Treatment for Type I DM

• What is the main treatment for DM type I?

  Exogenous insulin
• What is insulin?

  Insulin is a peptide hormone produced in the pancreas within the beta cells of islets of Langerhans
• What is the composition of insulin?

  Two peptide chains (A & B) connected by sulfide bonds
• What does basal insulin secretion indicate?

  • Administered to mimic basal insulin production
  • Only subcutaneous administration
  • Once or twice daily
• What does bolus insulin level indicate?

  • Administered to mimic the prandial release of insulin
  • Subcutaneous or intravenous administration
  • Rapidly lowers blood glucose
  • Administered 3 times per day 20-30 mins prior to a meal
• What is the mechanism of insulin synthesis?

  Insulin gene transcription and translation in the rER of pancreatic β-cells → preproinsulin (precursor protein)

  Signal proteases remove the signal peptide of preproinsulin → proinsulin

  Protein folding and formation of one disulfide bridge in the α-chain and two disulfide bridges between the α-chain and β-chain

  Proinsulin is transported to the Golgi apparatus → packaged in membrane-bound secretory granules with proprotein convertases

  Proinsulin is cleaved by proteases → mature insulin and C-peptide

  Secretion of insulin and C-peptide via exocytosis
• What is the mechanism of action of insulin?

  Enzyme-linked receptors

  Secretion pathway

  • Stimulated by an increase in blood glucose
  • Glucose enters the pancreatic B-cells via GLUT2 transporters & is metabolized to generated ATP
  • Intracellular ATP binds & blocks ATP-sensitive K+channels, increasing the intracellular K+ conc. & raising membrane potential (depolarization occurs)
  • Voltage gated Ca2+ channels opens & Ca2+ enters the pancreatic B-cells
  • Increased intracellular Ca2+ triggers the fusion of insulin-containing secretory granules to the cell membrane
  • Exocytosis of insulin into the bloodstream

  
• What are the target organs of insulin?

  • Liver
  • Adipose tissue
  • Muscles
• What are the effects of insulin from the lowering blood glucose POV?

  • Facilitates glucose uptake by peripheral tissues
  • Stimulates glycogenesis
  • Inhibits glycogenolysis
• What are the effects of insulin from the fat-sparing effect?

  • Promotes lipogenesis
  • Inhibits lipolysis
• What are the effects of insulin from the anabolic effect POV?

  • Stimulates amino acids by tissue
  • Increases protein synthesis
  • Inhibits proteolysis
• What are the type of insulin preparations?

  Human insulins

  • Humulin R-short acting
  • Isophane (NPH,Protamine) & Lente (Zinc)-Intermediate acting

  Insulin analogues

  • Lispro-Ultrashort acting
  • Glargine-Long acting

  Mixed insulins
• What are the characteristics of human insulins?

  • Have the same amino acid sequence
  • Produced by human recombinant DNA tehnology with genetically altered E.Coli strains
• What are the benefits of human insulins comapred to animal insulins?

  • Less allergic reactions
  • Less insulin resistance
  • Less local adverse drug reactions at the site of injections
• What are the characteristics of insulin analogues?

  • Genetic engineered altered insulin
  • Has modified pharmacokinetics but performs the same pharmacodynamic effect
• What are the characteristics of insulin Lispro?

  • Rapid acting
  • Due to the amino acid sequence at position 28 & 29 in the B-chain
• What are the characteristics of insulin Glargine?

  • Long acting
  • Has no peak plasma conc. due to precipitation at the injection site
  • Precipitates due to solubility in differrent pH levels 7 & depot formation at subcutaneous tissue
  • Has slower onset & prolonged effect
• Insulin preparations

  
• Graph form of insulin preparations

  
• When is insulin included part of the treatment?

  • Type I DM
  • Type II DM when it is not controlled by any oral anti-diabetic drugs
  • Complications like DKA
  • Pregnancy
• What are the sites of insulin injections?

  • Upper outer arm
  • Belly (Below the belly button)
  • Upper outer thighs
  • Buttocks
• Why must be the injection sites for insulin be rotated?

  To avoid lipodystrophy
• What are the types of insulin delivery systems?

  • Syringe
  • Pen
  • Pump
  • Intranasal insulin
• What are the advantages of using an insulin pen?

  • More convenient
  • More accurate dosage
  • Less painful
• What are the advantages of insulin pump?

  • Used for continuous subcutaneous insulin infusion therapy
  • Mimics both basal & bolus insulin releases
  • Decreases the risk of hypoglycemia
• What are the adverse effects of insulin?

  • Hypoglycemia
  • Lipodystrophy at injection sites
  • Allergy
  • Insulin resistance
• What is meant by liposdystrophy?

  Repeated insulin injections at the same spot causing atrophy of subcutaneous fatty tissue at the site of injection due to local immune reaction
• How to prevent lipodystrophy?

  Rotate the site of insulin injections
• What are the two types of hyperglycemic emergencies?

  • Diabetic ketoacidosis (DKA)
  • Hyperglycemic hyperosmolar state (HHS)
• What are the characteristics of DKA?

  • Absolute insulin defieciency resulting in severe hyperglycemia, ketone body production & systemic acidosis
  • Develops over hours to 1-2 days
  • Most common in type I DM
  • Plasma glucose >250mg/dL
  • ArterialpH <7.3
  • Bicarbonate <15 mEq/L
  • Moderate ketonuria
  • Anion gap >12mEq/L
• What are the characteristics of HHS?

  • Severe relative insulin deficiency resulting in profound hyperglycemia & hyperosmolality and no significant ketone production/acidosis
  • Develops over days to weeks
  • Most common in type II DM
  • Higher mortality rate
  • Plasma glucose >600 mg/dL
  • Arterial pH >7.3
  • Bicarbonate >15mEq/L
  • Minimal ketonuria
  • Serum osmolality >320 mosm/L
• What is the pathophysiology of potassium loss?

  • Due to acidosis
  • Extracellular accumulation of H+ ions
  • Leads to shift of K+ from intracellular to extracellular space
  • Most K+ is lost in urine due to osmotic diuresis
  • Leading to loss of fluids & electrolytes
  • Dehydration activates RAA axis
  • All which leads to hypokalemia
• What is the key component of hyperglycemic ketoacidosis?

  • Hyperglycemia
  • Glycosuria
  • Ketonuria
  • Acidosis
  • Low intracellular K+
  • Fluid & electrolyte imbalance
• What are the recommended treatment for hyprglycemic ketoacidosis?

  • Correct fluid imbalance with normal saline
  • Correct serum potassium
  • Subcutaneous rapid/Short acting IV insulin
  • Bicarbonate - Extreme acidosis