Blood Glucose (Homeostasis)

Glucose is one of the body’s principal fuels. It is an energy-rich

monosaccharide(simplest form of CHO) sugar that is broken down in our cells
to produce adenosine triphosphate.
ATP is a small packet of chemical energy that powers the millions of biochemical
reactions that take place in the body every second. In the small intestine,
glucose is absorbed into the Blood and travels to the liver via the hepatic portal
vein where it is converted in form of glycogen.
This is stored in the liver and can be reconverted into glucose when blood-
glucose levels fall. All of the body’s cells need to make energy and most can use
other fuels such as lipids. However, neurons (nerve cells) rely almost exclusively
on glucose for their energy. This is why the maintenance of blood-glucose levels
is essential for the proper functioning of the
nervous system. If glucose levels fall to too low a concentration (hypoglycaemia)
or rise too high (hyperglycaemia) then this situation can lead to the neurological
processes in the brain being compromised.
 Glucose regulation
Blood-glucose levels fluctuate as a person’s intake of food varies over a 24-hour period.
After meals, the body is said to be in an absorptive state as it absorbs nutrients from
the gut.
Blood-glucose levels rise although this is buffered by glucose storage in the liver. When
digestion is complete and the absorption of nutrients decreases, the body is in a post-
absorptive state and, as the body’s cells use glucose to make energy, blood-glucose
levels fall.

• Target Range:
• Glucose levels in the blood are usually measured in terms of milligrams per deciliter
(mg/dl), with a normal range of 70 to 110 mg/dl. Generally speaking, if glucose levels
stray out of this range, the amounts of insulin and glucagon produced by the pancreas
will be adjusted to bring glucose levels back into this range. It should be noted here
that insulin and glucagon signaling are not all-or-nothing responses in normal
individuals. When the system is functioning properly, there is always some insulin and
some glucagon being produced by the pancreas that is trying to find a balance between
glucose release into the blood, and glucose uptake into cells.
Regulation of blood glucose depends on 2 phenomenon:
( a) Rate of glucose entrance into the blood
(b) Rate of its removal from blood
• This chart shows the concentrations of glucose, insulin, and glucagon in the blood, both before and after
a meal that is high in carbohydrates. Before the meal, glucagon levels represented by the red line are
high, because no glucose is being absorbed by the small intestine, so it must be released by the liver, and
stimulating glucose synthesis and release from the liver are glucagon's main functions. However, very
soon after a high-carbohydrate meal, glucose levels in the blood spike higher, and as you can see in the
graph here, insulin levels spike higher, too. The insulin spike is in response to the higher glucose levels,
but it happens so quickly that the two spikes happen almost simultaneously. In fact, you can see by this
graph that insulin levels rise whenever glucose levels rise and fall whenever glucose levels fall.
 Diabetes
• Diabetes is a group of metabolic diseases characterized by hyperglycemia
resulting from defects in insulin secretion, insulin action, or both. The
chronic hyperglycemia of diabetes is associated with long-term damage,
dysfunction, and failure of differentorgans, especially the eyes, kidneys,
nerves, heart, and blood vessels.
• Several pathogenic processes are involved in the development of diabetes.
• These range from autoimmune destruction of the β-cells of the pancreas
with consequent insulin deficiency to abnormalities that result in resistance
to insulin action.
• The basis of the abnormalities in carbohydrate, fat, and protein metabolism
in diabetes is deficient action of insulin on target tissues.
• Deficient insulin action results from inadequate insulin secretion and/or
diminished tissue responses to insulin at one or more points in the complex
pathways of hormone action.
• Impairment of insulin secretion and defects in insulin action frequently
coexist in the same patient, and it is often unclear which abnormality, if
either alone, is the primary cause of the hyperglycemia.
 Symptoms of marked hyperglycemia :
• Include polyuria, polydipsia, weight loss, sometimes with polyphagia,
and blurred vision. Impairment of growth and susceptibility to certain
infections may also accompany chronic hyperglycemia. Acute, life-
threatening consequences of uncontrolled diabetes are
hyperglycemia with ketoacidosis or the non-ketotic hyperosmolar
syndrome.
• Long-term complications of diabetes include retinopathy with
potential loss of vision; nephropathy leading to renal failure;
peripheral neuropathy with risk of foot ulcers, autonomic neuropathy
causing gastrointestinal, genitourinary, and cardiovascular symptoms
and sexual dysfunction. Patients with diabetes have an increased
incidence of atherosclerotic cardiovascular, peripheral arterial, and
cerebrovascular disease. Hypertension and abnormalities of
lipoprotein metabolism are often found in people with diabetes.
 CLASSIFICATION OF DIABETES MELLITUS
Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency)
Immune-mediate diabetes
This form of diabetes, which accounts for only 5–10% of those with diabetes, previously encompassed by the terms
insulin-dependent diabetes, type 1 diabetes, or juvenile-onset diabetes, results from a cellular-mediated
autoimmune destruction of the β-cells of the pancreas.
Autoimmune destruction of β-cells has multiple genetic predispositions and is also related to environmental factors
that are still poorly defined. Although patients are rarely obese when they present with this type of diabetes,
the presence of obesity is not incompatible with the diagnosis. These patients are also prone to other
autoimmune disorders such as Graves' disease, Hashimoto's thyroiditis, Addison's disease, vitiligo, celiac sprue,
autoimmune hepatitis, myasthenia gravis, and pernicious anemia.
Type 2 diabetes (ranging from predominantly insulin resistance with relative insulin
deficiency to predominantly an insulin secretory defect with insulin resistance)
This form of diabetes, which accounts for ∼90–95% of those with diabetes, previously referred to as non–insulin-
dependent diabetes, type 2 diabetes, or adult-onset diabetes, encompasses individuals who have insulin
resistance and usually have relative (rather than absolute) insulin deficiency At least initially, and often
throughout their lifetime, these individuals do not need insulin treatment to survive. There are probably many
different causes of this form of diabetes. Although the specific etiologies are not known, autoimmune
destruction of β-cells does not occur, and patients do not have any of the other causes of diabetes listed above
or below.
Most patients with this form of diabetes are obese, and obesity itself causes some degree of insulin resistance.
Gestational diabetes mellitus
For many years, GDM has been defined as any degree of glucose intolerance with
onset or first recognition during pregnancy. Although most cases resolve with
delivery, the definition applied whether or not the condition persisted after
pregnancy and did not exclude the possibility that unrecognized glucose
intolerance may have antedated or begun concomitantly with the pregnancy.
Etiologic classification of diabetes mellitus
•Type 1 diabetes (β-cell destruction, usually leading to absolute insulin
deficiency)
–Immune mediated
–Idiopathic
•Type 2 diabetes (may range from predominantly insulin resistance with
relative insulin deficiency to a predominantly secretory defect with
insulin resistance)
•Other specific types
–Genetic defects of β-cell function
•Mitochondrial DNA
•Others
 – Diseases of the exocrine pancreas
• Pancreatitis
• Trauma/pancreatectomy
• Neoplasia
• Cystic fibrosis
• Others
– Drug or chemical induced
• Thyroid hormone
• Diazoxide
• β-adrenergic agonists
• Thiazides
• Dilantin
• γ-Interferon
• Others
– Other genetic syndromes sometimes associated with diabetes
• Down syndrome
• Turner syndrome
• Wolfram syndrome
• Porphyria
• Others
• Gestational diabetes mellitus
Insulin • Insulin is a hormone that is
exclusively produced by pancreatic
beta cells. Beta cells are located in
the pancreas in clusters known as
the islets of Langerhans. Insulin is a
small protein and is produced as
part of a larger protein to ensure it
folds properly.
• Insulin production involved
intermediate steps. Initially,
preproinsulin is the inactive that is
secreted into the endoplasmic
reticulum. Post-translational
processing clips the N-terminal
signal sequence and forms the
disulfide bridges. Lastly, the
polypeptide is clipped at two
positions to release the intervening
chain C. This and active insulin are
finally packaged into secretory
granules for storage.
 Insulin release
 The process by which insulin is released from beta cells, in response to changes in blood
glucose concentration is complex .
 Type 2 glucose transporters (GLUT2) mediate the entry of glucose into beta cells glucose is
phosphorylated by the rate-limiting enzyme glucokinase.
 This modified glucose becomes effectively trapped within the beta cells and is further
metabolized to create ATP, the central energy molecule.
 The increased ATP:ADP ratio causes the ATP-gated potassium channels in the cellular
membrane to close up, preventing potassium ions from being shunted across the cell
membrane. The ensuing rise in positive charge inside the cell, due to the increased
concentration of potassium ions, leads to depolarization of the cell.
 The net effect is the activation of voltage-gated calcium channels, which transport calcium
ions into the cell. The brisk increase in intracellular calcium concentrations triggers export of
the insulin-storing granules by a process known as exocytosis.
 The ultimate result is the export of insulin from beta cells and its diffusion into nearby blood
vessels. Insulin release is a biphasic process.
 The initial amount of insulin released upon glucose absorption is dependent on the amounts
available in storage. Once depleted, a second phase of insulin release is initiated. This latter
release is prolonged since insulin has to be synthesized, processed, and secreted for the
duration of the increase of blood glucose.
 Furthermore, beta cells also have to regenerate the stores of insulin initially depleted in the
fast response phase.
 Mode Of Action Of natural Insulin
• Insulin molecules circulate throughout the blood stream until they bind to
their insulin receptors. The insulin receptors promote the uptake of glucose
into various tissues that contain type 4 glucose transporters (GLUT4). Such
tissues include skeletal muscles (which burn glucose for energy) and fat
tissues (which convert glucose to triglycerides for storage). The initial binding
of insulin to its receptor initiates a signal transduction cascade that
communicates the message delivered by insulin: remove glucose from blood
plasma .The key step in glucose metabolism is the immediate activation and
increased levels of GLUT4 glucose transporters. By the facilitative transport of
glucose into the cells, the glucose transporters effectively remove glucose
from the blood stream. Insulin binding results in changes in the activities and
INSULIN FATE
concentrations of intracellular enzymes such as GLUT4.

The enzyme insulinase (found in the liver and kidneys) breaks down blood-circulating
insulin resulting in a half-life of about six minutes for the hormone. This degradative
process ensures that levels of circulating insulin are modulated and that blood glucose
levels do not get excessively low.
It is modulated by:
Insulin Secretion
• Glucose(most imp) ,AA’s,Ketone bodies,and fatty acids.
• Glucagon and somatostatin inhibit release.
• Alpha adrenergic stimulation inhibits release.
• Beta adrenergic stimulation promotes release.
• Elevated intracellular Ca prmotes release.
• Oral glucose elicits more insulin secretion than IV glucose;oral administration elicits gut
hormones which augment the insulin response.
• Insulin is normally catabolized by insulinase produced by the kidneys.
 Insulin Preparations
 Rapid action :

 Crystalline zinc insulin:

 Bovine pancreas and human source
 S.C administration
 Onset 0.5 hours and effet last for 6-8 hours
 Can be given in combination with long and I.M acting.

 Semilente insulin:
 Prompt insulin zinc suspension
 Excess zinc no protamine
 Administered s.c only
 Onset 1-2 hours last effect for upto 12 hours
INTERMEDIATE PREPARATION:

Isophane insulin(NPH Insulin):

 Crystalline zinc insulin with protamine at ph7
 Protamine retards the absorption of insulin thereby prolong its
duration of action
 Onset 2hours effect last for upto 12-24 hours.
 Not useful in DKA

Lente Insulin:
 Mixture of 30% semilente with 70% ultralente insulin
 Effects similar to NPH insulin
Long acting preparations:

Protamine zinc insulin:

 Protmine added to crystalline zinc insulin to form large crystals
 Onset 5-7 hours,effect upto 24-36 hours
 Prep is less soluble serves as tissue depot after s.c administration
providing slow absorption into circulation.

Ultralente Insulin:
 High zinc content makes it poorly soluble.