulation days.

Accompanying drawing 22C has shown that according to an embodiment preferred of the present invention the glucagon that causes owing to the application of stimulus effect train of impulses reduces.Stimulation result is the average of 3 researchs, and uses a comparative study, and all these researchs are selected from the experiment of accompanying drawing 22, wherein measure the glucagon level.It is mainly relevant with the baseline reduction to should be pointed out that glucagon reduces, and wherein normal behaviour is that glucagon increases when insulin and glucose growth.Yet absolute minimizing of some of glucagon is significantly, but may not have statistical significance.As if after stimulation stopped, the minimizing of glucagon secretion had continued one suitable period.The glucagon secretion that reduces has stoped liver to increase glucose level.Though perhaps this result has shown the use electricity irritation glucagon has directly been controlled that another kind of the explanation is that the Somat level that increases has reduced insulin and glucagon.Another possible explanation is that the α cell of secretion glucagon desensitizes.Another possible explanation is that glucagon (as described, itself being the indirect consequence of controlling through the glucose level of non-insulin mechanism) has been controlled in insulin control indirectly.

Accompanying drawing 25 has illustrated embodiment preferred according to the present invention, for single experiment, fixes in the IV hyperglycemia under (IV hyperglycemic clamping) situation, and the stimulation that glucose reduces is worked.The reduction that it should also be noted that glucose level is just to baseline values and can be not lower.In this experiment, clamp pig, use the IV glucose to make glucose to high level, use the initial fast injection of 50% glucose of about 20-25cc, then at experimental session with 70-90ml/ hour CI, comprise making the dextrose equivalent recovery.After glucose level is stable, begin experiment.Stimulation lengths is 15 minutes.As shown, glucose level recovered at about 20 minutes.

Accompanying drawing 26 has shown that stimulation according to an embodiment of the invention is to the influence that is safe from danger of normal glucose level.What show is 2 contrast days and 4 averages that stimulate day.As implied above, this can be used as the basis of design both open loop scheme, and that wherein possible overstimulation effect is not considered to is dangerous (but may consumed energy).

In an additional experiment, use 5Hz, 5ms, two-phase, two pigs of one day 24 hours continued stimuluses of the train of impulses of 5mA continued for 2 weeks, did not observe side reaction or side effect to pancreatic function or pancreatic tissue.Especially, do not observe eccrine influence by the feces variation.

The result of human experimentation

Tried to finish among the patient a series of experiments in mankind's aspiration.The patient is 45 years old women, suffers from type ii diabetes 1 year.The patient is the India blood lineage, body weight 71Kg, and 1/61 meter of height is taken gliclazide (Gliclazide) 80mg and metformin (Metformin) 500mg, one day 2 times.The abdominal surgery that patient experience excises one's gallbladder.Before operation, patient's fasting insulin level is 11.1 micro-units/ml, and fasting C peptide level is 2ng/ml, and HbAlC is 5.8%.

Carry out the center line laparotomy ventrotomy to remove gallbladder.Open less bag by omentum majus then.The harmonization of the stomach intestinal shrinks respectively, exposes the pancreas of about 7 * 5cm.With A﹠amp; 4 kinds of commercial rustless steel temporary heart pace-making lines that E pharmaceuticals generates are implanted pancreatic tissue, and are at one end a pair of, a pair of at the other end.Two pancreas record leads also connect, an also close electrode between 2 electrodes of pancreas one side, and another record lead is between 2 PST electrodes.Open up a drainage of abdomen passage that comprises the 7Fr JP of electronic circuit at electrode, suture is fixed on the pancreas pseudocapsule.Opening up electrode and drainage channel also extracts by the stomach wall in left side.Near pancreas, place one second negative pressure drainage channel and it passes to the right side stomach wall.The electrode connection procedure has been spent 1.25 hours.First day amylase value is 127.5U/L, second day is～30U/L, and this has shown that recovery is good.The GI vigor recovered at first day, did not find heating paresthesia after experimental session and experiment.Removed electrode, any situation does not take place in postoperative the 6th day.Carry out the stimulation and the measurement of several series in postoperative several days.Laying electrode, stimulation and remove the side effect of also not reporting any kind after the operation.Carry out two types scheme.A kind of is the contrast scheme, and a kind of is the stimulation scheme.In the contrast scheme, when patient's fasting, extract 3 blood samples.In the time is 0 o'clock oral 75gr glucose.After the glucose administration, collected blood sample 3 hours.Lead before the implantation, carried out a control experiment morning on the same day, carried out another time at postoperative second day in operation.Except parameter is provided during the glucose administration or after the glucose administration is that the stimulation scheme is similar to the contrast scheme outside (5Hz, 5ms, two-phase 5mA) electricity irritation effect.Carried out the stimulation scheme in postoperative second day and the 4th day.

Accompanying drawing 27 has shown according to the present invention the embodiment of an illustration, and the effect of human body moderate stimulation is to the influence of glucose level.Identical with the situation in the miniature pig, glucose peak is lowered and/or postpones.

Accompanying drawing 28 has shown in the experiment of accompanying drawing 27 influence to insulin level.As shown, in first control experiment, do not measure insulin level, but in other experiment, measured insulin level.With compare under the control case, insulin peak obviously descends and postpones.

Accompanying drawing 29 has shown in some experiment of accompanying drawing 27 influence of C peptide level.C peptide value reduces, and the peak obviously postpones.Only in a contrast scheme and a stimulation scheme, carry out these measurements.This measurement is used to verify the insulin measurement result.

Accompanying drawing 30A or 30B have shown two different opportunitys during five day convalescent period of accompanying drawing 27, and the electricity irritation effect is to the influence of glucose level during the fasting.The substance of not observing glucose level reduces.

Accompanying drawing 31A conforms to accompanying drawing 30A or 30B with 31B, has shown that the electricity irritation effect is to the influence of insulin level during the fasting.Except the possibility insulin level increases a little, do not observe the substantial variation of insulin level, show to be back to baseline.In any case, stimulate tendency before patient's fear can cause, if ignore this tendency, before stimulation, between or can observe insulin level afterwards and keep stable relatively.In addition, the insulin value remains on low level (for example below 20) during whole.

The reduction of insulin and glucose in the animal

Figure 32 A and 32B illustrate according to exemplary of the present invention, the glucose in the pig and the reduction of insulin.The glucose of pig and the accumulation level of insulin among Figure 32 C and 32D displayed map 32A and the 32B.

Pig (being the pig of Figure 22 ff type) oral and 14g fish glue (fish gelatin) and one glass of blended 75g glucose of water.Eating time is about 2-3 minute, begins in 0 time.Horizontal line among the figure shows the time that applies pulse, and described pulse is used as mentioned, has the parameter of diphasic pulse, forward 5msec is negative sense 5msec and then then, the every 200msec of such pulse applies once (for example, the delay of each charging room is 190msec), and continues 1 hour.Utilize the Acucheck glucose meter, be used to measure jugular vein blood glucose and insulin level, that gathered in per 5 or 10 minutes, measure glucose.Insulin level utilizes radioimmunoassay method.Usually, identical test parameters is used for all pigs, except other has explanation, and persistent period difference for example.Except as otherwise noted, implantable stimulation device.

Use is with bottom electrode: the wire electrode of stitching, its length is for example 15-22mm.Adopt following method of attachment.Make the pin (for pancreas elbow pin) that has No. 00 nylon wire pass tissue and by little silicone pad.Electrode is arranged along the line, thereby mainly is arranged in tissue.The silicone pad utilizes the standard procedures clamping due to tissue.Electrode package is buried thereon position the closer to near-end, then needs little silicone pad with holes to be used to be sutured in tissue (only carrying out under one's belt).Electrode itself is platinum-iridium electrode, scribbles titanium nitride, to increase its electric capacity and to apply bigger electric field thus.Other electrode also can use.

Shown in Figure 32 A, with respect to contrast peak (8 times multiple average), under situation about stimulating (7 times multiple average), glucose level reduces (peak has delay slightly).Shown in Figure 32 B, insulin spikes reduces and postpones.First 30 minutes, the time integral of insulin level and glucose level also obviously reduced, shown in Figure 32 C and 32D.Time integral promptly is the area of curve between institute's sign time (for example, 0 and 60 minute).

Figure 33 A-33D shows the similar results of another pig, totally 8 controlled trials and 4 irritant tests.In this case, the insulin spikes height is constant, and only width reduces.

Figure 34 shows according to exemplary of the present invention, the accumulation level of (contrast, 15min signal and 60min signal) glucose under the various electric field applying conditions.Particularly, dose response is more obvious under the long period.

Figure 35 A-35D illustrates according to exemplary of the present invention, and the glucose in the another pig and insulin reduce, and wherein device (AEI) is connected in the pancreas outside by interim pacing electrode (temporary pacingelectrode).Only applying stimulated 15 minutes.Observe the delay of insulin and glucose peaks, and the reduction of total amount.Figure 35 C and 35D are presented at the only accumulation within 15 minutes.Carry out 7 contrasts and 5 irritant tests.Figure 35 A and 35B can comprise the result of the test that also is used for Figure 22 A and 22B.

Figure 36 shows that according to exemplary of the present invention, the glucose level in the another pig reduces, and wherein utilizing outside stimulus device (and internal electrode) to apply stimulated 15 minutes.Observe the reduction of peak and total glucose level.In addition, glucose response is not delayed.Notice in the some diseases situation, need to postpone this glucose peaks.In other disease situation, needs keep the response time but reduce its amplitude.In the some diseases situation, only reducing reaction with certain amplitude is required effect.Have 11 controlled trials and 9 irritant tests.

Figure 37 A and 37B illustrate according to exemplary of the present invention, and glucose in the Canis familiaris L. and insulin reduce.Canis familiaris L. pancreas lobus dexter is applied stimulation 60 minutes, repeat once.As seen, glucose peaks and insulin spikes reduce but not obvious delay.The pulse that applies is same with the pulsion phase that pig is applied.By pipe glucose is injected stomach, and provide with the every Kg body weight of 1.5g.

Though may be not obvious statistically, compare with truncate with delay, aspect the truncate at peak, the reaction of Canis familiaris L. seems near people's reaction.These may be different in different crowd and/or morbid state.

Figure 38 A and 38B illustrate according to exemplary of the present invention, and the glucose in two Canis familiaris L.s reduces, and wherein electrode is positioned at the Weishang.For first Canis familiaris L., have 6 contrasts and repeat and stimulate for 5 times to repeat; For second Canis familiaris L., be respectively 7 and 6 times.Glucose peaks reduces, and the peak effect of truncate may be provided, rather than that postpone and/or narrow peak.Among Figure 38 A, the field is put on the rear wall and the antetheca of stomach simultaneously, two electrodes are each positioned at a side.Among Figure 38 B, signal is only put on antetheca.Described identical with the sequential that is used for pig, and synchronization is with the electric field in the induction gastric antrum.In each " local sense events " (for example about 10 seconds), apply 4 seconds stimulation sequential (sequence ofstimulation).

Figure 38 C shows the series of four tests in the Canis familiaris L., and wherein signal only puts on paries posterior gastricus as using in the pig.Carry out 6 controlled trials and 4 irritant tests.Irritant test is divided into two pairs.First pair of glucose reduction wherein is bigger, and the glucose of second centering reduces more not obvious.In the experiment with more obvious glucose reduction, described stimulus signal is in applying every (every other) induced " local event ".Infer more not frequent exciting and allow the mechanism that works to recover, allow to obtain bigger effect thus and do not have relevant change (associated adaptation).In the specific embodiments of the present invention, described application can be more not frequent, for example with 1: 5, and 1: 10 or lower ratio, or more frequent, for example 1: 1.5 or higher.Optional or in addition, the persistent period can be lower than 4 seconds, for example 1 second or 2 seconds, or longer, for example 6 or 10 seconds.Other intermediate value is also possible.

As a reference, Figure 38 D has shown the line chart of pancreas (lobus dexter) stomach function regulating of Canis familiaris L..

Figure 39 A and 39B illustrate according to exemplary of the present invention, and the glucose in two Canis familiaris L.s reduces, and wherein electrode is positioned at the Weishang.This has description in the U.S. Provisional Application of submitting on July 21st, 2,003 60/488,964, it is for referencial use to fit into this paper in this.

With reference to Figure 39 A, it illustrates the glucose level of being measured in the experiment of carrying out according to exemplary of the present invention.A Canis familiaris L. is anaesthetized, and the preceding lateral wall that two electrodes are implanted this Canis familiaris L. gastric antrum is apart from the about 3cm of the about 2-of pylorus.Drive electrode applies the signal of telecommunication, and it has the rectangular wave of 100 diphasic pulses, and the amplitude of each phase of each pulse is 8mA, and the persistent period is 6ms.Waveform applies (about 4-5 time of per minute) after each slow wave that detects the Canis familiaris L. stomach begins.Though this is and the different pulse sequence of other pulse sequence that is used for test of the present invention that it should be noted that has some similaritys between sequential, explain described effect thus.

Can measure at two days that separate, every day, 24 hours about identical time carried out after fasting, and Canis familiaris L. regains consciousness therebetween.The signal of telecommunication a day in these days applies, and another day is as contrast.Begin and lasting about 2 minute in 0 time by oral ingestion of glucose every day.The signal of telecommunication began to apply and lasting about 15 minutes in 0 time.Utilize identical glucose meter to measure in the middle of described two days, each mensuration utilizes two groups of different mensuration test kits to confirm.

Dotted line and solid line show that respectively contrast day and signal apply the mensuration of day.As seen, use the signal of telecommunication and cause the substantial reduction of the blood sugar level of all time points (substantial reduction) between test period.

Referring to Figure 39 B, it illustrates the determination of blood glucose level in the process of the test of carrying out according to embodiment of the present invention.Second Canis familiaris L., different with the described Canis familiaris L. of Figure 39 A, it is anaesthetized, and two electrodes are implanted their the preceding lateral wall of gastric antrum.The about 3cm of the about 2cm-of electrode distance pylorus that implants.Apply the signal of telecommunication shown in Figure 39 A, carry out 5 identical testing programs then.But in the experiment that causes result shown in Figure 39 B, the signal of telecommunication has applied about 20 minutes.

Dotted line and solid line show that respectively contrast day and signal 10 apply the mensuration of carrying out day.As seen, apply the substantial reduction that the signal of telecommunication causes blood sugar level between test period.

Discuss

The above results shows, obviously do not raise at insulin level, even when reducing, the control of glucose level is possible in the human body, can partly control at least.When physiological mode when to use these results be unnecessary, various pulse application logics can make up with particular model.In addition, should be noted that every kind of such model can only be explained this effect of part, all effect is the result of different physiology's approach and combination of effects.

A kind of possible explanation that reduces the effect of pulse for insulin and glucose is, one or more non-insulin hormones are released, and for example GLP1 or other GI hormone are known or non-known, and these hormonal effects glucose absorption or glucose secretion.Possibly, such hormone directly acts on somatic cell or hypothalamus.These hormones can increase effectiveness or the sensitivity of insulin in various peripheral cells or brain.Selectively or extraly, the secretion of excretory glucagon of affecting glucose or different hormone is lowered.

Except being included in the stimulus of direct current of the cell in the pancreatic hormone secretion, other probability also exists.Possibly, electricity irritation has changed blood flow pattern in the pancreas, as mentioned above, has its effect.The another kind of explanation is that electricity irritation influences the fatty tissue level in the pancreas self.Another kind of possible explanation is that electricity irritation influences the nervous system path in pancreas and/or the liver.Possibly, such nervous pathway is controlled glucagon secretion or is activated non-insulin-dependent glucose conveyer in the remote histiocyte.For example, be well known that the islets of langerhans of implantation has incorrect glucagon secretion.This may be because lack neural connection.The nerve that is stimulated can be for example to stimulate to cause secretion and/or stop excretory nerve.Selectively or extraly, this nerve can be perception, for example the nerve of pancreas, blood glucose and/or hormonal activity.Selectively or extraly, neural and/or other can excited pancreatic tissue between the gap connect and can be affected.Should be noted that for types influence of some nervous tissues, the pancreas percentage ratio of stimulation can be not too important, because by propagation at the propagation effect of stimulation of nerve signal among this pancreas and/or outside this pancreas.

A kind of possible explanation is that electric field directly or indirectly influences in the pancreas or near the nerve it.Possibly, these neural materials that influence muscle, brain or other organ that discharge.Possibly, described nerve directly influences brain, and brain discharges described material then.Optional or in addition, described nerve influences other tissue to discharge described material, may connect the above-mentioned effect that produces via neuroganglion.It below is the part tabulation of the signal chemical substance of its secretion possibility irriate function influence (for example increase and/or reduce): nitric oxide, ATP, adenosine, dopamine, norepinephrine, acetylcholine, 5-hydroxy tryptamine (5-HT), GABA, glutamate, Glu (ester), aspartate (ester), glycine, histamine, angiotensin (Angiotensins), Magainin (Bombesin), Kallidin I (Bradykinin), calcitonin (Calcitonin), calcitonin-gene-related peptide carnosine (Calcitonin Gene-Related Peptide Carnosine), cholecystokinin (Cholecystokinin), thyroliberin (Corticotropin), corticotropin releasing hormone, Delta sleep derivation type peptide (Delta Sleep-Inducing Peptide), FMRFamidGalanin, the gastrin peptide for inhibiting, gastrin releasing peptide, gastrin, glucagon, interstitialcellstimulating hormone (ICSH) liberin (Gonadorelin) MSH, MSH release inhibting hormone, MSH-releasing hormone, energy therbligs (Motilin) neuropeptide tyrosine, neurophysin (Neurophysin), neurotensin (Neurotensin), Opium class peptide-endorphins, the pancreas polypeptide, peptide PHI pituitary hormone release inhibniting hormone, pituitary hormone releasing hormone, prolactstatin, prolactin releasing hormone, thyrotrophin-releasing hormone (Protirelin), secretin somatomedin, amicine, growth hormone releasing hormone, the tachykinin vasoactive intestinal peptide, vassopressin, orexin, insulin and/or P material, and/or other any known or unknown signal chemical substance.

Another possible explanation is other a organ in the electricity irritation function influence abdominal cavity, liver for example, and stomach maybe may be the adipose cell in the nethike embrane, and causes that their change their activity and/or secreting hormone.In any case the arbitrary end of the pancreas in the pig and the mankind is placed electrode and is had desired effect.

Should be noted that, for being used for laboratory or operating means, actual equipment can comprise one or more pick offs, wherein whether the pick off marker pulse (for example has above-mentioned influence, to glucagon, one of to the glucose secretion, to glucose uptake and/or to nervous tissue), and the control of service routine and/or pancreas controller 102 is assisted.

Illustrative application

After determining diabetic disease states, can use above pancreas controller 102.Yet randomly, controller is used for diagnosing better the morbid state that is in evolution and/or is used to prevent final diabetic disease states to take place, for example by supporting pancreas.Therefore, except permanent implanted device, randomly provide the embodiment of provisional device.

In another was used, insulin output and blood sugar level can not only be used for the prevention of obesity patient owing to overworking of pancreas develops into diabetes in the strict control volume, and can be used for (while or selectively) reduction body weight.For avoiding the injury to health, this scheme needs glucose level raising in the strict preclude blood.Yet, wish by at " normally " thus glucose level reduces the production inhibition hunger sensation of insulin, and reduce the growth in most fatty tissuees.

In illustrative embodiment of the present invention, controller is the device of an individualism.Yet dual organ controller can be used in some morbid state.In an example, it is pointed out that many patients that suffer from pancreatic diseases also have cardiac problems.Therefore, provide heart/pancreas combined controller, it may share one or more sleeve pipes, programming mode, power supply and control circuit.In another example, can make up uterus controller and pancreas controller to defend pregnancy-related diabetes and inappropriate uterine contraction.

Another illustrative dual organ controller is used for harmonization of the stomach pancreas.Such controller is applicable to the obese patient, and it is used to suppress the stomach contraction and avoids hunger sensation.Simultaneously, can control insulin level avoiding hungry, or in diabetics prevention hyperglycemia or hypoglycemia.In addition, aforesaid, the delay of gastric emptying also can be used for postponing glucose absorption, causes insulin spikes to postpone and/or reduction.In addition, in some embodiments of the present invention, this delay also can be used for or alternative direct pancreas stimulation in addition.

In illustrative embodiment of the present invention, identical electrode is used to make the charging of pancreas stomach function regulating, utilizes identical electrode group that obesity control and glucose control are provided thus.It should be noted that reducing feed also can reduce glucose load.Described multipurpose electrode for example can place on the pancreas, the Weishang, or between the pancreas stomach function regulating.Electrode placed on stomach wall and/or stomach and/or other internal organs to stimulate for non-pancreas also come in handy, connect responsive relatively for electrode and/or be difficult to situation about arriving relatively by required operation method if for example be used for organ to be stimulated.

Should be understood that, can change the method for above-mentioned control pancreas in many aspects, comprise the application type and the order that change operating procedure order, electrode arrangement, pulse, and/or particular order and the logical scheme used, wherein said some operating procedure is carried out frequently more and some operating procedure is so not frequent.Further, under the situation that does not exceed spirit disclosed by the invention, the position of different elements can change, for example, and the position of power supply.A large amount of different characteristics of method and apparatus have been described in addition.Should be understood that, can make up different features with different modes.Especially, all features of a certain specific embodiments that more than shows are not all to be necessary in each similar illustrative embodiment of the present invention.Further, above combination of features also is considered to be in the scope of some illustrative embodiments of the present invention.In addition, other the illustrative embodiment according to the present invention, some feature of the present invention described herein can be used for the use of some device of prior art through transformation.In addition, the various methods that are used to implement above-mentioned functions comprise within the scope of the invention, for example charging method, method for generating pulse and/or inducing method.Be used to explain special geometry of the present invention and should be considered to limit the scope of the present invention to and have only those shapes, for example, the sphere pole of demonstration is the ellipsoid shaped electrode in other embodiments.Although just some restriction is described as method or device restriction, but scope of the present invention also comprises programmer and/or is designed for the device of these methods of execution, for example, use hardware or software programming, and to the method for device energising so that its this device has the function of expection.

Surgical cassette (kit) also within the scope of the invention, it comprises the medical treatment device that is applicable to implant controller and the equipment group (set) of sort controller.The section header that provides only is used for assisting to handle using, and should not be interpreted as described a certain joint content necessarily is limited to this joint.Only as the illustrative measuring method of individual cases, suitable actual measurement method will change along with the difference of using the measuring method that provides.When using in following claim, term " comprises ", " comprising " or similar description refer to " including but not limited to ".

Should be understood that, for those of ordinary skills, the content that the invention is not restricted to describe.Yet scope of the present invention only limits to following claim.

Claims

1. method of controlling glucose level comprises:

Use described at least one electrode that electric field is applied on the pancreas, make with same experimenter in insulin regular reacting phase ratio, blood sugar level significantly reduces and blood insulin levels does not significantly improve.

2. according to a kind of method of claim 1, comprise subsequently second electric field is applied on the described pancreas that this second electric field can improve insulin level.

3. according to a kind of method of claim 1, wherein said electric field effectively reduces the secretion of glucagon.

4. according to a kind of method of claim 1, wherein said electric field effectively reduces and the glucose secretion of described pancreas at liver relevant on physiology.

5. according to a kind of method of claim 1, wherein said electric field effectively increase comprises the picked-up of the cells in vivo of described pancreas to glucose.

6. according to a kind of method of claim 1, wherein said electric field is the nervous tissue of the described pancreas of influence effectively.

7. according to a kind of method of claim 1, wherein said electric field right and wrong are excitatoty, and it does not induce the active new outburst of islets of langerhans in the pancreas basically.

8. according to a kind of method of claim 1, wherein said electric field is used as electric field two-phase and that the charge balance time is variable.

9. according to a kind of method of claim 8, wherein the short time is used described electric field in each period.

10. according to a kind of method of claim 9, the frequency of utilization in the wherein said period is 1Hz to 15Hz.

11. according to a kind of method of claim 9, the frequency of utilization in the wherein said period is about 5Hz.

12. according to a kind of method of claim 9, the wherein said period is less than 30 minutes.

13. according to a kind of method of claim 9, the wherein said period is about 10 minutes.

14. according to a kind of method of claim 1, wherein said electric field is being less than the repetition of 30 minute period.

15. according to a kind of method of claim 1, wherein said electric field repeated 30 to 180 minute period.

16. according to a kind of method of claim 1, wherein said electric field used in basic all periods of glucose absorption incident.

17. according to a kind of method of claim 1, wherein said electric field uses before the glucose uptake incident of expection.

18., comprise by the described electric field of glucose uptake Event triggered according to a kind of method of claim 1.

19. according to a kind of method of claim 1, wherein use described electric field, do not consider the picked-up activity.

20., wherein use described electric field to the irrelevant time of small part and blood sugar level according to a kind of method of claim 1.

21. according to a kind of method of claim 1, wherein said electric field used at least in 24 hours continuously.

22. according to a kind of method of claim 1, wherein said electric field has used did not have its effect of perception at least in 15 minutes.

23. according to a kind of method of claim 1, wherein said electric field has certain size and time range, causes it when nothing is ingested incident, can significantly not change blood insulin and glucose level.

24. according to a kind of method of claim 1, at least 20% of the glucose level that increase of wherein said electric field minimizing more than fasting glucose baseline level.

25. according to a kind of method of claim 1, wherein in average measurement more than 5 minutes, described electric field increases blood insulin levels and is no more than 20%.

26. the process of claim 1 wherein that described electric field reduces blood insulin levels, as measuring by the cumulant of glucose uptake incident like that, and to compare with described experimenter's popular response, described reduction is above 20%.

27., comprise stomach treated to postpone gastric emptying according to a kind of method of claim 1.

28. according to a kind of method of claim 1, wherein said electric field effectively postpones glucose peak at least between its operating period.

29. according to a kind of method of claim 1, wherein said electric field effectively postpones glucose peak at least 10 minutes.

30. according to a kind of method of claim 1, wherein said electric field effectively postpones insulin peak at least 10 minutes.

31. the process of claim 1 wherein the effective truncate insulin spikes of described electric field.

32. the process of claim 1 wherein the effective truncate glucose peaks of described electric field.

33. the process of claim 1 wherein that described electrode is not attached to pancreas.

34. the process of claim 1 wherein that described electrode is connected in pancreas.

35. a method of controlling glucose level comprises:

Electric field is applied to pancreas, when blood sugar level raises, effectively reducing blood sugar level, and if blood sugar level when not raising is basically then taked sharp mode, remarkable blood sugar lowering level.

36. the method for claim 35, wherein said electric field reduces the glucose level at least 20% that raises.

37. being the sharp glucose level that does not improve that reduces, the method for claim 35, wherein said electric field do not surpass 10%.

38. the method for claim 35, wherein said electric field does not influence the exocrine function of pancreas.

39. the device of glycemic control comprises:

Utilize and non-ly excite electric field be fit to give described at least one electrifying electrodes and be configured to utilize non-excitability electric field to give the circuit of described electrifying electrodes in the mode of the loss that compensates the sharp response of described pancreas.

40. according to the device of claim 39, wherein said circuit compensates by the secretion that causes insulin bolus form.

41. according to the device of claim 39, wherein said circuit reduces glucose level in the non-insulin mode and compensates.

42. according to the device of claim 41, wherein said circuit compensates by the secretion that reduces glucagon.

43. according to the device of claim 39, wherein said circuit reduces or is suppressed at significantly improving of insulin secretion between the described amortization period.

44. according to the device of claim 39, wherein at least 20% the incident of ingesting, described circuit only uses the acumen control of insulin level.

45. according to the device of claim 44, wherein said device the insulinize method setting program that described pancreas is provided based on the long response time chemistry.

46., comprise the induction apparatus of ingesting automatically that is used for detecting automatically feeding activity according to the device of claim 39.

47., comprise the automatic glucose induction apparatus of the situation of the sharp response of automatic detection needs according to the device of claim 39.

48. according to the device of claim 39, comprise automatic glucose induction apparatus, be used for detecting automatically the situation of the sharp insulin response of needs.

49. according to the device of claim 39, wherein said response is sharp insulin response.

50. the device of claim 39, wherein said electrode is suitable for being connected in pancreas.

51. the device of claim 39, wherein said electrode is suitable for being connected in muscular organ.

52. the device of glycemic control comprises:

The circuit of be fit to giving described at least one electrifying electrodes and disposing for the mode of the blood sugar level that improves with remarkable minimizing gives described electrifying electrodes, when glucose level did not raise, the circuit of described configuration also used described electric field.

53. according to the device of claim 52, wherein said circuit is a closed-loop system, comprises the faradism effect, and under doubt situation, sets overstimulation for described circuit.

54. according to the device of claim 52, wherein said circuit is semi-open circuit system, wherein uses long relatively stimulation series, not feedback.

55. according to the device of claim 52, wherein said circuit is open loop, wherein uses stimulation series to reply and excites and do not have and feed back.

56. the device of glycemic control comprises:

Be fit to give at least one described electrifying electrodes and reducing glucose level, but when glucose level improves, do not significantly improve the circuit that the mode above the insulin level of baseline value disposes to described electrifying electrodes.

57. according to the device of claim 56, wherein said circuit is the closed-loop system that comprises the faradism effect, wherein under doubt situation, sets overstimulation for described circuit.

58. according to the device of claim 56, wherein said circuit is semi-open circuit system, wherein uses long relatively stimulation series, not feedback.

59. according to the device of claim 56, wherein said circuit is an open loop system, wherein uses stimulation series to reply and excites and do not have and feed back.

60. according to the device of claim 56, wherein said circuit uses the electric field of constant voltage.

61. according to the device of claim 56, wherein said circuit uses the electric field of constant current.

62. according to the device of claim 56, wherein said pancreatic tissue comprises intravital pancreas.

63. according to the device of claim 56, wherein said pancreatic tissue comprises the pancreatic tissue of implantation.

64. the device of claim 56, wherein said baseline are the baseline insulin responses that adopts the experimenter of described device.

65. the method for insulin level control comprises:

Use described at least one electrode that electric field is applied on the pancreas, make blood sugar level significantly not increase and blood insulin levels significantly reduces.

66. electric field put on pancreas or on function and position the method for the tissue relevant with pancreas, comprising:

At least one electrode is connected in tissue except pancreas; With

Make to described electrifying electrodes tangible electric field is put on pancreas or linked groups, at least a with in control pancreatic secretion level and the blood sugar level.

67. the method for claim 66 comprises and also utilizes described at least one electrode control feed custom.

68. electric field put on pancreas or on function and position the device of the tissue relevant with pancreas, comprising:

Be suitable for being connected at least one electrode of the tissue except pancreas; With

Make to described electrifying electrodes tangible electric field is put on pancreas or linked groups, with at least a device in control pancreatic secretion level and the blood sugar level.