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Dr. S. A. Ziai

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1 million islets of Langerhans Insulin, the storage and anabolic hormone of the body Islet amyloid polypeptide (IAPP, or amylin), which modulates appetite, gastric emptying, and glucagon and insulin secretion Glucagon, the hyperglycemic factor that mobilizes glycogen stores somatostatin, a universal inhibitor of secretory cells Pancreatic peptide, a small protein that facilitates digestive processes by a mechanism not yet clarified

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Table. Pancreatic islet cells and their secretory products. Cell Types Approximate Percent of Islet Mass Secretory Products A cell (alpha)20Glucagon, proglucagon B cell (beta)75 Insulin, C-peptide, proinsulin, amylin D cell (delta)3-5Somatostatin F cell (PP cell) 1 < 2Pancreatic polypeptide (PP) 1 Within pancreatic polypeptide-rich lobules of adult islets, located only in the posterior portion of the head of the human pancreas, glucagon cells are scarce (< 0.5%) and F cells make up as much as 80% of the cells.

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type 1, insulin-dependent diabetes severe or absolute insulin deficiency immune and idiopathic causes type 2, noninsulin-dependent diabetes tissue resistance combined with a relative deficiency in insulin secretion Affects fat metabolism FFA & TG, HDL) 30% or more will benefit from insulin therapy 10-20% of individuals actually have both type 1 and type 2 ketoacidosis may occur as the result of stress (infection), corticosteroids, nonketotic hyperosmolar coma type 3, other multiple other specific causes of an elevated blood glucose: nonpancreatic diseases, drug therapy, etc. type 4, gestational diabetes mellitus (GDM) Noted first time in the pregnancy In 4% of all pregnancies most pronounced in the last trimester placenta and placental hormones create an insulin resistance

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51 amino acids arranged in two chains (A and B) linked by disulfide bridges Proinsulin C-peptide crystals consisting of two atoms of zinc and six molecules of insulin The entire human pancreas contains up to 8 mg of insulin ~ 200 biologic units 28 units per milligram

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Glucose Other sugars (eg, mannose) Certain amino acids (eg, leucine, arginine) Glucagon-like polypeptide-1 Vagal activity

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The liver (60%) and kidney (35-40%) in insulin-treated diabetics receiving subcutaneous insulin injections, this ratio is reversed The half-life of circulating insulin is 35 minutes.

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Basal insulin values of 5-15 U/mL (30-90 pmol/L) Peak rise to 60-90 U/mL (360-540 pmol/L) during meals

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Translocation of glucose transporters Increased glycogen formation Protein synthesis, lipolysis, and lipogenesis Cell growth and division Glucocorticoids lower the affinity of insulin receptors for insulin

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Table. Glucose transporters. Transport er Tissues Glucose K m (mmol/L) Function GLUT 1 All tissues, especially red cells, brain 1-2 Basal uptake of glucose; transport across the blood- brain barrier 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 < 1 Uptake into neurons, other tissues GLUT 4Muscle, adipose 5 Insulin-mediated uptake of glucose GLUT 5Gut, kidney1-2Absorption of fructose

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Reversal of catabolic features of insulin deficiency Inhibits glycogenolysis Inhibits conversion of fatty acids and amino acids to keto acids Inhibits conversion of amino acids to glucose Anabolic action Promotes glucose storage as glycogen (induces glucokinase and glycogen synthase, inhibits phosphorylase) Increases triglyceride synthesis and very- low-density lipoprotein formation

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Increased protein synthesis Increases amino acid transport Increases ribosomal protein synthesis Increased glycogen synthesis Increases glucose transport Induces glycogen synthase and inhibits phosphorylase

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Increased triglyceride storage Lipoprotein lipase is induced and activated by insulin to hydrolyze triglycerides from lipoproteins Glucose transport into cell provides glycerol phosphate to permit esterification of fatty acids supplied by lipoprotein transport Intracellular lipase is inhibited by insulin

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Frederick G. Banting Student assistant Charles H. Best and Frederick G. Banting are standing on the roof of the medical building with one of the diabetic dogs used in their experiments with insulin.

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Intensive regimens involving multiple daily injections (MDI) use long-acting insulin analogs to provide basal or background coverage, and rapid-acting insulin analogs to meet the mealtime requirements. Conventional therapy consists of split- dose injections of mixtures of rapid- or shortacting and intermediate-acting insulins.

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Binding, activity, half-life, immunogenicity & mitogenicity are similar to human regular insulin Their duration of action is rarely more than 45 hours, which decreases the risk of late postmeal hypoglycemia. The lowest variability of absorption (approximately 5%) compared with 25% for regular insulin and 25% to over 50% for long-acting analog formulations and intermediate insulin, respectively Insulin lispro, the first monomeric insulin analog Low tendency to dimers formation To enhance the shelf life of insulin in vials, insulin lispro is stabilized into hexamers by a cresol Onset of action within 515 minutes and peak activity as early as 1 hour.

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Its effect appears within 30 minutes, peaks between 2 and 3 hours after subcutaneous injection, and generally lasts 58 hours. Regular insulin (crystal) Dimers hexamers (Zn) 3 rates of absorption Risk of late postprandial hypoglycemia It should be injected 3045 or more minutes before the meal to minimize the mismatching. Onset, duration, peak increase with the size of the dose S.c. & i.v (i.v. in DKA, after surgery, acute infection)

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NPH (neutral protamine Hagedorn, or isophane) insulin Isophane 1:10 ratio Protamin proteolyzed after s.c. inj. NPH insulin has an onset of approximately 25 hours and duration of 412 hours Mixed with regular, lispro, aspart and glulisine given 2-4 times daily

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Glargine Peakless Insulin Glargine has a slow onset of action (1 1.5 hours) and achieves a maximum effect after 46 hours. This maximum activity is maintained for 1124 hours or longer. Some very insulin-sensitive or insulin- resistant individuals benefit from split (twice a day) dosing. Soluble in acidic pH Should not mixed Separate syringes Less immunogenic No mitogen 6-7 fold greater binding affinity to IGF-1 receptor

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Detemir Myristic acid Increasing both self- aggregation in subcutaneous tissue and reversible albumin binding. Less hypoglycemia than NPH Dose-dependent onset of action of 12 hours and duration of action of more than 12 hours. It is given twice daily to obtain a smooth background insulin level.

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Insulin lispro, aspart, and glulisine can be acutely mixed (ie, just before injection) with NPH insulin without affecting their rapid absorption. NPH = NPL & NPA NPL/Lispro (50/50 & 75/25) NPA/Aspart (70/30) Glargin & Detemir as separate inj., and syringes.

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Regular, lispro, aspart, glulisine In pregnancy

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TIGHT GLYCEMIC CONTROL HbA 1c of 7.2% (normal

colesevelam hydrochloride Persons with type 2 diabetes who are taking other medications or have not achieved adequate control with diet and exercise. Interruption of the enterohepatic circulation and a decrease in farnesoid X receptor (FXR) activation. The drug may impair glucose absorption Colesevelam is administered as a pill or an oral suspension in a dosage of 1875 mg twice daily or 3750 mg once daily. It lowered HbA 1c about 0.5%, and LDL > 15% AE: constipation, indigestion, flatulence Impair absorption of drugs Should not be used in individuals with hypertriglyceridemia, a history of pancreatitis secondary to hypertriglyceridemia, or esophageal, gastric, or intestinal disorders

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Pramlintide Approved for preprandial use in persons with type 1 and type 2 diabetes. Pramlintide suppresses glucagon release via undetermined mechanisms, delays gastric emptying, and has central nervous system mediated anorectic effects. Rapidly absorbed after SC; peak within 20 min., and the duration of action is not more than 150 minutes. Pramlintide is renally metabolized and excreted The most reliable absorption is from the abdomen and thigh Pramlintide should be injected immediately before eating Initiated with the lowest dose and titrated upward Concurrent rapid- or short-acting mealtime insulin doses should be decreased by 50% or more. It cannot be mixed with insulin AE: hypoglycemia and gastrointestinal symptoms, including nausea, vomiting, and anorexia.

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Exenatide and liraglutide Potentiation of glucose mediated insulin secretion, suppression of postprandial glucagon release, slowed gastric emptying, and a central loss of appetite, decreased beta-cell apoptosis, increased beta-cell formation. Exenatide is approved as an injectable, adjunctive therapy in persons with type 2 diabetes treated with metformin or metformin plus sulfonylureas who still have suboptimal glycemic control. Exenatide peak 2 hrs. duration of action of up to 10 hrs.

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Exenatide is injected subcutaneously within 60 minutes before a meal; therapy is initiated at 5 g twice daily, with a maximum dosage of 10 g twice daily. It undergoes glomerular filtration, and dosage adjustment is required only when the creatinine clearance < 30 mL/min. The oral hypoglycemic dosage may need to be decreased HbA 1c reductions from 0.2% to 1.2%. SE: nausea (about 44% of users) and vomiting and diarrhea. necrotizing and hemorrhagic pancreatitis.

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Liraglutide Liraglutide is approved for the treatment of type 2 diabetes as an injectable therapy in patients who achieve inadequate control with diet and exercise, and are receiving concurrent treatment with metformin, sulfonylureas, or Tzds. It is not recommended as a first-line therapy or for use with insulin. Treatment is initiated at 0.6 mg and is titrated in weekly increments of 0.6 mg as needed, and as tolerated, to achieve glycemic goals. Peak in 812 hrs., T 1/2 is about 13 hrs.

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Reduction of HbA1c from 0.8% to 1.5%; Weight loss ranges from nominal to 3.2 kg. AE: headache, nausea, and diarrhea; antibody formation, urticaria, and other immune reactions also are observed Hypoglycemia can occur with concomitant sulfonylurea use and may require a dose reduction of the oral hypoglycemic agent. Pancreatitis is another serious adverse effect CI: liraglutide is contraindicated in individuals with a history of pancreatitis and should be permanently discontinued if pancreatitis develops. in individuals with a personal or family history of medullary cancer or multiple endocrine neoplasia type 2.

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Although they require injection, the GLP- 1 receptor ligands have gained popularity because of the improved glucose control and associated anorexia and weight loss in some users. Safety issues, however, may determine future use.

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Sitagliptin, saxagliptin, and linagliptin Inhibitors of DPP-4, the enzyme that degrades incretin hormones. Increase GLP-1 and GIP, which ultimately decreases postprandial glucose excursions by increasing glucose-mediated insulin secretion and decreasing glucagon levels. Approved as adjunctive therapy to diet and exercise in the treatment of individuals with type 2 diabetes who have failed to achieve glycemic goals.

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Sitagliptin usual dosage is 100 mg orally once daily. Bioavailability > 85%, peak within 14 hrs, and T 1/2 12 hrs. It is primarily (87%) excreted in the urine. Sitagliptin has been studied as monotherapy and in combination with metformin, sulfonylureas, and Tzds. HbA 1c reductions of between 0.5% and 1.0%. AE: nasopharyngitis, upper respiratory infections, headaches, and hypoglycemia when the drug is combined with insulin secretagogues or insulin. PMS reports of acute pancreatitis (fatal and nonfatal) and severe allergic and hypersensitivity reactions.

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Saxagliptin Saxagliptin is given orally as 2.55 mg daily The drug reaches maximal concentrations within 2 hours (4 hours for its active metabolite). The terminal plasma half-life is 2.5 hours for saxagliptin and 3.1 hours for its active metabolite. Dosage adjustment is recommended for individuals with renal impairment and concurrent use of strong CYP3A4/5 inhibitors Saxagliptin is approved as monotherapy and in combination with biguanides, sulfonylureas, and Tzds. HbA 1c reduction in the range of 0.40.9%. AE: an increased rate of infections (upper respiratory tract and urinary tract), headaches, peripheral edema (when combined with a Tzd), hypoglycemia (when combined with a sulfonylurea), and hypersensitivity reactions (urticaria, facial edema).