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Insulin Therapy In Type1DM

Insulin Therapy In Type1DM. H. Delshad M.D Endocrinologist Research Institute For Endocrine Sciences. The most powerful agent we have to control glucose. I NSULIN. First trial with Pancreatic extract. Banting 1921. Charles Best and Frederick Banting.

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Insulin Therapy In Type1DM

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  1. Insulin Therapy In Type1DM H. Delshad M.D Endocrinologist Research Institute For Endocrine Sciences

  2. The most powerful agent we have to control glucose INSULIN

  3. First trial with Pancreatic extract Banting 1921 Charles Best and Frederick Banting

  4. 1923 Nobel price in Physiology/Medicine MacLeod Banting

  5. Banting Banting,s wedding day

  6. In one of the most important advances in modern medicine, a team of investigators isolated and purified insulin in a building which stood on this site. On May 17, 1921, Frederick Banting, a young surgeon, and Charles Best, a recent graduate in physiology and biochemistry, began a series of experiments on pancreatic secretions in an attempt to find a treatment for "diabetes mellitus". Working under the general direction of J.J.R. Macleod, an expert in carbohydrate metabolism, they developed a promising anti-diabetic extract. James Collip, a noted biochemist, then increased the purity and potency of the substance. Medical Sciences Building, at the University of Toronto Toronto's Historical Plaques

  7. The miracle of Insulin With the first successful clinical test of insulin on a human diabetic on January 23, 1922, Banting, Best, Macleod and Collip ensured prolonged lives for millions of diabetics throughout the world. A 3 - year - old boy before and after 3 months of insulin therapy (1922).

  8. Hypoglycemia and its treatment in 1920s

  9. Characteristics of first commercial insulin • 1U/ml • Acidic • Bovine origin • Impure • Only short acting Academia Request : Longer acting insulin

  10. Longer acting insulin • 1930: Insulin plus adrenalin • 1934: Zinc insulin crystallisation • 1936: Protraction with Protamin Academia Requirement: Purity

  11. Purification / Higher Concentration • 1946 : Neutral Protamin Hagedorn(NPH) • 1951 : Neutral insulin solution • 1960 : Lente, Semilente, Mixed insulin Professor Hagedorn

  12. NPH : Is the most important discovery for diabetes treatment since the discovery of insulin” P Joslin 1947

  13. Gene technology– 1986Transfer and cloning of the insulin gen 1990 Human insulin (Short- and long-acting and Mixed insulin )

  14. - Academia Requirement : Simple Administration

  15. 1926 : The first pens

  16. Diabetes care today

  17. Types of Insulin • More than 20 types of insulin • Different time of onset and duration of action. • Among the criteria considered in choosing insulin are: How soon it starts working (onset) When it works the hardest (peak time) How long it lasts in the body (duration)

  18. Available insulin injections

  19. Insulin Analogues : 2000 LisproAspartGlulisineGlargineDetemir June 29 , 2010 , ADA 70th Scientific Session : Ultrarapid = Technosfer ( Inhaled Insulin) Ultralong = Degludec

  20. Conventional Insulins • REGULAR : Traditional Bolus insulin since 1921 • NPH : Traditional Basal insulin replacement since 1950 • Several well known limitations : * Absorption Variation : unfavorable plasma profiles * Duration of acton * Peak effect * Fasting hyperglycemia * Nocturnal hypoglycemia

  21. Regular Insulin • Exist in solution in hexameric form • Onset of action : 0.5 – 1 hour after SC • It peaks 2 – 4 hours after SC • The duration of action range 8 – 10 hours • It peaks much later than the blood glucose rise • Exerts its effect for too long • Risk of hyperglycemia in the first 30 minutes and hypoglycemia many hours after meals

  22. NPH Insulin • Protamine molecule + human regular • Slower absorption and longer duration of action • Onset of action = 1 - 2 hours after SC • It peaks 4 – 8 hours after SC • The duration of action range 10 – 20 hours Relative Insulin Effect 0 2 4 6 8 10 12 14 16 18 20 Time (Hours)

  23. Rapid Analogs Lispro Aspart Glulysine • Exist in solution in monomeric form • Onset of action : up to 0.5 hour after SC • Peaks 1– 2 hours after SC • The duration of action up to 4 hours • Peak when the blood glucose rise • No risk of hyper- or hypoglycemia

  24. Long acting analogous • Glargine & Detemir • Were designed to provide a reliable, constant basal insulin concentration • to control basal metabolism. • They are more predictable than conventional insulins and allow simplified insulin-replacement strategies

  25. Insulin Glargine G l y - A-Chain Substitution A s n 2 0 1 0 1 5 5 1 1 0 2 0 1 1 5 2 5 3 0 5 B-Chain Extension A r g A r g A- chain has an Asparagine to Glycine substituiation at position A21 Two positively charged Arginine are added at the C terminus of the B chain

  26. Clear Solution pH4 pH 7.4 Precipitation Dissolution Hexamers Dimers Monomers 10-3 M 10-5M 10-8 M Capillary Membrane Insulin in Blood Mechanism of Action Injection of an acidic solution (PH 4.0) Precipitation of insulin glargine in subcutaneous tissue (PH 7.4) Slow dissolution of free insulin glargin hexamers from micro precipitates (stabilized aggregates) Protracted action

  27. PHARMACOKINETICS : Slow dissolution of the Glargine hexamers at the injection site results in a relatively constant release with no pronounced peak over a period of up to 24 hours. Onset of action = 2 hours Peak = flat Duration = 24 hours

  28. Presentation of Glargine (Lantus) • Clear solution • Once-daily dosing ● Pen delivery system • Not suitable for mixing with other insulins

  29. Insulin Detemir • A soluble derivative of human insulin • Threonine has been removed at position B30 • A 14-carbon fatty acid side-chain has been attached to position B29

  30. PHARMACOKINETICS : The fatty acid , enable Detemir to bind albumin in subcutaneous tissue and circulation. 98% of Detemir in the blood stream is albumin bound. Detemir distribute more slowly to peripheral target tissues . It dose not precipitate during administration or absorbtion. Protracted absorption may contribute to reduced variability in Detemie action. Onset of action = 2 hours Peak = flat Duration = 14 – 16 hours (dose dependent : 0.4 IU/Kg , average 20 hours )

  31. Insulin treatment regimens

  32. Insulin Secretion After A Meal In Normal Individual

  33. How is insulin normally secreted ? Breakfast Lunch Dinner • Basal ( 50%) serves to balance the rate of hepatic glucose production and peripheral uptake during overnight and prolonged periods between meals • Bolus (50%) serves to control postprandial hyperglycemia in response to food intake Bolus Basal Time of day

  34. Insulin secretion in Type 1 and 2 DM Prandial Bolus Bolus Normal Type 1 Type 2

  35. Optimizing insulin therapy • The type of insulin • Insulin time action curves • Rational for selecting an insulin regimen - Conventional insulin regimen - Advanced insulin regimen ( intensive, multidose , flexible, functional, physiologic, basal-bolus )

  36. Rapid (Lispro, Aspart , Glulysine) Short (Regular) Intermediate (NPH) Long (Glargine) Insulin Time Action Curves Relative Insulin Effect 0 2 4 6 8 10 12 14 16 18 20 Time (Hours)

  37. Single insulin dose • Is rarely able to achieve normoglycemia, Least effective regimen and rarely suitable - Occasionally in newly diagnosed T1DM - Diabetic patients with ESRD on dialysis

  38. 120 100 B L D Bd 80 Insulin concentration (U/mL) 60 40 20 0 6 8 12 18 24 6 AM PM AM Time of day (h) NPH = 0.5-1.0 U/kg (20-30 IU) in the morning SINGLE INJECTION Normal pattern NPH

  39. Twice-daily injection • The most frequently used regimen • NPH+ Regular insulin • Starting dose : 0.5 – 1 U/Kg (TDD) - 2/3 of TDD in the morning - 1/3 of TDD in the evening • Frequent late afternoon and midnight hypoglycemia

  40. (Regular) 120 100 (NPH) 80 Insulin concentration 60 40 20 0 Twice-daily injection Normal pattern 0 2 4 6 8 10 12 14 16 18 20 Time (Hours)

  41. In many patients with type1 diabetes, especially those with a long duration of diabetes, it may not be possible to achieve optimal glycemic control with two injections.

  42. Multiple daily insulin injection • Is an effective diabetic treatment plan • Reduce wide and erratic excursions in blood glucose levels • Provides additional flexibility in a patient's daily routine • Bedtime NPH + Meal time Regular

  43. 120 100 B L D Bd 80 60 Insulin concentration Intermediate (NPH) 40 20 0 6 8 12 18 24 6 Time of day (h) 4 8 12 4 8 12 4 8 12 ampmam Multiple daily insulin injection • Frequent monitoring of blood glucose • 3 or more daily injections of insulin • combined regular and intermediate- or long-acting • Adjusted to needs of individual patient Regular Normal pattern

  44. Determining initial insulin dosages for MDI • Bedtime NPH : 35 – 50 % TDD • Meal Boluses Regular ( % of TDD): - Breakfast = 20 – 25 % - Lunch = 10 – 15 % - Dinner = 15 – 20 %

  45. Determining initial insulin dosages for MDI Total Daily Dose = 45 IU • Bedtime NPH : 45 X 0.50= 22 IU • Meal Boluses Regular - Breakfast = 45 X 0.20 = 9 IU - Lunch = 45 X 0.15 = 7 IU - Dinner = 45 X 0.15 = 7 IU

  46. Making adjustment in insulin dosage • Based on blood glucose levels : 1800 ⁄ TDD = mg /dl of glucose which can be reduced with 1.0 U of regular insulin ( 1.0 U of Regular Insulin for 40-50 mg/dl ) • Based on food intake : - 1.0 U of Regular Insulin for every 15 gr. CAH (one starch exchange or equivalents = one fruit , one milk, two meats , three vegetables)

  47. Conventional regimens problems • Lack of flexibility • Inadequate coverage of post-lunch glycemia • Fasting hyperglycemia • Nocturnal hypoglycemia

  48. Lunch Dinner Snack Breakfast Conventional insulins do not replicate the pattern of basal and postprandial endogenous insulin secretion Split-mix twice-Daily Pre-Mixed twice-Daily Plasma levels Time of day Conventional insulins fail to meet the two fundamental features of normal insulin secretion

  49. 0600 1800 0800 0600 1200 2400 Detemir The new analogues are more predictable than conventionalInsulins and allow simplified insulin replacement strategies. Lispro, glulisine, or aspart or regular U/mL 100 Glargine 80 60 Normal pattern 40 20 Time of day

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