Endocrine

• Diabetes mellitus (DM)


  A group of heterogenous metabolic diseases in which there are high blood sugar levels (hyperglycemia) over a prolonged period due to defect in insulin formation, secretion, and action
• Characteristics of diabetes mellitus

  • Hyperglycemia (fasting blood glucose >7 mmol/L; >120 mg/dL)
  • Altered carbohydrate metabolism
  • Altered protein and Lipid metabolism
• Types of diabetes mellitus

  • Type 1 (10%)
  • Type 2 (80%)
  • Gestational (4%)
  • Other specific types (6-10%)
• Type 1 diabetes mellitus

  Earlier called Insulin-dependent (IDDM), or juvenile-onset diabetes
• Type 1A diabetes mellitus


  • Autoimmune destruction of beta-cells leading to insulin deficiency
• Type 1B diabetes mellitus

  • Insulin deficiency with tendency to develop ketosis but negative for autoimmune markers
• Type 2 diabetes mellitus


  Earlier called non-insulin-dependent (NIDDM), or maturity-onset diabetes (MOD)
• Type 2 diabetes mellitus


  • Impaired insulin secretion and/or insulin resistance
• Insulin


  Isolated in 1921 by Banting & Best and used clinically in 1922
• Insulin structure


  • Made up of two polypeptide chains (A chain and B chain) linked by two disulphide bridges
• Insulin biosynthesis


  Propreinsulin (RER) -> Preinsulin (Golgi apparatus) -> Insulin
• Effects of insulin


  • Promotes glucose uptake, glycogen synthesis, lipogenesis, and protein synthesis
  • Inhibits gluconeogenesis, glycogenolysis, lipolysis, and proteolysis
• Insulin preparations


  • Rapid-acting
  • Short-acting
  • Intermediate-acting
  • Long-acting
  • Insulin mixtures
• Short-acting insulin


  • Regular human insulin
• Intermediate-acting insulin


  • NPH human insulin
• Sulfonylureas


  Oral antidiabetic drugs that stimulate the release of insulin from the pancreas
• Structure-activity relationship of sulfonylureas

  • Benzene ring with substitution at para position enhances activity
  • Aryl carboxamidoalkyl substitution (second-generation) further enhances activity
  • N-terminal size affects lipophilicity and activity
• Sulfonylurea drugs


  • Tolbutamide
  • Chlorpropamide
  • Glipizide
  • Glimepiride
• Mechanism of action of sulfonylureas

  1. Stimulate insulin release from pancreatic beta cells by binding to sulfonylurea receptors (SUR1)

  2. Reduce K+ channel conductance leading to depolarization and Ca2+ influx

  3. Enhance insulin secretion, primarily the second phase
• 1. terminal size


  Most important for lipophilicity and activity. N-methyl or ethyl has no activity, while N-propyl and higher homologues were active up to 11-C atom. N-substitution with more than 12-C atom lost their activity.
• Selected Drugs


  • Tolbutamide
  • Chlorpropamide
  • Glipizide
  • Glimepiride
• Mechanism of Action of Sulfonylureas

  1. Stimulate the release of insulin from pancreas

  2. Act on 'sulfonylurea receptors' (SUR1) on the pancreatic β cell membrane

  3. Cause depolarization by reducing conductance of ATP sensitive K+ channels

  4. Enhance Ca2+ influx

  5. Stimulate the rate of insulin secretion at any glucose concentration
• Sulfonylureas


  Primarily augment the 2nd phase insulin secretion with little effect on the 1st phase
• Tolbutamide


  1. butyl-3-(4-methyl phenyl) sulfonyl urea
• Chlorpropamide


  1. propyl-3-(4-chloro phenyl) sulfonyl urea
• Glipizide


  1. [2-[4-(cyclohexyl carbamoyl sulfamoyl) phenyl] ethyl]-5-methyl pyrazine-2-carboxamide
• Glimepiride


  1. ethyl-3-methyl-N-[2-[4-[(4-methyl cyclohexyl) carbamoyl sulfamoyl]phenyl]ethyl]-5-oxo-2H-pyrrole-1-carboxamide
• Phenformin is currently not in used due to high risk of lactic acidosis
• Metformin


  1. (diamino methylidene)-1,1-dimethyl guanidine
• Mechanism of Action of Biguanides

  1. Do not cause insulin release, but for the action insulin is essential

  2. Activate the AMP-dependent protein kinase (AMPK)

  3. Decrease the hepatic gluconeogenesis and glucose output from liver

  4. Improve the peripheral glucose utilization by reducing insulin resistance

  5. Enhance the cellular respiration
• Rosiglitazone is currently banned in India since 2010 due to high risk of in risk of myocardial infarction, CHF, stroke and death
• Mechanism of Action of Thiazolidinediones

  1. Enhance the transcription of several insulin responsive genes

  2. Reverse the insulin resistance by enhancing GLUT4 expression and translocation

  3. Improve the Entry of glucose into muscle and fat cells

  4. Supress the hepatic gluconeogenesis

  5. Reduce lipolysis and plasma fatty acid levels
• Pioglitazone


  1. [[4-[2-(5-ethyl pyridin-2-yl)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione
• Rosiglitazone


  1. [[4-[2-[methyl(pyridin-2-yl)amino]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione
• Meglitinides


  Repaglinide and Nateglinide are meglitinide analogue oral hypoglycaemic designed to normalise mealtime glucose excursions
• Mechanism of Action of Meglitinides


  Though not a sulfonylurea, it acts in an analogous manner by binding to SUR→ closure of ATP dependent K+ channels→depolarisation→insulin release
• Repaglinide


  1. ethoxy-4-[2-[[(1S)-3-methyl-1-(2-piperidin-1-ylphenyl)butyl]amino]-2-oxoethyl]benzoic acid
• Mechanism of Action of Nateglinide

  It is a D-phenylalanine derivative which principally stimulates the 1st phase insulin secretion by closing β cell KATP channels resulting in faster onset and shorter lasting hypoglycaemia than repaglinide
• Nateglinide


  (2R)-3-phenyl-2-[(4-propan-2-yl cyclohexanecarbonyl)amino]propanoic acid
• Alpha Glucosidase Inhibitors


  Reversibly inhibit α-glucosidases, which is responsible for digestion of carbohydrates in the brush border of small intestine mucosa. It slows down and decreases digestion and absorption of polysaccharides (starch, etc.) and sucrose