1. 1 Chapter 34 Insulin & Oral Antidiabetic Drugs Diabetes mellitus Definition: a syndrome of disordered metabolism due to a combination of hereditary and environmental causes.hereditary Classification: Type 1: Lack of insulin. Type 2: Cells resistance to insulin Signs & symptoms : Very thirsty Feeling tired Using the toilet often to urinate Constant hunger High level of glucose in urine & in fasting blood

2. 2 Harms (complications) ▲ Acute Diabetic ketoacidosis (DKA) Nonketotic hyperosmolar coma ▲ Chronic Microvascular disease: impotence & poor wound healing Atherosclerosis : Strokes, coronary heart disease Renal failure, retinal damage, nerve damageRenal failureretinal damagenerve damage Infective disease: Tuberculosis

3. 3 Treatment Type 1: Insulin must be injected or inhaled Type 2: Food control, exercise, medicines (1) agents which increase insulin secretion; (2) agents which increase the sensitivity of target organs to insulin; (3) agents which decrease glucose absorption (4) Insulin needed for patients with serious complications or an emergency.

4. 4 Section 1 Insulin ● Chemistry: 51 aa arranged in two chains (A & B) linked by disulfide bridges. ● Secretion: By βcells in pancreatic islet. ● Degradation: Liver & kidney Endogenous: Liver (60 %) & kidney (35 %-40 %) Exogenous: Liver (35 %-40 %) & kidney (60 %) ● T1/2 in plasma: 3-5 min

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6. 6 ● Physiological & pharmacological actions 1.Sugar metabolism: Stimulates glucose uptake & use by cells; inhibits gluconeogenesis → blood sugar ↓ 2. Fatty metabolism: Improves fatty acid transportation & fat anabolism; inhibits fat catabolism & fatty acid and acetone body generation 3. Protein metabolism: Improves aa transportation & protein anabolism; inhibits protein catabolism & aa utilization in liver

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8. 8 ● Physiological & pharmacological actions 4. Potassium : Stimulates K + entering cells→blood K + ↓ 5. Long-term action: Improves or inhibits the synthesis of some enzymes. ● Mechanism of its action ＊ Insulin receptor in cell membrane mediates the effect; ＊ Insulin receptor is consisted by 2αsubunits, which constitutes the recognition site, and 2β subunits, which contains a tyrosine kinase

9. 9 Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1) which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6).plasma membraneglycogenglycolysisfatty acid

10. 10 ● Sources of exogenous insulin ＊ Bovine & porcine insulin ＊ Human insulin by replacement of porcine insulin 30- alanine in B chain by threonine ＊ Recombinant human insulin by Escherichia coli Clinical use 1.Diabetes mellitus ＊ The only effective drug for type 1 diabetes ＊ The following situations of type 2 diabetes (1) Not effectively controlled by food limitation & oral antidiabetic drugs;

11. 11 (2) Accompanies DKA & nonketotic hyperosmolar hyperglycemia coma; (3) Accompanies serious infection, hyperpyrexia, injury, gestation and consumptive diseases. 2. Others ＊ Hyperkalemia ＊ A component of GIK solution which is for limiting myocardial infarction & arrhythmias

12. 12 ● Adverse reactions 1.Insulin allergy: itching, redness, swelling, anaphylaxis shock 2.Insulin resistance 3.Hypoglycemia: nausea, hungry, tachycardia, sweating, and tremulousness. ＊ First aids needed while convulsions & coma happens 4. Lipodystrophy at injection sites: atrophy

13. 13 DurationInsulinPath Times on action (h) Given time startpeakduration ShortRegular i.vSt!0.52 Cito! ( (DKA and etc.). i.h0.5~12~36~8 0.5 h, a.c., t.i.d. or q.i.d. Medium Isophane Isophanei.h2~48~1218~24 1 h, a.c., q.d. or b.i.d. Globin zinc i.h2~46~1012~18 Long Protamine zinc i.h3~6 16~1 8 24~36 1 h, a.c., q.d. Insulin preparations and administration

14. 14 Section 2 Oral Antidiabetic Drugs ● Classification Sulfonylureas Thiazolidinediones Biguanides α-glucosidase inhibitors Meglitinides

15. 15 І. Sulfonylureas Representative Drugs Representative Drugs 1st generation: 1st generation: tolbutamide chlorpropamide tolazamide tolbutamide chlorpropamide tolazamide 2nd generation: 2nd generation: glybenclamide glyburide glybenclamide glyburide glipizide glymepride glipizide glymepride 3rd generation: 3rd generation: glyclazipe glyclazipe

16. 16 Pharmacological effects Pharmacological effects 1. Hypoglycemic effect 1. Hypoglycemic effect 2. Antidiuretic effect 2. Antidiuretic effect chlorpropamide & glybenclamide chlorpropamide & glybenclamide 3. Antiplatelete-aggregation effect 3. Antiplatelete-aggregation effect glyclazipe glyclazipe

17. 17 Hypoglycemic mechanism Hypoglycemic mechanism 1. Rapid mechanism: stimulation of insulin secretion Sulfonylurea receptor in β-cell membrane activated ATP-sensitive K + -channel inhibited Cellular membrane depolarized Ca 2+ entry via voltage-dependent Ca 2+ channel Insulin release mechanism 2. Long term profit involved mechanism ① Inhibition of glucagon secretion by pancreas α cells; ② Ameliorating insulin resistance ③ ③ Increase insulin receptor number & the affinity to insulin

18. 18 Clinical use Clinical use 1. Type 2 diabetes mellitus 1. Type 2 diabetes mellitus 2. Diabetes insipidus: chlorpropamide 2. Diabetes insipidus: chlorpropamide Adverse reactions Adverse reactions 1. Gastrointestinal disorders 1. Gastrointestinal disorders 2. Allergy 2. Allergy 3. Hypoglycemia 3. Hypoglycemia Chlorpropamide forbidden for ageds & patients with functional disorder in liver or kidney. Chlorpropamide forbidden for ageds & patients with functional disorder in liver or kidney. 4. Granulocytopenia, cholestasis & hepatic injury 4. Granulocytopenia, cholestasis & hepatic injury

19. 19 Ⅱ. Ⅱ. Thiazolidinediones (Tzds) Representative Drugs Representative Drugs rosiglitazone troglitazone pioglitazone ciglitazone Pharmacological effects Pharmacological effects ● Improving function of pancreas cells ● Improving function of pancreas β cells ● Ameliorating insulin resistance ● Ameliorating insulin resistance ● Ameliorating fat metabolic disorder ● Ameliorating fat metabolic disorder ● Preventing and treating type 2 diabetes mellitus and their cardiovascular complications ● Preventing and treating type 2 diabetes mellitus and their cardiovascular complications

20. 20 Mechanism (possible) Mechanism (possible) Peroxisome proliferator-activated receptor-γ(PPAR-γ) activated Nuclear genes involved in glucose & lipid metabolism and adipocyte differentiation activated Clinical use Clinical use Insulin resistance & type 2 diabetes mellitus Insulin resistance & type 2 diabetes mellitus Adverse reactions Adverse reactions occasionally induces hepatic injury Troglitazone occasionally induces hepatic injury

21. 21 Ⅲ. Biguanides Representative Drugs Representative Drugs phenformin metformin Key points Key points ● insulin secretion unchanged, and appetite unchanged ● insulin secretion unchanged, and appetite unchanged ● Hypoglycemic mechanism remains unclear ● Hypoglycemic mechanism remains unclear ● Use for obese diabetes and type 2 diabetes ● Use for obese diabetes and type 2 diabetes ● Alone or co-administered with insulin or ● Alone or co-administered with insulin or Sulfonylureas ● Metformin also used to treat atherosclerosis for down- regulation of LDL& VLDL ● Metformin also used to treat atherosclerosis for down- regulation of LDL& VLDL ● Ketonemia & lactic acidosis are major adverse reactions ● Ketonemia & lactic acidosis are major adverse reactions

22. 22 Ⅳ. α-glucosidase inhibitors Representative Drugs Representative Drugs acarbose voglibose miglitol Key points Key points ● To inhibit digestion of starch & disaccharides via competitively inhibiting intestinal ● To inhibit digestion of starch & disaccharides via competitively inhibiting intestinal α-glucosidase (sucrase, maltase, glycoamylase, dextranase) ● Used alone or together with to treat type 2 diabetes ● Used alone or together with sulfonylureas to treat type 2 diabetes ● Main adverse reaction: flatulence, diarrhea, bellyache. ● Patients with inflammatory bowel disease & kidney impaired forbidden.

23. 23 Ⅴ. Meglitinides Representative Drugs Representative Drugs Repaglinide Key point Key point ● To increase insulin release by inhibiting ● To increase insulin release by inhibiting ATP- sensitive K + -channel ● Unlike insulin release ● Unlike sulfonylureas, they have no direct effect on insulin release ● Used alone or together with to treat type 2 diabetes ● Used alone or together with biguanides to treat type 2 diabetes ● Carefully used for patients with kidney or liver impaired. ● Carefully used for patients with kidney or liver impaired.

24. 24 Michigan lake 2007.5 Thank you!