1. Use of Insulin in treatment of diabetes mellitus Prof. Hanan Hagar

2. Objectives: by the end of this lecture, students should be able to: Define diabetes and mention different types of diabetes Differentiate between difference in treating type I and type II diabetes. Understand mechanism of action, secretion, and actions of insulin. Describe different types of insulin analogues Be able to recognize the difference in pharmacokinetic of different insulin analogues. Know the uses of different insulin analogues

3. Diabetes mellitus Is a chronic metabolic disorder characterized by high blood glucose level caused by insulin deficiency and sometimes accompanied with insulin resistance.

4. Diabetes mellitus Fasting plasma glucose > 7 mmol/L ( 126 mg/dl) is diagnostic of diabetes or Plasma glucose > 11.1 mmol/L (200 mg/dl), 2h after a meal confirms a diagnosis of diabetes.

5. Complications of diabetes Cardiovascular problems – Micro-and macrovascular complications Renal failure (nephropathy). Blindness (retinopathy). Neuropathy Risk of foot amputation

6. Type I diabetes due to autoimmune or viral diseases Type II diabetes due to obesity and genetic factors Types of diabetes

7. Type I Diabetes absolute deficiency of insulin. Pancreatic β-cells are destroyed. Treated by insulin.

8. Type II Diabetes Inadequate insulin secretion ( β-cells are not able to produce appropriate quantity of insulin ). Insulin resistance in target tissues. Treated by oral hypoglycemic drugs.

9. CharacteristicType 1Type 2 Onset (Age)Usually during childhood or puberty Usually over age 40 Type of onsetAbruptGradual Prevalence10-20%80-90 % Genetic predispositionModerateVery strong Defectsβ-cells are destroyedβ-cells produce inadequate quantity of insulin Endogenous insulinAbsentPresent (not enough) Insulin resistanceabsentpresent Nutritional statusUsually thinUsually obese KetosisFrequentUsually absent Clinical symptomsPolydipsia, polyphagia, polyuria, Wt loss Often asymptomatic Related lipid abnormalities Hypercholesterolemia frequent Cholesterol & triglycerides often elevated TreatmentInsulinOral hypoglycemic drugs

10. INSULIN

11. Insulin receptors – Present on cell membranes of most tissues – Liver, muscle and adipose tissue

12. Effects of insulin

13. I. Carbohydrate Metabolism: Lowers of blood glucose by: –  glucose uptake & utilization. –  Glycogen synthesis –  Conversion of carbohydrate to fats. –  Glycolysis (muscle). –  Glycogenolysis. –  Gluconeogenesis.

14. II. Fat Metabolism: Liver: –  Lipogenesis &  Lipolysis. – Inhibits conversion of fatty acids to keto acids. Adipose Tissue: –  Triglycerides storage. –  Fatty acids synthesis. –  Lipolysis

15. III. Protein Metabolism: Liver: –  protein catabolism. Muscle: –  amino acids uptake. –  protein synthesis. –  glycogen synthesis (glycogenesis).

16. IV. potassium –  potassium uptake into cells.

17. Sources of Exogenous Insulin Beef Insulin Porcine Insulin Human Insulin – Prepared by recombinant DNA techniques – Less immunogenic. – Modifications of amino acid sequence of human insulin can change pharmacokinetics

18. 1. Basal level of insulin is 5-15 µU/ml. 2. Half life of circulating insulin is 3-5 min. Insulin degradation

19. Can not be given orally (why ?) Insulin is given subcutaneously (s.c) – Insulin syringes (arms, abdomen, thighs). – Portable pin injector (pre-filled). – Insulin pump (more convenient, no need for multiple daily injection, can deliver basal rate of insulin). – Intravenously (in a hyperglycemic emergency) Routes of administrations of exogenous insulin

20. Pin injectorInsulin pump

21. Differs in pharmacokinetic properties mainly Rate of absorption Onset of action Duration of action. Variation is due to Change of amino acid sequence. Size and composition of insulin crystals in preparations. Types of insulin preparations

22. Ultra-short acting insulins – e.g. Lispro, aspart – very fast onset of action and short duration Short acting insulins – e.g. regular insulin – fast onset and short duration. Types of insulin preparations Insulin Analogues

23. Intermediate acting – e.g. Isophane (lente), NPH slow onset, intermediate duration of action Long acting – e.g. glargine, detemir – slow onset and long duration of action. Types of insulin preparations

24.  Clear solutions at neutral pH.  monomeric analogue  Fast onset of action (5-15 min)  mimic the prandial mealtime insulin release  S.C. (5 – no more than 15 min before meal).  Short duration of action (3-5 h).  2-3 times/day. Ultra-short acting insulins Insulin lispro, insulin aspart

25. Uses: – Control postprandial hyperglycemia (s.c.) – In emergency situations as in diabetic ketoacidosis (i.v). Ultra-short acting insulins

26. Insulin release during day time meals

27. Insulin aspart

28. Soluble crystalline zinc insulin Clear solutions at neutral pH. Forms hexamers. Fast onset of action 30-45 min (s.c.). Short duration of action (6-8 h). 2-3 times/day. Can mimic postprandial insulin release. Short acting insulins (Regular insulin)

29. Uses: – control postprandial hyperglycemia (s.c.) – In emergency situations as in diabetic ketoacidosis (i.v). – Can be used in pregnancy. Short acting insulins (regular insulin)

30. Short-acting (regular) insulins e.g. Humulin R, Novolin R Usespostprandial hyperglycemia & emergency diabetic ketoacidosis Physical characteristics Clear solution at neutral pH chemistryHexameric analogue Route & time of administration S.C. 30 – 45 min before meal I.V. in emergency (e.g. diabetic ketoacidosis) Onset of actionrapid 30 – 45 min ( S.C ) Peak level2 – 4 hr Duration6 – 8 hr Short Usual administration 2 – 3 times/day Ultra-Short acting insulins e.g. Lispro, aspart, glulisine postprandial hyperglycemia & emergency diabetic ketoacidosis Clear solution at neutral pH Monomeric analogue S.C. 5 min (no more than 15 min) before meal I.V. in emergency (e.g. diabetic ketoacidosis) Fast 5 – 15 min ( S.C ) 30 – 90 min 3 – 5 hr Shorter 2 – 3 times / day

31. Advantages of Insulin Lispro vs Regular Insulin  Rapid onset of action  Short duration of action (regardless of dose).  Reduced risk of postprandial hypoglycemia

32. Isophane (NPH) insulin Lente insulin Intermediate acting insulins

33.  NPH, is a Neutral Protamine Hagedorn insulin in phosphate buffer.  a combination of protamine & crystalline zinc insulin.  Turbid suspension at neutral pH.  Given S.C. only NOT i.v.  Onset of action 1-2 h. Isophane (NPH) Insulin

34.  Peak serum level 5-7 h.  Duration of action 13-18 h.  NOT used in emergencies (diabetic ketoacidosis) Can be mixed with ultrashort or short insulin NPL= NPH / lispro NPA= NPH / aspart NPH/regular = 75/25 - 70/30 - 50/50. Isophane (NPH) Insulin

35. Prandial and basal insulin replacement

36. Mixture of semilente insulin and 70% ultralente insulin. Turbid suspension at neutral pH Given S.C., not intravenously Delayed onset of action (1-3 h) Peak serum level 4-8 h. Intermediate duration of action 13-20 h. Lente insulin

37. Lente is not used in emergency (diabetic ketoacidosis). Lente and NPH insulins are equivalent in activity. Lente insulin (Humulin L, Novolin L)

38. Clear solution BUT forms precipitate at injection site. Slow onset of action 2 h. Given s.c., not intravenously absorbed less rapidly than NPH & Lente insulin. Long duration of action (24 h). Once daily Long acting insulins Insulin glargine (lantus)

39. produce broad plasma concentration plateau (low continuous insulin level over 24 hr low). Long acting insulins Insulin glargine (lantus)

40. Advantages of long acting insulin over intermediate-acting insulins: Produce flat prolonged hypoglycemic effect with no pronounced peak. More safe than NPH & Lente insulins ( reduced risk of nocturnal hypoglycemia).

41. Glargine NPH NPH vs Glargine

42. Insulin preparations

43. Hypoglycemia Lipodystrophy at injection site Weight gain (due to anabolic effects of insulin ) Hypokalemia Insulin resistance (rare) Hypersensitivity reactions (rare). Complications of Insulin Therapy:

44. Summary Insulin analogues are used to treat type I diabetes. Fast acting insulins (lispro, aspart), given s.c. or i,.v., produce very fast action, used to mimic postprandial insulin & emergency Short acting insulin (Regular insulin), given s.c. or i.v. produce fast action, used to mimic postprandial insulin, emergency & pregnancy. Intermediate acting insulin (lente, Isophane) produce slower action, than regular insulin, given s.c. not i.v. Long acting insulins (glargine) produce constant circulating insulin over 24 hr with no peak (peakless profile), s.c. not i.v.