DIABETES MELLITUS TREATMENT.SLIDES PPTpptx

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1. Diabetic mellitus insulin treatment

2. Diabetes mellitus Defined as an elevated blood glucose associated with absent or inadequate pancreatic insulin secretion, with or without concurrent impairment of insulin action. Types ; type 1 type 2 other specific type gestational

3. Type 1 diabetes mellitus Caused by beta cell destruction and severe or absolute insulin deficiency. Onset occur at young age, susceptibility appears to involve a multifactorial genetic linkage. Type 1 diabetes, insulin replacement therapy is necessary to sustain life. Interruption of insulin replacement therapy can lead to DKA or death

4. Type 2 diabetes mellitus Tissue resistance to the action of insulin combined with a relative deficiency in insulin secretion. Impaired insulin action also affects fat metabolism, resulting in increased free fatty acid flux and triglyceride levels and reciprocally low levels of HDL. Complicate to nonketotic hyperosmolar coma

5. Other specific types of diabetes mellitus other specific causes of an elevated blood glucose include; pancreatectomy , pancreatitis non-pancreatic diseases drug therapy

6. Gestational diabetes Abnormality in glucose levels noted for the first time during pregnancy. During pregnancy, the placenta and placental hormones create an insulin resistance that is most pronounced in the last trimester.

7. Insulin structure 1- Large polypeptide 51 Amino Acids (MW 6000) 2- Tow chains linked by disulfide bonds. A chain (21 AA) B chain (30 AA) 3 disulfide bonds.

8. Insulin synthesis insulin gene encodes a large precursor of insulin ( preproinsulin ) During translation, the signal peptide is cleaved (proinsulin) During packaging in granules by Golgi, proinsulin is cleaved into insulin and C peptide

9. Insulin synthesis Insulin synthesis is stimulated by glucose or feeding and decreased by fasting Threshold of glucose-stimulated insulin secretion is 100 mg/dl. Glucose rapidly increase the translation of the insulin mRNA and slowly increases transcription of the insulin gene

10. Glucose is the primary stimulator of insulin secretion

11. Insulin receptor After insulin is in circulation, it diffuses into tissues, where it is bound by specialized receptors that are found on the membranes of most tissues. primary target tissues, include liver, muscle, and adipose tissue. This network of phosphorylation's within the cell represents insulin’s second message and results in multiple effects .

12. Insulin receptor Translocation of glucose transporters to the cell membrane with a resultant increase in glucose uptake; Increased glycogen synthase activity and increased glycogen formation Protein synthesis, lipolysis, and lipogenesis; Activation of transcription factors that enhance DNA synthesis and cell growth and division.

13. What happens when we inject human insulin in the subcutaneous space In the subcutaneous space, formation of hexamers occurs. Dissociation into dimers then monomers. Only monomers are released in the blood Monomers bind to the target cell receptor

14. Insulin degradation Happens in the liver and kidney. Liver and kidney clears endogenous insulin 60% and 35% to 40% . However, in insulin-treated diabetics receiving subcutaneous insulin injections, this ratio is reversed, with as much as 60% of exogenous insulin being cleared by the kidney and the liver removing no more than 30–40%. The half-life of circulating insulin is 3–5 minutes.

15. Endocrine effects on insulin on liver 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

16. Effects on muscle Increased protein synthesis   Increases amino acid transport    Increases ribosomal protein synthesis Increased glycogen synthesis    Increases glucose transport   Induces glycogen synthase and inhibits phosphorylase

17. Effects on adipose tissue 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

18. Indications for insulin use in diabetes HBA1c > 9.5 Type 1 diabetes Gestational diabetes or pre-existing diabetes Intensive care/ pre- operative setting

19. Indicators of insulin use in diabetes Diabetic emergencies ; DKA/ HHS Post myocardial infarction/ stroke in DM patient High-dose glucocorticoid therapy Newly Diagnosed type 2 DM with significant elevated blood glucose. Other patient not achieving glucose control on oral treatment Used together with glucose to treat hyperkalemia

20. Basics prior to insulin initiation Education prior to commencing insulin should include: Advice on recognition, treatment and causes of hypoglycemia Ensure proficiency in blood glucose monitoring Proposed benefits and aims of treatment, definition of good glucose control. Pen device / suitability – visually impared patient Dietetic/ nutritional review Hotline number.

21. Where/ sites to give insulin Insulin is a polypeptide and is susceptible to degradation in the GIT therefore it is typically administered by IV and subcutaneous injection. Inject into fat layer under skin, rotate sites Common sites; abdomen, thigh buttock , upper arms

22. Characteristics of available insulin preparations Commercial insulin preparations differ in a number of ways, such as differences in the recombinant DNA production techniques, amino acid sequence concentration, solubility, and the time of onset and duration of their biologic action

23. Classification of insulin; with examples Rapid-acting; insulin lispro , insulin aspart and insulin glulisine Short acting – regular insulin Intermediate acting – neutral protamine Hagedorn insulin(NPH insulin) Long- acting ; insulin glargine, insulin detemir and insulin degludec Combination insulin products – NPHinsulin is often combined with regular and rapid acting insulins.

24. Rapid - acting insulin Insulin lispro (Humalog, Lyumjev , Lilly; Admelog , Sanofic Aventis) Insulin aspart , insulin aspart niacinamide ( Novolog , Fiasp , Novo Nordisk) Insulin glulisine ( Apidra , Sanofi Aventis)

25. Short acting insulin Regular insulin ( Humulin R, Lilly; Novolin R, Novo Nordisk) Regular insulin inhaled ( MannKind )

26. Long acting NPH insulin ( Humulin N, Lilly; Novolin N, Novo Nordisk) Insulin glargine (Lantus, Toujeo , Sanofi Aventis; Basaglar , Lilly) Insulin detemir ( Levemir , Novo Nordisk) Insulin degludec ( Tresiba , Novo Nordisk)

27. Premixed insulin 70 NPH/30 regular ( Novolin , Novo Nordisk; Humulin , Lilly) 75/25 NPL, Lispro (Humalog mix 75/25, Lilly) 50/50 NPL, Lispro (Humalog mix 50/50, Lilly) 70/30 NPA, Aspart ( Novolog mix 70/30, Novo Nordisk 70/30 Degludec / Aspart ( Ryzodeg , Novo Nordisk)

28. 1. Regular insulin Regular insulin is a short-acting, soluble crystalline zinc insulin clear solutions at neutral pH The insulin molecules exist as dimers that assemble into hexamers in the presence of two zinc ions. pharmacokinetics rapid absorption into the circulation . hypoglycemic effect appears within 30 minutes after subcutaneous injection. peaks at about 2 hours, and lasts for 5–7 hours when usual quantities ( 5–15 U) are administered.

29. Regular insulin preparation available both in a vial and a disposable pen. indication When intravenous insulin is needed, regular insulin is used it is particularly useful in the treatment of diabetic ketoacidosis and during perioperative glucose management.

30. 2. Rapidly acting insulin analogs Insulin lispro , insulin aspart and insulin glulisine When injected subcutaneously, these three analogs quickly dissociate into monomers and are absorbed very rapidly, reaching peak serum values in as little as 1 hour. Optimal times of preprandial rapidly acting insulin analogs and regular human insulin are 15 minutes and 45 minutes before the meal, respectively.

31. Rapid acting insulin are more convenient as patients can inject immediately before eating ingest adequate carbohydrate early in the meal to avoid hypoglycemia duration of action is about 4 hours for most commonly used dosages. This contrasts with regular insulin, whose duration of action is significantly prolonged when larger doses are used. The rapidly acting analogs are the insulin of choice for insulin pumps

32. Long –acting insulin preparation NPH (neutral protamine hagedorn , or isophane ) insulin Insulin glargine Insulin detemir Insulin degludec

33. NPH (neutral hegedorn , or isophane ) insulin NPH insulin is an intermediate-acting insulin whose absorption and onset of action are delayed by combining appropriate amounts of insulin and protamine. After subcutaneous injection, proteolytic tissue enzymes degrade the protamine to permit absorption of insulin. NPH insulin has an onset of approximately 2–4 hours, peak action 6-7 hours and duration of 10–20 hours. Can be mixed with other rapid acting insulin

34. Insulin glargine Is soluble, peakless , long – acting insulin analogue. Has a slow onset of action (0.5–1 hours) and the effective duration of action is approximately 24 hours. Glargine is usually given once daily, although some very insulin-sensitive individuals (requiring small doses, less than about 20 units daily) or insulin-resistant individuals (requiring very large doses) benefit from split (twice a day) dosing.

35. Insulin glargine to maintain solubility, the formulation is unusually acidic (pH 4.0), should not be mixed with other insulins. It has sixfold to sevenfold greater binding than native insulin to the insulin-like growth factor 1 (IGF-1) receptor, but the clinical significance of this is unclear.

36. Insulin detemir The affinity of insulin detemir is four- to fivefold lower than that of human soluble insulin. Therefore, the U100 formulation of insulin detemir has a concentration of 2400 nmol /mL compared with 600 nmol /mL for NPH. The duration of action is about 17 hours at therapeutically relevant doses. It is recommended that the insulin be injected once or twice a day to achieve a stable basal coverage.

37. Insulin degludec The insulin is in the form of dihexamers but, when injected subcutaneously, it selfassociates into large multihexameric chains consisting of thousands of dihexamers . The chains slowly dissolve in the subcutaneous tissue, and insulin monomers are steadily released into the systemic circulation. The half-life of the insulin is 25 hours. Its onset of action is in 30–90 minutes, and its duration of action is more than 42 hours.

38. Insulin degludec It is recommended that the insulin be injected once or twice a day to achieve a stable basal coverage. Insulin degludec is available in two concentrations, U100 and U200, and in pre-filled disposable pens.

39. Mixtures of insulins NPH insulins require several hours to reach adequate therapeutic levels, their use in diabetic patients usually requires supplements of rapid- or short-acting insulin before meals. For convenience, these are often mixed together in the same syringe before injection. Insulin lispro , aspart , and glulisine can be acutely mixed ( ie , just before injection) with NPH insulin without affecting their rapid absorption. However this preparation can be unstable.

40. Mixtures of insulin To remedy this, intermediate insulins composed of isophane complexes of protamine with insulin lispro and insulin aspart have been developed. These intermediate insulins have been designated as “NPL” (neutral protamine lispro ) and “NPA” (neutral protamine aspart ) and have the same duration of action as NPH insulin. They have the advantage of permitting formulation as premixed combinations of NPL and insulin lispro , and as NPA and insulin aspart , and they have been shown to be safe and effective in clinical trials.

41. Duration of action of various types of insulin

42. Insulin delivery system Standard delivery subcutaneous injection with disposable syringes and needles Portable pen injectors – portable pen sized injectors with cartridges of insulin and replaceable needles. Continuous subcutaneous insulin infusion devices ( insulin pump). Inhalation insulin- dry powder formulation of recombinant regular insulin approved for use in adults

43. Complication of insulin therapy Hypoglycemia - most common result from inadequate carbohydrate consumption, unusual physical exertion or too large a dose of insulin. Immunopathology of insulin therapy- (a) insulin allergy/ hypersensitivity local or systemic urticaria result from histamine released from tissue mast cells sensitized by anti-insulin IgE antibodies. (b) immune insulin resistance – a low titre of circulating IgG ant-insulin antibodies that neutralize the action of insulin develop in most insulin treated patients.

44. Complication of insulin therapy Lipodystrophy at injection site – hypertrophy of subcutaneous fatty tissue remains a problem if injected repeatedly at the same time. Increased cancer risk – attributed to insulin resistance and hyperinsulinemia Weight gain Local injection site reactions Bronchospasm may occur with inhaled insulin.

45. references Basic and clinical pharmacology 15 edition by Bertram G. Katzung and J. Trevor. Rang and dales pharmacology 9 th dition Google images