- Insulin is used to treat diabetes by replicating the body's natural insulin secretion. Various insulin preparations have different onset and duration of action. Oral antidiabetic drugs include sulfonylureas, meglitinides, biguanides, thiazolidinediones, DPP-4 inhibitors, GLP-1 analogs, and alpha-glucosidase inhibitors which lower blood glucose through different mechanisms such as stimulating insulin secretion or increasing insulin sensitivity. Choice of treatment depends on the type of diabetes, severity of hyperglycemia, and individual patient factors. All drugs have potential adverse effects like hypoglycemia that require monitoring.

1. Drugs forDiabetesMellitus Internal Medicine 2010

3. cells – insulin

4. cells – SomatostatinPP cells – pancreatic polypeptide

5. Drugs used in Diabetes Mellitus Insulin per orem Rapid Short-Acting Insulin Secretagogue Biguanides Intermediate Acting Insulin Synthesizer Slow, long acting  Glucosidase inhibitor

6. Insulin duplicate normal physiologic secretion of insulin type 2 DM use during times of illness or stress to maintain glycemic control patients who are unable to maintain adequate control exact time course of each insulin will depend on each particular preparation and site of injection

7. Effects of Insulin Liver Increases storage of glucose as glycogen in liver Decrease protein catabolism Muscle Stimulates glycogen synthesis and protein synthesis Adipose Tissue Facilitates triglyceride storage by: activating plasma lipoprotein lipase Increasing glucose transport into cells via GLUT 4 transporters Reducing intracellular lipolysis

8. Normal Plasma Glucose and Insulin Profile

9. Human Insulin 1982: "recombinant DNA" into lab-cultivated bacteria or yeast very short half life insulin preparations are formulated to release insulin slowly into circulation recombinant human insulin has replaced animal-derived insulin, such as pork and beef insulin insulin analogs structure differs slightly from human insulin to change onset and peak of action

10. Insulin and Insulin Analogs

11. Short and Rapid-Acting Insulin act as mealtime insulin administer before meals to mimic physiologic increases of insulin which occurs after meals ASPART, GLULISINE, LISPRO more rapid onset of action and shorter duration of action than regular insulin premeal control before the next meal may be difficult due to short duration of action if used alone

12. Crystalline zinc (Regular) Insulin as a mealtime insulin, its use may be limited because onset is not so rapid to meet the quick, unpredictable increase in postprandial blood glucose considered basal insulin can be given IV or SQ given 30 to 45 minutes ac

13. Intermediate and Long-Acting Insulins given SQ only intend to mimic normal physiologic basal insulin secretion usually given 1-2 times/day LENTE Intermediate-Acting Insuline ULTRALENTE, DETEMIR, GLARGINE Basal/ Long-Acting Insulins

14. Combinations short- and long-acting combinations are available commercially or may be combined in a single syringe by the patient 30% R/ 70% NPH 50/50 20/80

19. Different Insulin Regimen 2 daily injections Multiple Daily Insulin Injection Continuous Subcutaneous Insulin Infusion Adverse Reactions Hypersensitivity reactions Hypoglycemia Lipoatrophy or lipohyperthrophy

20. Oral Antidiabetic Agents sensitizers Biguanides: Metformin TZDs (PPAR): Pioglitazone, Rivoglitazone, Rosiglitazone Dual PPAR agonist: Muraglitazar

21. Oral Antidiabetic Agents secretagogues K+ ATP sulfonylureas 1st gen: Gliclazide 2nd gen: Glibenclamide, Glipizide 3rd gen: Glimepiride meglitinides: nateglinide, repaglinide GLP-1 analogs: exenatide DPP-4 inhibitors: saxagliptin, sitaglipitin

22. Oral Antidiabetic Agents α –glucosidase inhibitors acarbose, voglibose, miglitol amylin pramlintide SLGT2 inhibitors dapaglifozine others benfluorex, tolrestat

24. Sulfonylureas Mechanism of Action Stimulate insulin release from pancreatic β cells Decrease hepatic clearance of insulin Primarily act by binding to the SUR subunit of the ATP-sensitive potassium (KATP) channel and inducing channel closure

25. Sulfonylureas Absorption, Fate, and Excretion absorbed from git decreased absorption with food and hyperglycemia 90 to 99% protein bound in plasma metabolize in liver metabolites excreted in kidney 2nd gen half life short (3 to 5h) long duration of action (12 to 24h)

26. Sulfonylureas 1st GENERATION Chlorpropamide/ Tolazamide/ Tolbutamide: once daily dosing, administer with breakfast 2nd GENERATION Glibenclamide/ Gliclazide/ Glimepiride: once daily, administer with breakfast Glipizide: 15-30 min before breakfast

27. Sulfonylureas Adverse Reactions: hypoglycemia, allergic reactions. GI upset use with caution in patients with hepatic or renal failure should not be used in DKA, major surgery, severe infections. stress or trauma, sulfa allergy disulfiram reaction may occur with chlorpropamide and alcohol

29. Meglitinides REPAGLINIDE initial dose: 0.5 mg PO prior to meals; max: 16mg/day MOA: derivative of benzoic acid; stimulate insulin release by closing ATP-dependent K channels in pancreatic β cells absorbed rapidly from GIT; peak blood levels within 1 hour Metabolize 90% in liver 10% in kidney

30. Meglitinides NATEGLINIDE 120mg PO 1-30min prior to main meals MOA: from D-phenylalanine; stimulate insulin release by closing ATP-dependent K channels in pancreatic β cells Reduce postprandial hypoglycemia Metabolize: 84% IN LIVER 16% IN KIDNEY

31. Biguanides METFORMIN absorbed mainly in small intestine stable but does not bind with protein excreted unchanged in urine half life – 2 hours MOA: decrease hepatic glucose production -  gluconeogenesis increase insulin action in muscle and fat

32. Biguanides METFORMIN CONTRAINDICATIONS: renal impairment, hepatic disease, past history of lactic acidosis, cardiac failure, chronic hypoxic lung disease Withheld for 48 hours after giving contrast media – to insure N kidney ADVERSE REACTIONS: lactic acidosis, diarrhea, GI discomfort, nausea, metallic taste, anorexia uptitrate slowly

33. Thiazolidinediones (TZDs) selective agonist for nuclear peroxisomeproliferator-activated receptor-gamma (PPAR) requires insulin  insulin resistance in peripheral tissue

34. Thiazolidinediones (TZDs) ROSIGLITAZONE AND PIOGLITAZONE OD dose Absorbed within 2 hours Max effect observed in 6 to 12 weeks Metabolized in Liver Cytochrome P450 enzymes Monitor liver enzymes regularly May be given to patients with renal insufficiency AE: anemia, weight gain, edema C/I: Heart Failure

35.  Glucosidase Inhibitor  GI absorption of starch, dextrin, disaccharide by inhibiting the action of intestinal brush border ( glucosidase) slow carbohydrate absorption

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