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Pancreatic hormones & antidiabetic drugs


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  • Physiologic anatomy of an islet of Langerhans in the pancreas.
  • Structure of human proinsulin and insulin. Insulin is shown as the shaded (green color) peptide chains, A and B. Differences in the A and B chains and amino acid modifications for the rapid-acting insulin analogs (aspart, lispro, and glulisine) and long-acting insulin analogs (glargine and detemir) are discussed in the text.
  • Worldwide prevalence of diabetes mellitus. The prevalence of diabetes in 2000 and the projected prevalence in 2030 are shown by geographical region.
  • Spectrum of glucose homeostasis and diabetes mellitus (DM). The spectrum from normal glucose tolerance to diabetes in type 1 DM, type 2 DM, other specific types of diabetes, and gestational DM is shown from left to right. In most types of DM, the individual traverses from normal glucose tolerance to impaired glucose tolerance to overt diabetes. Arrows indicate that changes in glucose tolerance may be bi-directional in some types of diabetes. For example, individuals with type 2 DM may return to the impaired glucose tolerance category with weight loss; in gestational DM diabetes may revert to impaired glucose tolerance or even normal glucose tolerance after delivery. The fasting plasma glucose (FPG) and 2-h plasma glucose (PG), after a glucose challenge for the different categories of glucose tolerance, are shown at the lower part of the figure. These values do not apply to the diagnosis of gestational DM. Some types of DM may or may not require insulin for survival, hence the dotted line.
  • Temporal model for development of type 1 diabetes. Individuals with a genetic predisposition are exposed to an immunologic trigger that initiates an autoimmune process, resulting in a gradual decline in beta cell mass. The downward slope of the beta cell mass varies among individuals and may not be continuous. This progressive impairment in insulin release results in diabetes when ~80% of the beta cell mass is destroyed. A "honeymoon" phase may be seen in the first 1 or 2 years after the onset of diabetes and is associated with reduced insulin requirements.
  • Schematic diagram of the insulin receptor heterodimer in the activated state. IRS, insulin receptor substrate; MAP, mitogen-activated protein; P, phosphate; tyr, tyrosine
  • Schematic of the insulin receptor. Insulin binds to the a-subunit of its receptor, which causes autophosphorylation of the b- ubunit receptor, which in turn induces tyrosine kinase activity. The receptor tyrosine kinase activity begins a cascade of cell hosphorylation that increases or decreases the activity of enzymes, including insulin receptor substrates, that mediate the effects of glucose on glucose, fat, and protein metabolism. For example, glucose transporters are moved to the cell membrane to facilitate glucose entry into the cell.
  • GLUT: glucose transporter
  • Insulin signal transduction pathway in skeletal muscle. The insulin receptor has intrinsic tyrosine kinase activity and interacts with insulin receptor substrates (IRS and Shc) proteins. A number of "docking" proteins bind to these cellular proteins and initiate the metabolic actions of insulin [GrB-2, SOS, SHP-2, p65, p110, and phosphatidylinositol-3'-kinase (PI-3-kinase)]. Insulin increases glucose transport through PI-3-kinase and the Cbl pathway, which promotes the translocation of intracellular vesicles containing GLUT4 glucose transporter to the plasma membrane
  • Extent and duration of action of various types of insulin as indicated by the glucose infusion rates (mg/kg/min) required to maintain a constant glucose concentration. The durations of action shown are typical of an average dose of 0.2–0.3 U/kg. The durations of regular and NPH insulin increase considerably when dosage is increased.
  • Insulin preparations in Iran
  • Changes in blood constituents in diabetic coma, showing normal values (lavender bars) and diabetic coma values (red bars).
  • Representative insulin regimens for the treatment of diabetes. For each panel, the y-axis shows the amount of insulin effect and the x-axis shows the time of day. B, breakfast; L, lunch; S, supper; HS, bedtime; CSII, continuous subcutaneous insulin infusion. *Lispro, glulisine, or insulin aspart can be used. The time of insulin injection is shown with a vertical arrow. The type of insulin is noted above each insulin curve. A. A multiple-component insulin regimen consisting of long-acting insulin (^, one shot of glargine or two shots of detemir) to provide basal insulin coverage and three shots of glulisine, lispro, or insulin aspart to provide glycemic coverage for each meal
  • Representative insulin regimens for the treatment of diabetes. For each panel, the y-axis shows the amount of insulin effect and the x-axis shows the time of day. B, breakfast; L, lunch; S, supper; HS, bedtime; CSII, continuous subcutaneous insulin infusion. *Lispro, glulisine, or insulin aspart can be used. The time of insulin injection is shown with a vertical arrow. The type of insulin is noted above each insulin curve. B. The injection of two shots of long-acting insulin (^, NPH or detemir) and short-acting insulin [glulisine, lispro, insulin aspart (solid red line), or regular (green dashed line)]. Only one formulation of short-acting insulin is used.
  • FIGURE 41–2 One model of control of insulin release from the pancreatic beta cell by glucose and by sulfonylurea drugs. In the resting cell with normal (low) ATP levels, potassium diffuses down its concentration gradient through ATP-gated potassium channels, maintaining the intracellular potential at a fully polarized, negative level. Insulin release is minimal. If glucose concentration rises, ATP production increases, potassium channels close, and depolarization of the cell results. As in muscle and nerve, voltage-gated calcium channels open in response to depolarization, allowing more calcium to enter the cell. Increased intracellular calcium results in increased insulin secretion. Insulin secretagogues close the ATP-dependent potassium channel, thereby depolarizing the membrane and causing increased insulin release by the same mechanism.
  • Basic mechanisms of glucose stimulation of insulin secretion by beta cells of the pancreas. GLUT, glucose transporter.
  • Diabetes and abnormalities in glucose-stimulated insulin secretion. Glucose and other nutrients regulate insulin secretion by the pancreatic beta cell. Glucose is transported by the GLUT2 glucose transporter; subsequent glucose metabolism by the beta cell alters ion channel activity, leading to insulin secretion. The SUR receptor is the binding site for drugs that act as insulin secretagogues. Mutations in the events or proteins underlined are a cause of maturity onset diabetes of the young (MODY) or other forms of diabetes. SUR, sulfonylurea receptor; ATP, adenosine triphosphate; ADP, adenosine diphosphate, cAMP, cyclic adenosine monophosphate.
  • Transcript

    • 1. Pancreatic Hormones & Antidiabetic Drugs By M.H.Farjoo M.D. , Ph.D. Shahid Beheshti University of Medical Science
    • 2. Pancreatic Hormones & Antidiabetic Drugs  Introduction  Classification of Diabetes  Insulin  Insulin receptor  Types of Insulin Preparations  Insulin therapy basics  Insulin Delivery Systems  Glycemic Control in Diabetes  Hypoglycemia  Treatment of Hypoglycemia  Oral Antidiabetic Agents  Combination Therapy of Diabetes  Glucagon  Drug Pictures
    • 3. Introduction  The pancreatic hormones:  Insulin: the anabolic hormone of the body  Glucagon: hyperglycemic factor  Somatostatin: universal inhibitor of secretory cells  Islet amyloid polypeptide (IAPP, or amylin)  Pancreatic peptide: facilitates digestive processes  Diabetes: inadequate insulin secretion, with or without concurrent impairment of insulin action
    • 4. Classification of Diabetes  The disease is classified into four categories:  Type 1: insulin-dependent diabetes  Type 2: noninsulin-dependent diabetes  Type 3: specific causes  Type 4: gestational diabetes mellitus
    • 5. Type 1 Diabetes Mellitus  There is selective B cell destruction and severe insulin deficiency  Administration of insulin is essential  It is further subdivided into immune and idiopathic causes  The immune form is the most common form of type 1 diabetes  Most patients are younger than 30 years of age at the time of diagnosis
    • 6. Type 2 Diabetes Mellitus  Characterized by tissue resistance to the action of insulin combined with a relative deficiency in insulin secretion  A given individual may have more resistance or more B cell deficiency  Patients may not require insulin to survive, but 30% will benefit from insulin therapy  15% of patients have both type 1 & type 2, or a slowly progressing type 1, and ultimately require full insulin replacement
    • 7. Type 2 Diabetes Mellitus Cont,d  Patients will not develop ketosis  Ketoacidosis occurs in stress (infection) or use of drugs that enhances resistance, (corticosteroids)  Dehydration in poorly controlled patients leads to a lethal condition: "non-ketotic hyperosmolar coma“  Blood glucose may rise to 6–20 times the normal range and the person may lose consciousness
    • 8. Other types of diabetes  Type 3 diabetes mellitus  Other causes of elevated blood glucose: nonpancreatic diseases, drug therapy, etc  Gestational diabetes (GDM)  Any abnormality in glucose levels for the first time during pregnancy  Diagnosed in 4% of pregnancies  Placental hormones create insulin resistance especially in the last trimester
    • 9. Insulin  Present insulin standards contain 28 units per milligram  Beef insulin differs by three amino acids from human insulin  Only a single amino acid distinguishes pork and human insulins
    • 10. Insulin receptor  The network of phosphorylations within the cell is insulin's second message  Insulin increases:  Glucose uptake  Glycogen formation  Protein synthesis  Lipogenesis  DNA synthesis, cell growth and division  Various hormonal agents (glucocorticoids) lower the affinity of insulin receptors for insulin
    • 11. Transporter Tissues Function GLUT 1 All tissues, especially red cells, brain Basal uptake of glucose; transport across the blood-brain barrier GLUT 2 Beta cells of pancreas; liver, kidney; gut Regulation of insulin release, other aspects of glucose homeostasis GLUT 3 Brain, kidney, placenta, other tissues Uptake into neurons, other tissues GLUT 4 Muscle, adipose Insulin-mediated uptake of glucose GLUT 5 Gut, kidney Absorption of fructose Different types of GLUT
    • 12. Types of Insulin Preparations  Four types of insulins are available:  Rapid-acting : very fast onset and short duration  Short-acting : rapid onset of action  Intermediate-acting  Long-acting : slow onset of action  Rapid & short acting insulins are clear solutions.  Other types of insulin are turbid.
    • 13. Regular Aspart recombinant in 3 ml prefilled pen Biphasic Isophane Isophane Insulin 70% + Insulin Reg 30% in Cartridge for PEN Biphasic Isophane Isophane Insulin 75% + Insulin Regular 25% in Cartridge for PEN Glargine Recombinant Isophane NPH Insulin Zinc Types of insulin preparations in Iran
    • 14. Rapid-Acting Insulin  Three rapid-acting insulins:  Aspart  Lispro (Not yet in Iran)  Glulisine (Not yet in Iran)  Mimic endogenous prandial insulin secretion  Allow insulin to be taken immediately before the meal without sacrificing glucose control  Have the lowest variability of absorption of all available insulin formulations (5% vs. Up to 50%)
    • 15. Rapid-Acting Insulin Cont,d  Onset of action is in 5–15 min.  Reach peak activity in 1 hr.  Duration of action is 3–5 hr. Which decreases the risk of late postmeal hypoglycemia  The time of insulin Lispro for peak action is constant, regardless of the dose
    • 16. Short-Acting Insulin (regular insulin)  Its effect appears in 30 minutes, peaks 2-3 hr. And lasts 5–8 hr.  Creates insulin hexamers which causes a delayed onset and prolongs the time to peak action  Is the only type that should be administered intravenously for dilutional breaking of hexamers  It is particularly useful for:  Intravenous therapy in ketoacidosis  Insulin requirement is changing rapidly (after surgery or during acute infections)
    • 17. Intermediate Acting Insulin  NPH (Neutral Protamine Hagedorn, or isophane)  Combination of insulin and protamine in an isophane form  Has an onset of 2–5 hrs and duration of 4–12 hrs  it is usually mixed with regular, lispro, aspart, or glulisine insulin  The action of NPH is highly unpredictable, and its variability of absorption is over 50%.  So its clinical use is waning
    • 18. Long-Acting Insulin  Two types of long-acting insulins:  Glargine  Detemir (Not yet in Iran)  Glargine is a "peakless“, ultralong-acting insulin  Onset of action is in 1 hr. and peak effect is in 4–5 hours. Duration of action is ≥24 hr.  Since its formulation is acidic (ph 4.0) so:  Glargine should not be mixed with another insulin  Separate syringes must be used
    • 19. Insulin Therapy Basics  Rapid-acting or short-acting insulin is used for mealtime  Intermediate or long acting insulin is used for basal coverage  Split-dose injections of mixtures of rapid or short-acting and intermediate-acting insulins are used  For mixing an intermediate-acting insulin with regular insulin, NPH is usually used.
    • 20. Insulin Therapy Basics Cont,d  Insulin Lispro & Aspart can be mixed just before injection with NPH, lente, or ultralente insulin but premixed preparations are unstable  The time of onset, peak and duration of action of regular, NPH, lente, and ultralente insulins are dose- dependent  Clinical profile of small doses of these insulins vary greatly with large doses
    • 21. Healthy Diabetic
    • 22. Insulin Delivery Systems  Continuous subcutaneous insulin infusion devices (CSII, insulin pumps)  Programmable pump that delivers basal & bolus insulin based on blood glucose self-monitoring results  The pump contains an insulin reservoir, the program chip, the keypad, and the display screen is the size of a pager  The abdomen is the favored site for subcutaneously inserted infusion set  CSII delivery is regarded as the most physiologic method of insulin replacement
    • 23. Insulin Delivery Systems Cont,d  Portable pen injectors  Contain cartridges of insulin and replaceable needles  Inhaled insulin  Not yet applicable
    • 24. Insulin Aspart Pen
    • 25. Insulin Aspart Protamin Pen
    • 26. Insulin Glargine Pen
    • 27. Glycemic Control in Diabetes  Intensive insulin therapy is the standard therapy in type 1 patients after puberty  Exceptions include:  Advanced renal disease (hypoglycemia)  The elderly (hypoglycemia)  Children under the age of 7 years (brain damage)
    • 28. Hypoglycemia  Is the most common complication of insulin therapy  Rapid development of hypoglycemia causes  Sympathetic activity: tachycardia, palpitations, sweating, tremulousness  Parasympathetic activity: nausea, hunger  Convulsions and coma  If frequent hypoglycemia occur, autonomic warning signals may be absent (hypoglycemic unawareness)  These patients show only: weakness, bizarre behavior, coma and seizure
    • 29. Treatment of Hypoglycemia  Any sugar-containing beverage or food may be given  Liquid form is preferable  In an unconscious patient:  Intravenous infusion of 20–50 ml of 50% glucose solution in 2–3 minutes  If intravenous therapy is not available: 1 mg of glucagon injected either SC or IM is usually effective in 15 minutes  If glucagon is not available: small amounts of honey or syrup can be inserted into the buccal pouch  Oral feeding is contraindicated in unconscious patients
    • 30. Oral Antidiabetic Agents  Insulin secretagogues  Sulfonylureas  Meglitinides  D-phenylalanine derivatives  Biguanides: Metformin  Thiazolidinediones  Alpha glucosidase inhibitors  Bile Acid Sequestrants  Amylin Analog  Incretin-based Therapies  SGLT2 Inhibitors Hypoglycemia, is a side effect common to almost ALL these drugs Almost ALL of them are contraindicated in severe liver, renal and cardiac disease and should be used with extreme caution in elderly
    • 31. Sulfonylureas  Mechanism of action  Increases insulin release from the pancreas  Inhibits the efflux of potassium ions through the channel and results in depolarization  Depolarization, opens a voltage-gated calcium channel, calcium influx and the release of insulin  Chronic administration of sulfonylureas also reduces serum glucagon levels  Divided into first and second generations
    • 32. First-Generation Sulfonylureas  Tolbutamide (Not yet in Iran)  Its half-life is relatively short (5 hr.)  Is the safest sulfonylurea for use in elderly  Chlorpropamide  Has a long half-life (32 hr.)  Contraindicated in elderly patients  Tolazamide (Not yet in Iran)  Comparable to chlorpropamide in potency but shorter acting (half life 7 hr.)
    • 33. Second-Generation Sulfonylureas  Glyburide (Glibenclamide in Iran)  Has few adverse effects other than hypoglycemia.  Contraindicated in the presence of hepatic and renal insufficiency.  Glipizide (Not yet in Iran)  Has the shortest half-life (3 hr.)  Is much less likely to produce serious hypoglycemia.  Glimepiride (Not yet in Iran)  Has the lowest dose of any sulfonylurea (a single daily dose of 1 mg)
    • 34. Meglitinides  Repaglinide  Modulates insulin release by regulating potassium efflux through the potassium channels  Has a very fast onset of action, with a peak effect within 1 hour, the duration of action is 5–8 hr.  Is indicated for use in controlling postprandial glucose excursions
    • 35. D-phenylalanine derivatives  Nateglinide (Not yet in Iran)  Stimulates release of insulin through closure of the ATP sensitive K+ channel  May have a special role in the treatment of isolated postprandial hyperglycemia  Dose titration is NOT required  Is ingested just prior to meals, absorbed within 20 min. And peak concentration of <1 hour  Incidence of hypoglycemia may be the lowest of all the secretagogues  It is safe in individuals with very reduced renal function
    • 36. Biguanides: Metformin  They decrease hepatic glucose production.  They are "euglycemic" since hypoglycemia actually does not occur  Biguanides are for patients with ineffective insulin action (insulin resistance syndrome)  Side effects of metformin (Glucophage) are: anorexia, nausea, vomiting, abdominal discomfort, diarrhea (in 20% of patients)  Contraindicated in alcoholism and anoxic states (cardiopulmonary dysfunction) because of an increased risk of lactic acidosis
    • 37. Thiazolidinediones (Tzds)  Tzds are ligands of peroxisome proliferator-activated receptor gamma (PPAR-γ)  PPAR is part of the steroid and thyroid superfamily of nuclear receptors.  Tzds decrease insulin resistance and are "euglycemics“.  PPAR-γ receptors modulate the expression of the genes involved in lipid and glucose metabolism, and insulin signal transduction.  Two Tzds are: Rosiglitazone (Not yet in Iran) & Pioglitazone.
    • 38. Thiazolidinediones (Tzds) Cont’d  Contraindicated during pregnancy.  The metabolism of estrogen containing OCPs may be affected by pioglitazone (unwanted pregnancy).  Pioglitazone may increase the risk of bladder cancer with high doses.  Tzds have a slow onset and offset of activity over weeks or even months.
    • 39. Alpha Glucosidase Inhibitors  Consist of : Acarbose & Miglitol (the latter not in Iran).  Reduce digestion and absorption of starch and disaccharides.  Adverse effects: flatulence, diarrhea, and abdominal pain (undigested carbohydrate is fermented in colon and releases gas).  Hypoglycemia should be treated with glucose (dextrose) and NOT sucrose.  Contraindicated in inflammatory bowel disease or any intestinal condition that could be worsened by gas & distention.
    • 40. Bile Acid Sequestrants  Colesevelam (Not in Iran) is used for type 2.  The mechanism of action involves:  An interruption of the enterohepatic circulation (decrease in hepatic glucose output)  A decrease in farnesoid X receptor (FXR) activation.  FXR is a nuclear receptor with multiple effects on cholesterol, glucose, and bile acid metabolism.  Bile acids are natural ligands of the FXR.  The drug may also impair glucose absorption.
    • 41. Amylin Analog  They decreases post-meal glucose levels and reduces appetite.  Pramlintide (Not in Iran), is an injectable agent.  It is administered in addition to insulin in those who do not achieve their target postprandial sugar levels.  Pramlintide also suppresses glucagon release, and has CNS mediated anorectic effects.
    • 42. Amylin Analog (Cont’d)  It peaks within 20 minutes, and the duration of action is not more than 150 minutes.  Pramlintide should be injected immediately before eating.  concurrent rapid- or short-acting mealtime insulin doses should be decreased by 50% or more.  Concurrent insulin secretagogue doses also may need to be decreased in type 2 diabetes.
    • 43. Incretin-based Therapies  In type 2 diabetes, the release of glucagon-like polypeptide (GLP-1) is diminished after food intake.  This leads to inadequate glucagon suppression and excessive hepatic glucose output.  The incretin-based drugs are:  Agonists of GLP-1 receptor  Inhibitors of Dipeptidyl peptidase-4 (DPP-4)
    • 44. Agonists of GLP-1 receptor  Two analogs of GLP-1are Exenatide (Not in Iran) and Liraglutide.  Exenatide , is obtained from Gila monster venom.  It has a reduced degradation susceptibility by DPP-4.  Exenatide is approved as an injectable, adjunctive therapy.  Liraglutide is a long-acting synthetic GLP-1 analog with 97% homology to native GLP-1.  Its prolonged half-life permits once-daily dosing.  Liraglutide caused thyroid C-cell tumors in rodents, and is contraindicated in individuals with a personal or family history of medullary cancer or multiple endocrine neoplasia type 2.
    • 45. Inhibitors of DPP-4  Sitagliptin, Saxagliptin, and Linagliptin (None of them in Iran) are inhibitors of DPP-4  They increase GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), which increases insulin and decreases glucagon levels.  They are adjunctive therapy in type 2 diabetics who have failed to achieve glycemic goals.
    • 46. SGLT-2 Inhibitors  Sodium-glucose Cotransporter 2 (SGLT2) is responsible for most renal glucose reabsorption in the kidney.  SGLT2 Inhibitors reduce the absorption of glucose in the kidney, so reduce the blood sugar.  Canagliflozin and Dapagliflozin (None in Iran) are in this group.  The urine will test positive for glucose while on this medication.  Effectiveness depends on your kidney function.  There is a risk of genital infections and urinary tract infections.
    • 47. Combination Therapy of Diabetes  Type 1 diabetes:  There is no indication for combining insulin with oral antidiabetic agents  Type 2 diabetes:  Patients who have not responded to maximal oral therapy, are candidates for bedtime insulin  If this combination fails, full insulin replacement and multiple daily injections of insulin is indicated
    • 48. Glucagon  Glucagon increases cAMP.  Raises blood glucose at the expense of hepatic glycogen.  Has a potent inotropic & chronotropic effect (by the cAMP)  Its effect is similar to β agonists without requiring functioning β receptors  Clinical uses:  Emergency treatment of hypoglycemia  β blocker poisoning
    • 49. HDD 1 ton 5 MGB 1956
    • 50. Thank you Any question?