PANCREATIC HORMONES, ANTIDIABETIC AGENTS: INSULIN AND ORAL ANTIDIABETICS- handout Iwona Zaporowska-Stachowiak

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1 PANCREATIC HORMONES, ANTIDIABETIC AGENTS: INSULIN AND ORAL ANTIDIABETICS- handout Iwona Zaporowska-Stachowiak The endocrine pancreas (the islets of Langerhans) consists of four types of endocrine cells: - A (alpha) cells, producing glucagon, proglucagon - B (beta) cells, producing insulin (the most numerous cells), C-peptide, proinsulin, amylin - D (delta) cells, producing somatostatin - G cells, producing gastrin - F cells (PP cells), producing pancreatic polypeptide (PP) Diabetes mellitus: the most common pancreatic disease a deficiency of insulin production or its effect treated with several formulation of insulin treated with seven types of oral antidiabetic agents DM type 1 selective beta-cell destruction severe/absolute insulin deficiency immune (more common) or idiopathic causes onset at any age, most cases < 30 year of age All ethnic groups, most cases in northern Europe and Sardinia 10-15% of patients has positive family history treatment: insulin replacement DM type 2 The resistance of tissues to insulin action/ relative deficiency in insulin secretion (mild-severe disturbance) the release of insulin is inadequate to overcome the tissue resistance disturbances in glucose and lipid metabolism glucose in blood, free fatty acid flux, TG, HDL DM type 3 pancreatectomy pancreatitis nonpancreatic diseases drugs side effect (i.e., glucocorticoids) Placenta, placental hormones insulin resistance

2 Gestational diabetes (GDM): abnormalities in glucose levels noted for the first time during pregnancy 4% of all pregnancies (USA) DM type 4 Placenta, placental hormones insulin resistance Gestational diabetes (GDM): abnormalities in glucose levels noted for the first time during pregnancy 4% of all pregnancies (USA) Drugs used for the treatment of diabetes mellitus INSULINS -Rapid- acting: lispro, aspart, glulisine, exubera (powder for inhallation) -Short-acting: regular soluble (crystalline) -Intermediate acting: NPH, lente -Slow, long acting: ultralente, protamine- zinc, glargine, detemir ORAL AGENTS I. Insulin secretogogues 1. Sulfonylurea 2. Meglitinide 3. D- phenylalanine derivatives 4. Biguanides II. Biguanides III.Thiazolidynediones IV.Alpha-glucosidase inhibitors Other- new drugs V. Incretin mimetic drugs VI.Amylin analog Insulins Indications type 1 diabetes mellitus type 2 diabetes mellitus not controlled adequately by the diet and/or oral hypoglycemic agents postpancreatectomy diabetes gestational diabetes emergency (i.e. hyperglycemic, nonketotic coma, perioperative management of diabetic patients) iatrogenic DM (induced by GCs)

3 Mode of administration i.m., i.v. s.c. (long-term treatment)- differs from physiological secretion of the hormone Unitage insulin doses are expressed in units one unit of insulin equals the amount required to reduce the concentration of blood glucose in a fasting rabbit to 45 mg/dl the current international standard is a mixture of bovine and porcine insulins and contains 24 units/mg homogenous preparations of human insulin contain between units/mg (28,7 units/mg) almost all commercial preparations of insulin are supplied at a concentration of 100 units/ml, which is about 3,6 mg insulin/ml (0,6 mm) insulin is also available in solution of 500 units/ml for resistant to hormone patients Insulin preparations In the early 1980s, human insulin produced by recombinant-dna technology (rh insulin) became available for the treatment of diabetes. protein engineering variant forms of insulin: insulin analogues- modified amino-acid sequences improved pharmacokinetic properties rapid-acting forms for use at meal times and long-acting insulins for basal requirements. the available insulin forms provide four rates of onset and durations of effects: 1. ultra-rapid onset and very short action = rapid-acting (i. analogs): - i. aspart - i. glulisine - i. lispro 2. rapid onset with short action = short-acting (humanized i.) - i. neutral 3. intermediate onset and duration of action = intermediate-acting - i. isophane (NPH) 4. slow onset with long action = long-acting - i. detemir - i. glargine Variability of insulin absorption

4 Rapid-acting insulins 5% Regular insulin 25% Long-acting analogs 25% Intermediate insulin 50%

5

6 Insulin- unwanted effects Hypoglycemia Insulin-induced neuroglycopenia Fluid retention generalized edema Increased body weight Lipodydsrophy - Lipoatrophy - Lipohypertrophy Neoplasms (breast, colon) Treatment regimens with insulin preparation(s) Conventional insulin therapy Intensive insulin therapy Insulin constant infusion (pump) Oral antidiabetic preparations Insulin secretagogues hypoglycaemic - Sulfonylurea - Meglitinide- repaglinide - D- phenylalanine derivative- nateglinide - Incretin mimetics (GLP-agonists)

7 - Incretin enhancers (DPP-4 inhibitors) - Amylin analogs Drugs that decrease hepatic glucose production/decrease insulin resistance/decrease glucose absorption euglycaemic - Biguanides - Thiazolidynediones - Alpha- glucosidase inhibitors - Bromocriptine - Amylin analog- Pramlintide - SGLT2-inhibitors - Selective free fatty acid receptor 1 (FFAR1)/GPR40 agonist Sulfonylureas Older agents (the first generation) (extensively bound to serum proteins): Tolbutamide Chlorpropamide (long duration of action) Tolazamide Acetohexamide Glipolamide The second-generation sulfonylureas: Glyburide (great potency) Glipizide (great potency) Glimepiride Gliclazide Gliquidone- 95% excreted with the bile, may be used in renal insufficiency (when creatinine< 3 mg/dl) Glybonuride The third generation Glimepiride SU- mechanism of action 1. Stimulation of insulin release 2. blood glucagon level 3. Potentiation of insulin action on target tissues ( binding of insulin to its receptors, nr of insulin rec., stimulation of glycogen synt. in skeletal muscles, stimulation of glucose transporters synth.) 4. Inhibition of hepatic gluconeogenesis

8 SU- unwanted effcts: hypoglycemia allergic reactions: generalized hypersensitivity reactions, rashes, hemolytic anemias GI: nausea, vomiting, cholestatic jaundice hematotoxicity; agranulocytosis, aplastic anemias antithyroid action teratogenic effect alcohol- induced flush similar to that caused by disulfiram (chlorpropamide, especially) hyponatremia (by potentiating the effect of vasopressin, chlorpropamide, especially) Biguanides- mechanism of action reduce hepatic gluconeogenesis increase insulin action in muscle and fat; increased glucose utilization in the tissues increase anaerobic glycolysis ATP production tissue metabolism changed removal of glucose from the blood stimulate glycolysis in peripheral tissues reduce of glucose absorption from the gastrointestinal tract reduce plasma glucagon levels cholesterol and TG in the blood plasminogen activator activity vasodilatatory effect cardioprotective effect weight loss

9 Biguanides- unwanted effects gastrointestinal distress (nausea, diarrhea, abdominal discomfort, metallic taste, anorexia- in up to 20% of patients) lactic acidosis (especially in patients with liver or renal disease, alcoholism, conditions that predispose to tissue anoxia- e.g., chronic cardiopulmonary dysfunction inhibition of vit. B12 and folate gut absorption

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