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The Endocrine Pancreas 1 million islets of Langerhans Cell Types Approximate Percent of Islet Mass Secretory Products A cells (Alpha) 20 Glucagon Proglucagon B cells (Beta) 75 D cells (Delta) 3-5 Somatostatin F cells (PP cells) <2 Pancreatic polypeptide Insulin, C-peptide, proinsulin, islet amyloid polypeptide (IAPP) or amylin Different Forms of Diabetes Mellitus General – genetic and other factors not precisely defined Type 1 (Insulin-Dependent Diabetes Mellitus) Autoimmune type 1 DM type 1A) Non-autoimmune or idiopathic type 1 DM (type 1B) Type 2 (Non-insulin Dependent Diabetes Mellitus) Specific – defined gene mutations Maturity-onset diabetes of youth (MODY) MODY 1 hepatic nuclear factor 4α (HNF4A) gene mutations MODY 2 glucokinase (GCK) gene mutations MODY 3 hepatic nuclear factor 1α (TCF1) gene mutations MODY 4 insulin promoter factor 1 (IPF1) gene mutations MODY 5 hepatic nuclear factor 1β (HNF1β) gene mutations MODY 6 neurogenic differentiation 1 (NEUROD1) gene mutation MODY X unidentified gene mutation(s) Maternally inherited diabetes and deafness (MIDD) Mitochomdrial leucine tRNA gene mutations Insulin gene mutations Insulin receptor gene mutations Diabetes secondary to pancreatic disease Chronic pnacreatitis Surgery Tropical diabetes (chronic pancreatitis asst’d with nutritional and/or toxic factors) Diabetes secondary to other endocrinopathies Cushing’s disease Glucocorticoids administration Acromegaly Diabetes secondary to immune suppression Diabetes associated with genetic syndrome (Prader-Willi syndrome) Diabetes associated with drug therapy Some Drugs That Cause Hypoglycemia or Hyperglycemia Drugs with Hypoglycemic Effects: Beta-adrenergic receptor antagonists Salicylates Indomethacin Naproxen Ethanol Clofibrate ACE inhibitors Li+ Theophyllin Ca++ Bromocriptine Mebendazole Sulfonamides Sulbactam-ampicillin Tetracycline Pyridoxine Pentamidine Drugs with Hyperglycemic Effects: Epinephrine Glucocorticoids Diuretics Atypical antipsychotic HIV-1 protease inhibitors Diazoxide Beta2 adrenergic agonists Ca++ channel blockers Phenytoin Clonidine H2-receptor blockers Pentamidine Morphine Heparin Nalidixic acid Sulfinpyrazone Marijuana Nicotine Insulin: Chemistry: * a small protein with molecular weight of 5808 * contains 51 amino acids * arranged in 2 chains ( A & B ) linked by disulfide bonds/bridges * stored crystals consisting of 2 atoms of zinc & 6 molecules of insulin * contain 8mg of insulin/human pancreas (=200 units) ivity) Insulin secretion: - respond to a variety of stimuli ( glucose, mannose, leucine, arginine & vagal - Insulin Degradation: 2 main organs: liver – 60% kidney – 35-40% hydrolysis of the disulfide bonds glutathione insulin transhydrogenase (insulinase ) half-life: 3-5 minutes - Measurement of Circulating Insulin: radioimmunoassay permits detecton of insulin in picomolar quantities basal insulin values: 5-15uU/ml (30-90pmol/L) peak rise: 60-90uU/ml (360-540pmol/L) - The Insulin Receptor: Effects of Insulin on its Targets A. Action of Insulin on Glucose Transporters: Transporters Tissues GlucoseKm (Mmo/L) Function GLUT 1 All tissues, esp.red cells, brain 1-2 Basal uptake of glucose; Transport across the BBB GLUT 2 B cells of pancreas; Liver; kidney; gut 15-20 Regulation of insulin release, other aspects of glucose homeostasis GLUT 3 Brain, kidney, placenta, other tissues GLUT 4 Muscle, adipose GLUT 5 Gut, kidney < 1 Uptake into neurons, other tissues 5 Insulin-mediated uptake of glucose 1-2 Absorption of fructose B. Action of Insulin on Liver - inhibits hepatic glucose production (decreases gluconeogenesis & glycogenolysis) - stimulates hepatic glucose uptake C. Effect of Insulin on Muscle - stimulates glucose uptake - inhibits flow of gluconeogenic precursors to the liver (alanine, lactate & pyruvate) D. Effect of insulin on Adipose Tissue - stimulate glucose uptake (amount is small compared to muscle) - inhibits flow of gluconeogenic precursor to liver (glycerol) and reduces energy substrate for hepatic gluconeogenesis (non-esterified fatty acids) A. Principal Types and Duration of Action 1. Short- and Rapid-acting insulins: = Regular insulin ( soluble crystalline zinc ) = Insulin lispro, Insulin aspart, insulin glulysine = Permit more physiologic prandial insulin replacement = Taken immediately before meal without sacrificing glucose control = With very fast onset (5-15 min, 10-20 min. & 30 minutes after SQ) and short duration (3-5 hours & 5-8 hours) = Peak serum values: 1 hour & 2 & 3 hours = The only type that should be administered intravenously = Useful in the management of diabetic ketoacidosis, surgery or during acute infection, and when the insulin requirement is changing rapidly 1. Intermediate-acting a. LENTE INSULIN (insulin zinc suspension) mixture of 30% semilente with 70% ultralente insulin provide a combination of relatively rapid absorption with sustained long action b.NEUTRAL PROTAMINE HAGEDORN or Isophane Insulin absorption & onset of action is delayed by combining appropriate amounts of insulin & protamine 6 molecules of insulin per molecule of protamine 3. Long-acting insulins a. ULTRALENTE INSULIN (extended insulin zinc suspension) b. PROTAMINE ZINC INSULIN SUSPENSION they have slower onset and a prolonged peak of action recommended dose be split into 2 or more doses c. INSULIN GLARGINE soluble, “peakless, ultra-long-acting insulin analog designed to provide reproducible, convenient, background insulin replacement has a slow onset of action (1-1.5 hours) achieves a maximum effect after 4-5 hours and maintained for 11-24 hours or longer given once a day A Species of Insulin 1. Beef and pork insulins The beef insulin differs by 3 amino acids, pork differs by 1 amino acid The beef hormone is most antigenic 2. Human insulins Less expensive, less immunogenic Production by recombinant DNA techniques B. Purity of Insulin Chromatography C. Concentration 100 units/ml, 500 units/ml Insulin Delivery Systems A. Portable Pen Injectors to facilitate multiple SQ injections B. Continuous Subcutaneous Insulin Infusion Devices (CSII, Insulin Pumps) encouraged for individuals who are unable to obtain target control while on multiple injection regimens & where excellent glycemic control is desired, such as during pregnancy velosulin (reg. insulin) & insulin aspart and lispro C. Inhaled Insulin have a rapid route and a relatively short duration of action used to cover mealtime insulin requirements to correct high glucose levels Factors that Affect Insulin Absorption: site of injection: abdomen, buttock, anterior thigh, or dorsal arm type of insulin subcutaneous blood flow: massage, hot baths, or exercise smoking regional muscular activity at the site of the injection volume & concentration of injected insulin depth of injection Treatment With Insulin Type 1 patients Type 2 Contraindication: advanced renal disease Elderly Complications of Insulin Therapy A. Hypoglycemia 1. Mechanisms and diagnosis result from a delay in taking a meal unusual physical exertion dosage error CM: tachycardia, palpitations, sweating, tremulousness, hunger, nausea, convulsion, coma Treatment: glucose administration Glucagons 1 mg SQ or IM Honey or syrup B. Immunopathology of Insulin Therapy 1. Insulin allergy an immediate type of hypersensitivity (IgE-antibodies) Tx: antihistamines, corticosteroids & desensitization 2. Immune insulin resistance (IgG antibodies) + circulating antibodies that neutralize the action of insulin to a small extent Tx: switching to a lesser antigenic purified insulin C. Lipodystrophy at injection sites corrected by avoidance of that specific injection site or with liposuction – hypertrophy Oral Anti-diabetic Agents 4 Categories: Insulin secretagogues (sulfonylureas, meglitinides, D-phenylalanine derivatives) b. Biguanides c. Thiazolidinediones d. Alpha-glucosidase inhibitors a. Insulin Secretagogues: A. Sulfonylureas Mechanism of Action: to increase insulin release from pancreatic B cells Sulfonylureas bind to S receptorinhibits efflux of K+depolarizationopens a voltage-gated Ca++ channelresults in Ca++ influx and the release of preformed insulin reduction of serum glucagon concentrations Chronic adm’n of sulfonylureas to type 2 diabetics reduces serum glucagon levels potentiation of insulin action on target tissues First Generation Sulfonylureas Tolbutamide: well absorbed but rapidly metabolized in the liver duration of action: 6-12 hours elimination half-life: 4-5 hours toxic reactions: skin rash hypoglycemia drug interactions: dicumarol, phenylbutazone, sulfonamides Chlorpropamide: duration of action: up to 60 hours half-life: 32 hours slowly metabolized in the liver 20-30% is excreted unchanged in the urine SE: hypoglycemia, hyperemic flush, dilutional hyponatremia, transient leukopenia, thrombocytopenia, jaundice CI: hepatic & renal insufficiency Dosage: 250mg daily Tolazamide: duration of action: 10-14 hours more slowly absorbed half-life: 7 hours SE: hypoglycemia Second Generation Sulfonylureas Glyburide: metabolized in the liver short plasma half-life duration of action: 10-24 hours SE: flushing, hypoglycemia Contraindication: hepatic & renal insufficiency Dosage: 5-10mg as single morning dose Glipizide: has the shortest half-life: 2-4 hours duration of action: 10-24 hours 90% is metabolized in the liver 10% excreted unchanged in the urine SE: hypoglycemia Contraindication: renal & hepatic insufficiency Dosage: 5-20mg as a single dose, 30 minutes before breakfast Glimepiride: duration of action: 12-24 hours half-life: 5 hours available as once-daily dosing completely metabolized by the liver dosage: 1 mg daily B. Meglitinides Repaglinide: modulate B cell insulin release by regulating K+ efflux through the K+ channels no direct effect on insulin exocytosis peak conc & peak effect: within 1 hour fast onset & duration of action (5-8 hrs.) hepatically cleared by CYP3A4 half-life: 1 hour indication: controlling postprandial glucose excursions Dosage: 0.25-4 mg SE; hypoglycemia Caution: hepatic & renal impairment C. D-phenylalanine derivative Nateglinide: stimulates very rapid and transient release of insulin from B cells through the closure of ATP-sensitive K+ channel may suppress glucagons release early in the meal and result in less endogenous or hepatic glucose production has minimal effect on overnight or fasting blood glucose levels ingested just prior to meals absorbed within 20 minutes after oral administration time to peak concentration: < 1 hour hepatically metabolized by CYP2C9 & CYP3A4 half-life: 1.5 hours duration of action: < 4 hours SE: hypoglycemia but lowest of all the secretagogues Biguanides Mechanism of action: - direct stimulation of glycolysis in tissues, with increased glucose removal from blood - reduced hepatic & renal gluconeogenesis slowing of glucose absorption from the GIT, with increased glucose to lactate conversion by enterocytes - reduction of plasma glucagon levels Metabolism & Excretion: Metformin: half-life: 1.5-3 hours duration of action: 10-12 hours not bound to plasma proteins not metabolized excreted by the kidneys as active compound may impair the hepatic metabolism of lactic acid Clinical Uses: - refractory obesity whose BS is due to ineffective insulin action (insulin resistance syndrome) use as in combination with sulfonylureas or thiazolidinediones in type 2 diabetics in whom oral monotherapy is inadequate - dosage: 500mg TID Toxic Effects: anorexia, nausea, vomiting, abdominal discomfort, diarrhea absorption of B12 appears to be reduced during long-term therapy Containdications: renal disease, alcoholism hepatic disease chronic cardiopulmonary dysfunction Thiazolidinediones Act to reduce insulin resistance Primary action: nuclear regulation of gene involved in glucose and lipid metabolism and adipocyte differentiation Are ligands of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) Have significant effects on vascular endothelium, the immune system, the ovaries and tumor cells In diabetes, a major site of action is adipose tissue, where the drug promotes glucose uptake and utilization and modulate synthesis of lipid hormones or cytokines and other proteins involved in energy regulation Also regulate adipocyte apoptosis & differentiation Are considered “euglycemics” Have a slow onset and offset of activity SE: hypoglycemia in combination Drop in triglyceride levels Slight rise in HDL & LDL cholesterol values Edema – fluid retention Anemia Dose-related weight gain (1-3 kg) CI: pregnancy Significant liver disease Heart failure Pioglitazone: may have PPAR-alpha as well as PPAR-gamma activity absorbed within 2 hours of ingestion metabolized by CYP2C8 and CYP3A4 to active metabolites DI: estrogen-containing oral contraceptives Taken once daily Dosage: 15-30mg Approved as monotherapy or in combination with metformin, sulfonylureas, and insulin Rosiglitazone: rapidly absorbed and highly protein bound metabolized in the liver by CYP2C8 & CYP2C9 administered once or twice daily dosage: 4-8 mg approved as monotherapy or in combination with biguanides & sulfonylureas Alpha-Glucosidase Inhibitors - are competitive inhibitors of the intestinal alpha-glucosidases and reduce the postprandial digestion and absorption of starch and disaccharides--> lowering postmeal glycemic excursions (4560mg/dl) and creating an insulin-sparing effect - members: acarbose & miglitol - taken in doses of 25-100 mg just prior to ingesting the first portion of each meal - both are absorbed from the gut - SE: flatulence, Diarrhea, Abdominal pain - CI: Chronic or inflammatory bowel disease, Renal impairment, Hepatic disease (acarbose)