INSULIN

By

Arijit ChakrabortyM-Pharm (Pharmacology)

09/10/20121

Diabetes Mellitus

Diabetes mellitus is a metabolic disorder characterized by hyperglycemia, glucosourea, hyperlipaemia, negative nitrogen balance and sometimes ketonaemia.

Two major types of diabetes mellitus: i) Insulin-dependent diabetes

mellitus (IDDM). ii) Non-Insulin-dependent

diabetes mellitus (NIDDM). Various symptoms are: Feeling very thirsty and tired,

high level of glucose in urine, constant hunger etc.

2

Insulin-dependent diabetes mellitus : There is β cell destruction in pancreatic islets; majority of cases are autoimmune antibodies that destroy β cell are detectable in blood, but some are idiopathic, there are no β cell antibody are found. In all cases circulating insulin levels are low.

Noninsulin-dependent diabetes mellitus : There is no loss or moderate reduction in β cell mass, insulin in circulation is low, normal or even high, no anti-β-cell antibody is demonstrable; has a high degree of genetic predisposition, generally has a late onset.

3

Treatment

IDDM : Insulin must be injected or inhaled

NIDDM : Food control, exercise, medicines:

i) Which increase insulin secretion;

ii) Which increase the sensitivity of

target organs to insulin;

iii) Which decrease glucose absorption.

4

INSULIN Insulin was the first protein for

amino acid sequence which consists of two peptides chains (21 and 30 amino acid residues) linked by disulfide bonds.

Secretion : β-cell in pancreatic islet.

Degradation : Liver & kidney. Endogenous: Liver (60 %) &

kidney (35 %-40 %) Exogenous: Liver (35 %-40 %) &

kidney (60 %)

Half life : 3-5 min in plasma.5

Physiological & pharmacological actions

Sugar metabolism : Stimulates glucose

uptake & use by cells; inhibits gluconeogenesis

→blood sugar↓

Fatty metabolism : Improves fatty acid

transportation & fat anabolism; inhibits fat

catabolism & fatty acid,

Protein metabolism : Improves a

transportation & protein anabolism; inhibits protein

catabolism & an utilization in liver, 6

7

Physiological & pharmacological actions

Potassium : Stimulates K+ entering cells → blood

K+↓

Long-term action : Improves or inhibits the

synthesis of some enzymes.

Mechanism of action : i) Insulin receptor in cell membrane

mediates the effect;

ii) Insulin receptor is consisted by 2α-

subunits, which constitutes the recognition site, and

2β-subunits, which contains a tyrosine kinase.8

Mechanism of action of insulin

9

Effect of insulin on glucose uptake and metabolism.

10

Clinical use Diabetes mellitus : Insulin is effective in all forms of diabetes

mellitus and is a must for IDDM cases, as well as for post pancreatectomy diabetes and gestational diabetes. Many NIDDM cases can be controlled by diet, reduction in body weight and appropriate exercise.

Insulin needed by some such patients: i) Not controlled by diet and exercise

or when these are not practicable. ii) Primary or secondary failure of oral

hypoglycemic or when these drugs are not tolerated.

11

iii) Under weight patients. iv) Temporarily to tide over

infections, trauma, surgery, pregnancy. v) Any complication of diabetes, e.g.

Ketoacidosis, nonketotic hyperosmolar coma, gangrene of extremities.

Other :

i) Hyperkalemia

ii) A component of GIK solution

which is for limiting myocardial infarction &

arrhythmias.12

Adverse reaction Insulin allergy : Itching, redness,

swelling, anaphylaxis shock Hypoglycemia : Nausea, hungry, tachycardia, sweating, and tremulousness.

Insulin resistance : i) Acute : Diabetic ketoacidoisis,

Nonketotic hyperosmolar coma. ii) Chronic : Microvascular disease: impotence

& poor wound healing Atherosclerosis : Strokes,

coronary heart disease Renal failure, retinal damage,

nerve damage Infective disease: Tuberculosis

13

Oral Hypoglycemic Drugs

Classification:

Sulfonylureas

Thiazolidinediones

Biguanides

α-glucosidase inhibitors

Meglitinides

14

Sulfonylureas

Representative Drugs: 1st generation: tolbutamide chlorpropamide

tolazamide 2nd generation: glybenclamide glyburide glipizide glymepride 3rd generation: glyclazipe

15

Pharmacological effects:

1. Hypoglycemic effect:

2. Anti-diuretic effect:

chlorpropamide & glybenclamide

3. Anti-platelete aggregation effect:

glyclazipe

16

Hypoglycemic MechanismRapid mechanism: Stimulation of insulin

secretion Sulfonylurea receptor in β-cell

membrane activated

ATP-sensitive K+-channel inhibited

Cellular membrane depolarized

Ca2+ entry via voltage-dependent Ca2+ channel

Insulin release

17

Long term profit involved mechanism: Inhibition of glucagon secretion by

pancreas α cells; Ameliorating insulin resistance Increase insulin receptor number & the

affinity to insulin

18

Clinical use: 1. Type 2 diabetes mellitus 2. Diabetes insupidus, chlorpropamide

Adverse reactions: 1. Gastrointestinal disorders 2. Allergy 3. Hypoglycemia Chlorpropamide forbidden for ageds &

patients with functional disorder in liver or kidney.

4. Granulocytopenia, cholestasis & hepatic injury 1

9

Thiazolidinediones

Representative Drugs:

rosiglitazone, troglitazone, pioglitazone, ciglitazone

Pharmacological effects:

Improving function of pancreas β cells.

Ameliorating insulin resistance.

Ameliorating fat metabolic disorder.

Preventing and treating type 2 diabetes mellitus and their cardiovascular complications.

20

Mechanism (possible):Per-oxisome proliferator-activated receptor-

γ(PPAR-γ) activated

Nuclear genes involved in glucose & lipid metabolism and adipocyte differentiation activated

Clinical use: Insulin resistance & type 2 diabetes

mellitus

21

22

Thank you