Insulin

INSULIN
Insulin is a two chain polypeptide having 51 amino acids and MW about 6000. The A-chain has
21 while B-chain has 30 amino acids.
Regulation of insulin secretion
Secretion of insulin from β cells is regulated by chemical, hormonal and neural mechanisms.
ACTIONS OF INSULIN
Insulin is a major anabolic hormone: promotes synthesis of gylcogen, lipids and protein. The
actions of insulin and the results of its deficiency can be summarized as:
1. Insulin facilitates glucose transport across cell membrane; skeletal muscle and fat are highly
sensitive. The availability of glucose intracellularly is the limiting factor for its utilization in
these and some other tissues. However, glucose entry in liver, brain, RBC, WBC and renal
medullary cells is largely independent of insulin.
2. Insulin facilitates glycogen synthesis from glucose in liver, muscle and fat by stimulating the
enzyme glycogen synthase. It also inhibits glycogen degrading enzyme phosphorylase →
decreased glycogenolysis in liver.
3. Insulin inhibits gluconeogenesis (from protein, FFA and glycerol) in liver by gene mediated
decreased synthesis of phosphoenol pyruvate carboxykinase.
4. Insulin inhibits lipolysis in adipose tissue and favours triglyceride synthesis.
5. Insulin enhances transcription of vascular endothelial lipoprotein lipase and thus increases
clearance of VLDL and chylomicrons.
6. Insulin facilitates AA entry and their synthesis into proteins, as well as inhibits protein
breakdown in muscle and most other cells. Insulin deficiency leads to protein breakdown → AAs
are released in blood → taken up by liver and converted to pyruvate, glucose and urea. The
excess urea produced is excreted in urine resulting in negative nitrogen balance. Thus,
catabolism takes the upper hand over anabolism in the diabetic state.
Actions of insulin producing hypoglycaemia
Liver Muscle Adipose tissue

 Increases glucose  Increase glucose  Increases glucose
uptake and glycogen uptake and utilization uptake as and storage
synthesis  Inhibits proteolysis and as fat and glycogen
 Inhibits glycogenolysis release of amino acids,  Inhibits lipolysis, and
and glucose output pyruvate, lactate into release of FFA +
 Inhibits blood which form the Glycerol
gluconeogenesis from substrate for which form substrate
protein, pyruvate, Free gluconeogenesis in the for gluconeogenesis in
fatty acids liver liver
 (FFA) and glycerol
MECHANISM OF ACTION
The insulin receptor
A specific transmembrane tyrosine – kinase linked receptor located in cell membranes of most
tissues
Activation of this receptor, triggers the phosphorylation of a tyrosine kinase enzyme which in
turn leads to the following two cascade pathways
1.Insulin receptor substrate -1(IRS-1) pathway: Leading to;
a)Regulation of proliferation and differentiation of several cell types
b)Regulation of DNA synthesis
2.Insulin receptor substrate -2 (IRS-2) pathway: Leading to;
a) Increased glucose uptake by the lipid and muscle cells

b) Increased glycogen formation
c) Regulation of gene transcription
TYPES OF INSULIN PREPARATIONS
Regular (soluble) insulin
It is a buffered neutral pH solution of unmodified insulin stabilized by a small amount of zinc.
Lente insulin (Insulin-zinc suspension):
Two types of insulin-zinc suspensions have been produced. The one with large particles is
crystalline and practically insoluble in water (ultralente). It is long-acting. The other has smaller
particles and is amorphous (semilente), is shortacting. Their 7:3 ratio mixture is called ‘Lente
insulin’ and is intermediate-acting.
Isophane (Neutral Protamine Hagedorn or NPH) insulin:
Protamine is added in a quantity just sufficient to complex all insulin molecules; neither of the
two is present in free form and pH is neutral. On s.c. injection, the complex dissociates slowly to
yield an intermediate duration of action. It is mostly combined with regular insulin (70:30 or
50:50) and injected s.c. twice daily before breakfast and before dinner (splitmixed regimen).
Insulin analogues
Using recombinant DNA technology, analogues of insulin have been produced with modified
pharmacokinetics on s.c. injection, but similar pharmacodynamic effects. Greater stability and
consistency are the other advantages.
Insulin lispro
Insulin aspart
Insulin glargine
DRUG INTERACTIONS
1. β adrenergic blockers prolong hypoglycaemia by inhibiting compensatory mechanisms
operating through β2 receptors (β1 selective blockers are less liable). Warning signs of
hypoglycaemia like palpitation, tremor and anxiety are masked. Rise in BP can occur due to
unopposed α action of released Adr.
2. Thiazides, furosemide, corticosteroids, oral contraceptives, salbutamol, nifedipine tend to raise

blood sugar and reduce effectiveness of insulin.
3. Acute ingestion of alcohol can precipitate hypoglycaemia by depleting hepatic glycogen.
4. Lithium, high dose aspirin and theophylline may also accentuate hypoglycaemia by enhancing
insulin secretion and peripheral glucose utilization.
Table below shows various types of insulin preparations and insulin analogues
Type Appear Onset Peak Duratio Can be mixed with

ance (hr) (hr) n (hr)
Rapid acting
Insulin lispro clear 0.2 - 0.3 1 – 1.5 3-5 Regular, NPH
Insulin aspart clear 0.2 - 0.3 1 – 1.5 3-5 Regular, NPH
Insulin glulisin clear 0.2 – 0.4 1-2 3-5 Regular, NPH
Short acting
Regular(soluble)insulin clear 0.5 – 1.0 2-3 6-8 All preparations except
insulin glargine/detemir
Intermediate acting
Insulin zinc suspension cloudy 1-2 8 – 10 20 – 24 Regular
or Lente
Neutral Protamine cloudy 1–2 8 - 10 20 - 24 Regular
Hegedorn (NPH) or
isophane insulin
Long acting
Insulin glargine clear 2–4 - 24 None
Insulin detemir clear 1-4 - 20 - 24 None
USES OF INSULIN
Diabetes mellitus
The purpose of therapy in diabetes mellitus is to restore metabolism to normal, avoid symptoms
due to hyperglycaemia and glucosuria, prevent short-term complications (infection, ketoacidosis,
etc.) and long-term sequelae (cardiovascular, retinal, neurological, renal, etc.)
Diabetic ketoacidosis (Diabetic coma)
Ketoacidosis of different grades generally occurs in insulin dependent diabetics. It is infrequent

in type 2 DM. The most common precipitating cause is infection; others are trauma, stroke,
pancreatitis, stressful conditions and inadequate doses of insulin.
Hyperosmolar (nonketotic hyperglycaemic) coma.
This usually occurs in elderly type 2 patients. Its cause is obscure, but appears to be precipitated
by the same factors as ketoacidosis, especially those resulting in dehydration. Uncontrolled
glycosuria of DM produces diuresis resulting in dehydration and haemoconcentration over
several days → urine output is finally reduced and glucose accumulates in blood rapidly to > 800
mg/dl, plasma osmolarity is > 350 mOsm/ L → coma, and death can occur if not vigorously
treated.
Insulin resistance
 Insulin resistance refers to suboptimal response of body tissues, especially liver, skeletal
muscle and fat to physiological amounts of insulin. As already stated, relative insulin
resistance is integral to type 2 DM.
 Advanced age, obesity and sedentary life-style promote insulin resistance.
 Insulin sensitivity has been found to decline with age. Glucose entry into muscle and
liver in response to insulin is deficient in individuals with large stores of body fat. Bigger
adipocytes have fewer insulin receptors.
 Exercise increases insulin sensitivity and lack of it contributes to insulin resistance.
 Pregnancy and oral contraceptives often induce relatively low grade and reversible
insulin resistance. Other rare causes are—acromegaly, Cushing’s syndrome,
pheochromocytoma, lipo-atrophic diabetes mellitus. Hypertension is often accompanied
with relative insulin resistance as part of metabolic syndrome.
Acute insulin resistance
This form of insulin resistance develops rapidly and is usually a short term problem. Causes
are— (a) Infection, trauma, surgery, emotional stress induce release of corticosteroids and other
hyperglycaemic hormones which oppose insulin action. (b) Ketoacidosis—ketone bodies and
FFA inhibit glucose uptake by brain and muscle. Also insulin binding may increase resulting in
insulin resistance. Treatment is to overcome the precipitating cause and to give high doses of
regular insulin. The insulin requirement comes back to normal once the condition has been
controlled.
Newer insulin delivery devices
A number of innovations have been made to improve ease and accuracy of insulin administration
as well as to achieve tight glycaemia control.
These are:
1. Insulin syringes
2. Pen devices
3. Insulin pumps
4. Implantable pumps

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INSULIN

Regulation of insulin secretion

4. Insulin inhibits lipolysis in adipose tissue and favours triglyceride synthesis.

Liver Muscle Adipose tissue

The insulin receptor

1.Insulin receptor substrate -1(IRS-1) pathway: Leading to;

a)Regulation of proliferation and differentiation of several cell types

b)Regulation of DNA synthesis

2.Insulin receptor substrate -2 (IRS-2) pathway: Leading to;

a) Increased glucose uptake by the lipid and muscle cells

c) Regulation of gene transcription

TYPES OF INSULIN PREPARATIONS

Regular (soluble) insulin

It is a buffered neutral pH solution of unmodified insulin stabilized by a small amount of zinc.

Lente insulin (Insulin-zinc suspension):

Isophane (Neutral Protamine Hagedorn or NPH) insulin:

2. Thiazides, furosemide, corticosteroids, oral contraceptives, salbutamol, nifedipine tend to raise

3. Acute ingestion of alcohol can precipitate hypoglycaemia by depleting hepatic glycogen.

Type Appear Onset Peak Duratio Can be mixed with

Diabetic ketoacidosis (Diabetic coma)

Ketoacidosis of different grades generally occurs in insulin dependent diabetics. It is infrequent

Hyperosmolar (nonketotic hyperglycaemic) coma.

Acute insulin resistance

Newer insulin delivery devices

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