PHARMACOLOGY OF INSULIN AND IT’S ANALOGUES

• An endocrine hormone
• Synthesized by β cells of pancreatic islets( of langerhans) , stored in
intracellular granules as PROINSULIN.
• PROINSULIN PROTEOLYSIS  INSULIN.
• Pancreas stores about 10 mg of Insulin – roughly 2 mg ( 50 U) is
released into portal vein daily.
• Release is controlled concentration of glucose in the plasma -
released in response to elevating blood glucose level ( within 30-50
seconds) . Elevated glucose is likely to stimulate insulin
biosynthesis. And in addition, Amino acids, Fatty acids, Some GIT
Products, Mannose and Fructose also stimulate insulin
biosynthesis.

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 1
PART 3
 PHYSIOLOGICAL EFFECTS OF INSULIN (Pharmacological )
• Overall effects of insulin favors the storage of energy.
• Influences the metabolism of Wide variety of tissues.
• Plays a key role in intermediary metabolism of muscle , adipose and
important effects of Liver.
• Helps mobilize glucose from the systemic circulation into storage sites –
Skeletal muscle and adipose- (fuel).
• Insulin helps peripheral mobilization and it’s utilization.
• Effects of insulin ranges from – WITHIN FEW SECONDS / MINUTES (
RAPID) – INTERMEDIATE TO LONG-TERM.
• EFFECTIVELY REDUCES ELEVATED BLOOD GLUCOSE LEVEL IN A DIABETIC
SUBJECT.
• INTERMEDIATE effects include – DNA mediated synthesis of glucose
transporter and synthesis of enzymes for amino acid metabolism .
• LONG-TERM – Includes multiplication and diffrensiataion of cells.

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 2
PART 3
 PHYSIOLOGICAL EFFECTS OF INSULIN (Pharmacological )
SKELETAL MUSCLE AND ADIPOSE
Facilitates glucose transport across cell membrane , conversion
of glucose into glycogen ( by stimulating glycogen synthatase).

LIVER
Facilitates glycogen synthesis from glucose. And
inhibits glycogen breakdown ( glycogenolysis).

ADIPOSE
Inhibits lipolysis – favors triglyceride synthesis . Stimulates
vascular endothelial lipoprotein lipase- thus increasing the
clearance of VLDL and Chylomicrons.

MUSCLE
Facilitates amino acid entry and it’s synthesis into proteins.

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 3
PART 3
 How insulin produces it’s effect?
Insulin I Insulin
I

α α
α α

___________________________________-
β
β β β
______________________________________

Protein Protein Phosphate Glucose transporter

Via 2ND MESSENGER Phosphorylation cascade

Activation / inhibition of
enzyme function
INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -
7th semester -2012-13 4
PART 3
 MECHANISM OF ACTION OF INSULIN
• Acts on specific receptors located on the cell membrane of
practically all cells and density of receptors varies among different
cells.
• Insulin receptor – a heterotetrameric glycoprotein consisting 2 α
and 2 β subunits linked together by disulfide linkage.
• The α subunit carry insulin binding sites and β subunits have
Tyrosine Protein kinase activity.
• Insulin on binding to α subunit >>> induces aggregation and
internalization of receptors along with bound insulin molecule>>>
which activates Tyrosine protein kinase activity (β subunits). >>>
autophosphrylation of residues of β subunits .
• This in turn, cascade of phosphorylation and de Phosphorylation
reaction is set into motion.

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 5
PART 3
 MECHANISM OF ACTION OF INSULIN

• Resulting in either STIMULATION / INHIBITION of enzymes

involved in rapid metabolic actions of insulin.
• Second messenger - generated by the activation of
Phospholipase C – believed to mediate the metabolic reactions.
• Insulin stimulates and accelerates glucose transport across cell
membrane.
• Similar mechanism may be involved in effects that is likely to
manifest after relatively long time.
• EFFECTIVELY REDUCES ELEVATED BLOOD GLUCOSE LEVEL IN A
DIABETIC SUBJECT.

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 6
PART 3
 PHARMACOLOGY OF INSULIN AND IT’S ANALOGUES
ADVERSE EFFECT
1. HYPOGLYCEMIA : Most frequent and serious especially in
labile patients. Happens either due to over dosage/
missing the meal / vigorous exercise . Prolonged
hypoglycemia can lead to irreversible neurological
damage.
2. LOCAL REACTIONS : at the site of injection – Swelling,
Erythema, stinging sensation and Lipid dystrophy.
3. ALLERGY : Although not common – due to contamination
with protein constituents ( impurity )- Urticaria,
Angioedema & anaphylaxis.

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 7
PART 3
 ADVERSE EFFECT
5. INSULIN RESISTANCE

• When requirement is above 100 Units / day.

• May be ACUTE : Which develops rapidly and is of short
duration.
Chronic : due to long term / years together use of
conventional insulin preparations.
• Commonly observed in Type 2 DM patients – can be
overcome by using purified forms of insulin.

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 8
PART 3
 INSULIN PREPARTIONS
• CONVENTIONAL –( Before 1970)- animal source – relatively old –
Needs repeated administration – Modified ones retards immediate
absorption. – S/C , IM. – IMPURE ( 1%) – CONTAMINATED WITH
OTHER PROTEINS – POTENTIALLY ANTIGENIC.
• MORE PURIFIED INSULIN – ( 1970 -80 ONWARDS) Highly purified
– practically non- antigenic- due to availability of purification
techniques.
• HUMAN INSULIN – (1980 onwards) – from Recombinant DNA
technology – E.coli/ yeast / enzymatic modification of porcine
insulin.

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 9
PART 3
1. VARIOUS CONVENTIONAL INSULIN PREPARATIONS

TYPE ONSET PEAK DURATION OF

OF EFFECT ACTION
ACTION BY ( HRS)
( HRS) ( HRS)
SHORT ACTING
1. Regular / soluble insulin 0.5 – 1 2-4 6-8
2. Prompt Insulin ZN / Semilente 01 3-6 12-16
insulin.
INTERMEDIATE ACTING
1. Insulin Zn suspension / lente 1-2 8-10 20-24
2. Natural Protamine --same as --same as --same as above
3. Isophane Insulin above above
LONG ACTING
1. Extended Action Zn Suspension / 4–6 12-18 24-36
ultralente 4- 6 14-18 24-36
2. Protamine Zn Insulin

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 10
PART 3
 2. MORE PURIFIED INSULINS
usually from pork insulin and Can still be immunogenic. , Expensive, lesser
chances of developing resistance, greater stability , less allergic .

TYPE CHARACTERISTIC FEATURES EXAMPLES

SINGLE PEAK 1. Purified by GEL filtration and 1. ACTRAPID

INSULIN repeated crystallization. ( Regular) 8 Hrs
2. Still contains 50-200 ppm of 1. LENTARD
PROINSULIN (10,000 ppm in ( Lente) 22 Hrs
conventional preparations) 1. ACTRAPHANE
( Regular + lente) 24
Hrs.
MONO 1. Purified by GEL Filtration and
COMPONENT purified using ION EXCHANGE
INSULIN Chromatography.
2. < 20 ppm (10,000 ppm in
conventional preparations)

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 11
PART 3
 EXAMPLES OF HUMAN INSULIN

Type Units Duration

of action
Human Actrapid / regular 40 and 100 u/ml 08 hrs
insulin
Human Monotard / lente insulin 40 and 100 u/ml 22 hrs

Human Actraphane 40 and 100 u/ml 24 hrs

Isophane insulin( 70%) and
Human insulin ( 30%)

-SUBSTITUTED FOR CONVENTIONAL INSULIN PREPARATION.

- NOT SUPERIOR COMPARED TO PURIFIED INSULIN.

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 12
PART 3
 INDICATIONS FOR PURIFIED & HUMAN
INSULIN ( when to use it?)
1. Insulin resistance ( confirmed by the presence of
insulin antibodies).
2. Allergic to conventional insulin.
3. Lipid dystrophy at the site of injection.
4. Short term use in diabetics , who are otherwise
stabilized on Diet and Exercise- with / without
Oral hypoglycemic drug. Especially during Tide
over surgery, Trauma, infection and
Ketoacidosis.
5. During Pregnancy/ Gestational Diabetes.

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 13
PART 3
 THERAPEUTIC USES OF INSULIN
• A must for TYPE I DM/ IDDM to restore metabolism to normal ,
avoid symptoms of hypoglycemia, glycosuria, preventing short term
complications and long term consequences.
• Likely to be used in TYPE II / NIDDM , When – Not adequately
controlled by Diet, exercise, intolerance to Oral drugs, Under weight
patients, Tide over temporary conditions like infections, surgery,
trauma, pregnancy etc. And in case of Ketoacidosis and gangrene
of extremities.
• Dose – IDDM – 0.4-0.8 U/kg / day, NIDDM – 0.2-1.6 U/ kg/ day.
• Diagnosis – to ensure completion of vagotaomy and
• used in combination with glucose in cyclic vomiting in children,
anorexia nervosa and acute alcohol intoxication.

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 14
PART 3
 ORAL HYPOGLYCEMIC AGENTS
• For TYPE II / NIDDM

• ORALLY EFFECTIVE, in lowering elevated BG level.

• When to use OHA?

1. Abnormality in glucoreceptor part of β unit of receptor of insulin.

2. Obesity- reduced sensitivity of peripheral tissues to the effect of insulin.

3. Reduced number of insulin receptors

4. Excess of hyperglycemic hormones.

• NOT A SUBSTITUTE FOR INSULIN

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 15
PART 3
 CLASSIFICATION of ORAL HYPOGLYCEMIC DRUGS
1. BIGUANIDES : Phenformin and Metformin. ( 1957)
2. SULFONYL UREA :
FIRST GENERATION ( 1957) : TOLBUTAMIDE,
CHLORPROPAMIDE, ACETOHEXAMIDE and TOLAZAMIDE.
SECOND GENERATION ( 1970) : GLYBENCLAMIDE
( Glyburide), GLIPIZIDE, GLICLAZIDE, GLIMPERIDE.
3. MEGLITINIDES : REPAGLINIDE, NATEGLINIDE
4. THIAZOLIDINEDIONES : ROSIGLITAZONE, PIOGLITAZONE
5. GLIPTINS / Dipeptidyl peptidase -4 Inhibitors
VIDAGLIPTIN, SITAGLIPTIN, ALOGLIPTIN
6. ALPHA GLUCOSIDASE INHIBITOR : ACARBOSE, MIGLITOL.

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 16
PART 3
 PHARMACOLOGY OF BIGUANIDES
• DONOT STIMULATE PANCREATIC Β CELLS. BUT NEEDS INSULIN FOR IT’S
BIOLOGICAL ACTIONS.
• Both have similar action, but differs in PK aspect.
• In addition, Metformin – reported to IMPROVE LIPID PROFILE in
diabetics.[ Advantageous – since diabetics have elevated lipid profile]
• MOA :
1. Suppress hepatic gluconeogenesis and glucose output from liver.
2. Enhances insulin mediated glucose disposal in muscle and fat.
Enhances GLUT1 transport from intracellular site to plasma
membrane.
3. Promotes peripheral glucose utilization by enhancing glycolysis.
4. Inhibit intestinal absorption of glucose, hexose, amino acids and
Vitamin B12. ( all these will result in reducing elevated glucose level , proper
storage of glucose in storage organs and shall not allow new glucose production /
output from liver)

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 17
PART 3
 PHARMACOLOGY OF BIGUANIDES

• ADME : Both orally active, Phenformin

incomplete absorption. Phenformin – ½ life 3-
10 hrs, 8-12 Hrs,
Metformin – ½ life 1.5-3 hrs, 6-8 hrs.
• Liver metabolized and Kidney Excretion.
• Adverse effects :
Abdominal pain, anorexia, metallic taste,
Diarrhea, and tiredness.
LACTIC ACIDOSIS And VITAMIN B Deficiency.

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 18
PART 3
 Pharmacology of SU
• MOA : both pancriatic and non pancriatic
• PANCRIATIC : Single dose provokes brisk release of insulin from
pancreas >>> Act on SU receptor on the pancriatic β cell membrane
>>> Enhancing Ca influx >>> degranualtion >>> Insulin release .

• Improves post prandial glycemic control (Possibly reducing

glycogen secretion.

• EXTRAPANCRIATIC : Only after repeated administration ,

insulinemic action[ to promote insulin secretion] of SU declines >>>
but improves glucose tolerance.- HOW ?

• By sensitizing the target tissue ( Esp. Liver) to the action of Insulin.

( Possibly by Increasing Insulin receptor)

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 19
PART 3
 Pharmacology of SU
ADME
 all are well absorbed, 90% and above plasma bound ,
with low volume of distribution , Most of extensive
metabolism [ some metabolites active
( Tolazamide)] ,
Urine excreted ( Some Unchanged)
 DOA – varies within groups
 ADVERSE EFFECTS : Hypoglycemia, Nausea, vomiting ,
Flatulence, Diarrhea, paresthesia, Hypersensitivity
reactions, Photosensitivity, transient leucopenia.
Cholestatic jaundice.

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 20
PART 3
 RELATIVE PK OF SULFONYL UREA
Drug
Drug Plasma
Plasma Duration
Duration Metabolized
Metabolized Remarks
Remarks
½
½life
life of
ofAction
Action by
by
Tolbutamide
Tolbutamide 6-8
6-8Hrs
Hrs 6-8
6-8Hrs
Hrs Liver
Liver Weaker,
Weaker,safer
saferand
andshort
short
((FGSU)
FGSU) acting
acting
Chlorpropamide
Chlorpropamide 30-36
30-36Hrs
Hrs 36-48
36-48Hrs
Hrs Liver
Liverand
and Long
Longlasting
lasting, , Chances
Chances
((FGSU)
FGSU) Kidney
Kidney of
of Prolonged
Prolonged
hypoglycemia
hypoglycemia
GLIBENCLAMIDE
GLIBENCLAMIDE 12
12Hrs
Hrs 18-24
18-24Hrs
Hrs Liver
Liver Potent,
Potent,slow
slowacting
actingwith
with
(SGSU)
(SGSU) initial
initialinsulinemic
insulinemic
action.
action.
GLIPIZIDE
GLIPIZIDE 3-5
3-5Hrs
Hrs 12
12Hrs
Hrs Liver
Liver Fast
Fastacting,
acting,Insulinemic
Insulinemic
((SGSU)
SGSU) action
actioneven
evenonon
prolonged
prolongeduse.
use.
GLICLAZIDE
GLICLAZIDE 12
12hrs
hrs 12-18
12-18Hrs
Hrs Liver
Liver In
Inaddition
additionto to
((SGSU)
SGSU) Insulinemic,
Insulinemic,
antiplatelet
antiplateleteffect
effect––can
can
be
bebeneficial
beneficialin in
preventing
preventingsecondary
secondary
complication.
complication.
INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -
7th semester -2012-13 21
PART 3
 ROLE OF BG and SUS In MANAGEMENT OF
NIDDM

1. Indicated only for uncomplicated NIDDM –

When Diet and Exercises fail to produce good
glycemic control.
2. It supplements diet control/ management.
3. SU is preferred over BGs
4. Lactic acidosis from Phenformin limits the
potential usefulness.

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 22
PART 3
 PHARMACOLOGY OF MEGLITINIDE ANALOGUES
THESE ARE QUICK AND SHORT ACTING INSULIN RELEASERS.
REPAGLINIDE : with MOA like SU, Designed to normalize meal time
insulin release. Induces rapid onset short term insulin release. And
help to control post prandial hyperglycemia. No chances of
Hypoglycemia ( Due to shorter duration of action).
NETAGLINIDE : Principally stimulates First Phase of Insulin release,
resulting in rapid onset and shorter duration of action. When
ingested 10-30 min before meal, LIMITS post prandial
hyperglycemia in NIDDM without causing post prandial
Hyperglycemia. Less frequent hypoglycemia.

Used as an ALTERNATIVE to SU / Supplement BIGUANIDE / LONG

ACTING Insulin - in the management of NIDDM.
INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -
7th semester -2012-13 23
PART 3
 Role of THIAZOLIDINEDIONES AS OHA drug
( PPAR √ AGONISTS)
Examples : Rosiglitazone, Pioglitazone
• Selective agonists for nuclear peroxisome proliferator -
activated receptor √ - THAT ENHANCES THE
TRANSCRIPTION OF SEVERAL INSULIN
RESPONSIVE GENES.
• REVERSES INSULIN RESISTANCE by stimulating
GLUT 4 expression and translocation & as a result – entry of
glucose into the muscle & fat is improved.
• Suppressed hepatic gluconeogenesis.
• Activates genes associated with fatty acid metabolism and
lipogenesis in adipose >>> resulting in insulin sensitizing
action.

• I M P R OV E S G LYC E M I C C O N T R O L a n d
PROMO TES LONG TERM EFFECTS OF INSULIN

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 24
PART 3
 Role of THIAZOLIDINEDIONES AS OHA drug
( PPAR √ AGONISTS)
Examples : Rosiglitazone, Pioglitazone

• Lowers Serum TG level and elevates HDL Cholesterol

level. ( Inconsistent)
• Orally well tolerated – edema, weight gain, head ache ,
Myaglia and mild anemia.
• Rarely Hypoglycemia and hepatic dysfunction.
• Some times CVS adverse effect .
• Indicated for NIDDM and not for IDDM. And
primarily used to supplement SU / BG in case of insulin
resistance. Some times to supplement Insulin ,
sometimes alone along with diet and exercise.
INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -
7th semester -2012-13 25
PART 3
 GLIPTINS
( Dipeptidyl peptidase -4 / DPP-IV Inhibitors )

• Gliptins have unique way of improving insulin secretion from β

cells in response to elevating blood glucose levels, simultaneously
reduce glucagon output from α cells of pancreas.

• Examples : VIDAGLIPTIN, SITAGLIPTIN, ALOGLIPTIN

• Also referred to as DPP –IV Inhibitors, since inhibits the function of

Dipeptidyl peptidase, an enzyme that metabolizes Glucagon like
peptide ( GLP -1).

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 26
PART 3
 NON –DIABETIC – WHEN EATS – EATING TRIGGERS BRAIN TO SEND SIGNALS TO THE GUT,
RESULTING IN
RELEASE OF GLUCAGON –LIKE PEPTIDE ( GLP -1)) – DEGRADED ( LATER ) BY DPP-IV ENZYME
[ INCRETIN EFFECT]

THIS AFFECTS PA N C R E A T I C BETA CELL

FUNCTION
ONE OF THEM BEING STIMULATION OF INSULIN
REGULATES GLUCOSE HOMEOSTASIS IN THE POST
SYNTHESIS AND INHIBITION OF GLUCAGON
PRANDIAL STATE BY SEVERAL MECHANISMS
SECRETION.

DIABETICS have LESSER AND LESSER INCRETIN EFFECT – reduced GLP-1 Release >> therefore,
lower insulin secretion >>>> inadequate glucose metabolism

THIS TRANSLATES INTO ENHANCED

GLIPTINS ARE DDP-IV INHIBITORS INCRETIN EFFECT.
INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -
7th semester -2012-13 27
PART 3
 Gliptins ENHANCES AND PROLONG THE PHYSIOLOGICAL ACTIONS OF
INCRETIN hormones by competitively antagonizing DPP –IV
Enzymes .

It means Use of Gliptins by a diabetic –resulting in

1. Improvement in the glucose tolerance.
2. Improvement in insulin secretion.
3. Improvement of beta cell function.
4. Increasing hepatic and peripheral insulin
sensitivity

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 28
PART 3
 Short term clinical trials show that Gliptins causes modest
reduction in glycosylated hemoglobin§ , when used as
monotherapy or as combination therapy ( + Metformin,
PPAR antagonists, SU, Insulin ) of around 0.7 to 1% .
Appears to be potent when the base line glycated Hb
level is higher.

In general well tolerated and taken orally, once a day.

Useful in treating Diabetic patients with NIDDM, as

monotherapy / combination therapy.

§ average BG level of 3 months – a GOLD Standard to assess control of BG

level in a diabetic patient.

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 29
PART 3
 ALPHA GLUCOSIDASE INHIBITOR as oral Antidiabetic drug
• ACARBOSE – a complex oligosaccharide which REVERSIBLY
INHIBITS α glucosidases- the final enzymes in the digestion of
carbohydrates in the brush border epithelium of small intestine.
• It means , Acarbose- slows down digestion and decreases
digestion and absorption of poly saccharide and sucrose – (That
is) post prandial glycemia is reduced without increasing insulin
level.
• Regular use is associated with reducing plasma TG levels, Body
weight and glycosylated hemoglobin.
• Also a mild antihyperglycemic and not hypoglycemic.
• Used as adjuvant to diet in obese diabetics.

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 30
PART 3
 DRUGS FOR DIABETES

• INSULIN : [RAPID ]EFFECTIVELY REDUCES ELEVATED BLOOD

GLUCOSE LEVEL IN A DIABETIC SUBJECT. [INTERMEDIATE effects ]
[LONG-TERM ] – [ FOR IDDM and also NIDDM]
• BIGUANIDES : REDUCES ELEVATED GLUCOSE LEVEL , PROPER
STORAGE OF GLUCOSE IN STORAGE ORGANS AND SHALL NOT
ALLOW NEW GLUCOSE PRODUCTION / OUTPUT FROM LIVER) .
• SU : HELPS INSULIN RELEASE AND RESTORES IMPROVED POST
PRANDIAL GLYCEMIC CONTROL (POSSIBLY REDUCING GLYCOGEN
SECRETION.
• MEGLITINIDE ANALOGUES : INDUCES RAPID ONSET SHORT TERM INSULIN
RELEASE.
• PPAR √ AGONISTS: IMPROVES GLYCEMIC CONTROL AND
PROMOTES LONG TERM EFFECTS OF INSULIN .
• GLIPTINS HAVE UNIQUE WAY OF IMPROVING INSULIN
SECRETION FROM Β CELLS IN RESPONSE TO ELEVATING
BLOOD GLUCOSE LEVELS, SIMULTANEOUSLY REDUCE
GLUCAGON OUTPUT FROM Α CELLS OF PANCREAS.

INSULIN AND ORAL HYPOGLYCAEMIC DRUGS -

7th semester -2012-13 31
PART 3