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Insulin Therapy : Initiation and Optimiztion

Insulin Therapy : Initiation and Optimiztion. Dr Shahjada Selim Assistant Professor Department of Endocrinology Bangabandhu Sheikh Mujib Medical University, Dhaka Email: selimshahjada@gmail.com , info@shahjadaselim.com. 2 chains 2 bonds Secreted as basal & meal related (2)

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Insulin Therapy : Initiation and Optimiztion

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  1. Insulin Therapy:Initiation and Optimiztion Dr Shahjada Selim Assistant Professor Department of Endocrinology Bangabandhu Sheikh Mujib Medical University, Dhaka Email: selimshahjada@gmail.com, info@shahjadaselim.com

  2. 2 chains • 2 bonds • Secreted as basal & meal related (2) • Meal related in 2 phases What is Insulin? (1) • Polypeptide hormone • Beta-cells of islets of Langerhans in pancreas • Profound effects on • carbohydrate, fat & protein metabolism • To some extent on water & electrolyte balance

  3. Insulinstructure Insulin is a peptide hormone Composed of 51 amino acids and has a molecular weight of 5808 Da.

  4. Insulin Structure A - Chain S S GLY ILE VAL ASN 1 GLU CYS GLN 2 TYR CYS ASN CYS GLU 3 THR 21 LEU SER SER TYR GLN ILE CYS LEU 4 20 5 19 6 18 7 17 8 16 15 14 9 12 10 11 13 ALA B - Chain S S S PHE S THR 1 VAL LYS ASN PRO 30 GLN THR HIS TYR 2 29 LEU PHE CYS PHE 3 GLY GLY 28 SER HIS ARG LEU GLU VAL GLY ALA LEU GLU 4 VAL TYR 27 LEU CYS 5 26 6 25 7 24 8 23 9 22 10 15 21 14 11 12 20 16 13 17 18 19

  5. Glucose ATP Glucose Metabolism Insulin Mechanism of release Leads to depolarization Decreases potassium conductance Glucose transporter Closes Potassium channel Calcium channels R Ca+ Insulin granules

  6. Glucose Glycogen synthetase Glycogen Gluco-1- phosphatase Energy utilization Gluconeogenesis Ketone Bodies Lipase Free Fatty Acids Protein Urea excretion Liver Lipid Amino Acids Role in metabolic processes Insulin effects Increases Decreases Insulin R

  7. Bolus Bolus Bolus Basal Basal Basal B L S HS Insulin Secretion Normally secreted as basal (between meals & night time) & Meal-related peaks (1st & 2nd phase)

  8. Insulin is produced by beta cells in the islets of Langerhans, which release insuln in two phases: • The first phase release is triggered in response to rising or increased blood glucose levels. • The second phase is a sustained, slow release of newly formed vesicles triggered independently of sugar. • Beta cells in the islets of Langerhans take up as much as 60%-80% of all the cells.

  9. Insulin is produced and stored in the body ashexamer, while the active form isthe monomer.

  10. Hexamer is more stable then the monomer, which is better for practical reasons. • Monomer is a much faster-reacting drug, it means that insulin injections do not have to precede mealtimes by hours.

  11. Actions of Insulin (1) • Integrated action on carbohydrate, protein and fat metabolism • Dominant effect on glucose homoeostasis predominantly exerted in 3 tissues • Liver • Skeletal muscle • Fat

  12. Actions of Insulin (2) In Liver • Inhibition of glycogenolysis & gluconeogenesis • Stimulation of glycogenesis & storage In skeletal muscle & adipocytes • Stimulation of glucose uptake, utilization & storage • Increases glucose transport • Activation/inactivation of enzymes responsible for storage & metabolism of glucose

  13. Lipase Free Fatty Acids Role in metabolic processes Insulin deficiency Hyperglycemia Increases Decreases Glycogen synthetase Insulin R Glycogen (Ketonemia and Acidosis) Gluco-1- phosphatase Energy utilization Gluconeogenesis Ketone Bodies Urea excretion (Azoturia) Protein Liver Lipid Amino Acids Hyperlipemia

  14. Effect of insulin deficiency • Insulin deficiency results in • Elevated plasma glucose -Hyperglycemia • Elevated plasma lipid - Hypertriglyceridemia • Altered protein metabolism - Metabolic & Immune defects • Insulin replacement in diabetes tends to restore normalcy.

  15. Insulin: The Definitive Therapy for Diabetes • DM • Impaired insulin secretion (insulin deficiency) • Impaired insulin action (insulin resistance) • Insulin can overcome both the defects • Hence: Insulin-the definitive therapy for all types of diabetes Insulin- a valuable therapeutic tool for early intervention, to attain and maintain target levels of blood glucose control.

  16. Discovery of insulin (1) “One of the greatest milestones in history of medicine”.

  17. Discovery of insulin (2) Experiments in Toronto University F Banting, surgeon C Best, medical college student 30 July 1921 Banting & Best- extracted insulin from dog & proved that it controls symptoms of diabetes in dogs – 1921 Banting & Macleod-Nobel Prize for Medicine & Physiology in 1923

  18. JB Collip FG Banting JJR Macleod CH Best 1923 – Nobel prise to Banting and Macleod

  19. Discovery of Insulin (3) • 1st patient to receive pancreatic extract (insulin)-14-yr old Leonard Thompson. • 1st attempt (11th Jan 1922)- failed but the 2nd attempt (3rd May 1922) succeeded in reducing urine glucose excretion. • Grew cheerful, started eating more, gained weight, & cheeks started swelling out First patient to benefit from insulin –saved from death Leonard Thompsom-1908-1935

  20. Connecting peptide A-chain s-s s-s s-s B-chain Discovery of Insulin (4)Description of Structure • 1955- Frederick Sanger identified the amino acid sequence of insulin: • Insulin is a protein, consisting of • Alpha (21) and beta (30) chains • Half life time in blood is 4-5 min. Another Nobel Prize in insulin history – 1958

  21. Manufacture of Insulin (1) • 1923-Eli Lilly started manufacturing • 1923- Novo started manufacturing • ‘Most developments in insulin therapy have originated from the laboratories of Novo-Nordisk’ • NPH insulin • highly purified insulin • monocomponent insulin • semisynthetic insulin • biosynthetic human insulin • Insulin analogues: Insulin Aspart, Premixed analogue & Insulin Detemir Insulin

  22. Manufacture of insulin (2) • Currently NN- human insulin from yeast (Saccharomyces cerevisiae) using rDNA technology. • Eli Lilly-human insulin using E. coli, a gram-negative bacterium.

  23. Advancing insulin therapyTowards a new stage in the evolving story of insulin therapy Insulin degludec plus Insulin degludec 2015 Basal insulin analogues 2013 Biphasicinsulin Advancements Rapid-acting insulin analogues 2000s Recombinant human insulin Animal insulin preparations Isolation of insulin (Banting & Best) 1990s 1977 Time 1922

  24. Types of insulin

  25. Types of insulin

  26. Types of insulin

  27. Common Insulin Regimens (1)Split Mix Regimens • Two injections (intermediate + soluble) per day * before breakfast & before bedtime • Proportion/dosage of insulin titrated based on BG profile • Drawback • Mixing insulins is tedious and problematic • Inaccuracy of dose Not preferred –more problems for patients

  28. Common Insulin Regimens (2) Basal insulin Usually given at night • Proportion/dosage of insulin titrated based on FBG • Drawback • Expensive • Fasting blood glucose is primary targeted • May be with sensitizer and or secretagogue

  29. Common Insulin Regimens (3)Basal Plus • Basal insulin at night • Any rapid acting insulin premeal. • May be useful during early years of T2DM and in uncomplicated well motivated patients. • May be needed to shifted to Basal bolus regimen • titrated based on BG profile • Drawback • Mixing insulins is tedious and problematic • Inaccuracy of dose Not preferred –more problems for patients

  30. Common Insulin Regimens (4)Basal Bolus • Basal insulin at night and one rapid acting insulin immediately before each major meal (3 times). • Basal insulin is titrated following FBG • Rapid acting insulin is titrated by post meal BGs • Drawback • Expensive • 4 times needle prick a day. Most preferred –most fexible

  31. Basal Bolus Insulin

  32. Common Insulin Regimens (5) • Continuous subcutaneous insulin infusion (CSII): • Recommended for adults and children 12 years and older with T2DM provided: • To achieve target HbA1c levels with MDIs result in the person experiencing disabling hypoglycaemia or • HbA1c levels have remained high (8.5% or above) on MDI therapy despite a high level of care.

  33. CSII sets

  34. Indications of insulin Continuous Use * Type 1 Diabetes * Type 2 Diabetes with OAD failure - Primary - Secondary Intermittent Use * Type 2 diabetes during - major surgery - pregnancy, labour and delivery - myocardial infarction - acute infections - Hypergycemic emergencies: DKA & HHS * GDM Life-saving in T1DM Essential in T2DM

  35. Approach to start and adjust insulin in T2DM

  36. Starting dose of insulin • T1DM: 0.1 -0.2-1 U/kg / day1 • T2DM: 0.2-0.3 U/kg / day • In split mixed regimen- 2/3 as intermediate acting & 1/3 as short- acting 2 • In basal bolus regimen: ½ basal at bed time and ½ bolus in 3 divided doses. • Dosage is individualized and titrated soon 1Goodman & Gillman’s The pharmacological basis of therapeutics ed. 9th .pg. 1501 2 Harrison’s Principles of Internal Medicine (15th Edition) pg. 2131

  37. Current recommendations for the treatment of type 2 diabetes Diabetes Disease Progression An alternative approach Start insulin Add incretin therapy Start metformin Diet/exercise

  38. Beneficial effects on • lipids Improves beta-cell function (reduces glucotoxicity & lipotoxicity) Insulin provides 4 benefits beyond glycemic control Insulin Reverses insulin resistance Improves Quality of Life Why Early insulin initiation? Clinical & Pharmacological Reasons(4)

  39. Aid for Insulin Decision (AID): 1 The value 74 mg/dL: calculating PPGE for the diagnostic cut-offs for diabetes (200 mg/dL and 126 mg/dL) The value 40 mg/dL: calculating PPGE for the diagnostic cut-offs for prediabetes (impaired glucose tolerance 140 mg/dL, and impaired fasting glucose 100 mg/dL)

  40. Example • Middle aged executive • FPG 200 mg/dL; PPG 230 mg/dL: • Patient agrees to only one injection a day • Patient agrees to take two injections per day • FPG 200 mg/dL; PPG 330 mg/dL: • Patient agrees to two injections per day • Patient agrees to take 4 injections a day • Patient has limb threatening foot ulcer

  41. AID: 2 The value 0.6: calculating PFI for the diagnostic cut-offs of diabetes (200 mg/dL and 126 mg/dL)The value 0.4: calculating PFI for the diagnostic cut-offs of prediabetes

  42. Calculating prandial fasting index • FPG 200 mg/dL; PPG 230 mg/dL • PFI = (PPG – FPG)/FPG = (230-200)/200 = 30/200 = 0.15 • FPG 200 mg/dL; PPG 330 mg/dL • PFI = (PPG – FPG)/FPG = ?

  43. Calculating prandial fasting index • FPG 200 mg/dL; PPG 330 mg/dL • PFI = (PPG – FPG)/FPG = (330-200)/200 = 130/200 = 0.65

  44. AID: 3FPG and HbA1c to produce a ratio = FPG/HbA1c The value 20: calculated with the diagnostic cut-offs for diabetes using FPG (126 mg/dL) and currently accepted HbA1c (6.3%) levels

  45. Calculating FPG/HbA1c • FPG 200 mg/dL; HbA1c 9.0 % • FPG/HbA1c = 200/9 = 22.22 = greater contribution of FPG

  46. Calculating FPG/HbA1c • FPG 150 mg/dL; HbA1c 9.0 % • FPG/HbA1c = 150/9 = 16.66 = relatively greater contribution of PPG as compared to previous example

  47. Insulin vials and syringes

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