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  1. 1. INSULIN By Arijit Chakraborty M-Pharm (Pharmacology) 09/10/2012 1
  2. 2. 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 2
  3. 3. 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
  4. 4. 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
  5. 5. 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
  6. 6. 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 6
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  8. 8. 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, 8
  9. 9. Mechanism of action of insulin 9
  10. 10. Effect of insulin on glucose uptake and metabolism. 10
  11. 11. 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
  12. 12. 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
  13. 13. 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 13
  14. 14. Oral Hypoglycemic Drugs Classification:  Sulfonylureas  Thiazolidinediones  Biguanides  α-glucosidase inhibitors  Meglitinides 14
  15. 15. Sulfonylureas Representative Drugs: 1st generation: tolbutamide chlorpropamide tolazamide 2nd generation: glybenclamide glyburide glipizide glymepride 3rd generation: glyclazipe 15
  16. 16. Pharmacological effects: 1. Hypoglycemic effect: 2. Anti-diuretic effect: chlorpropamide & glybenclamide 3. Anti-platelete aggregation effect: glyclazipe 16
  17. 17. Hypoglycemic Mechanism Rapid 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 17
  18. 18. 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
  19. 19. 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
  20. 20. 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
  21. 21.  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
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