Bio lec 4

• Diabetes mellitus


  A group of metabolic disorders of carbohydrate metabolism in which there is raised blood glucose levels (Hyperglycemia) because of state of diminished insulin action
• Diabetes is the fourth most common cause of death in the developed world
• Regulation of Plasma Glucose Level

  1. Hyperglycemic hormones

  2. Hypoglycemic hormone

  3. Insulin action stimulates glucose uptake by the tissues

  4. Insulin action stimulates liver glycogen formation and inhibits glycogen breakdown

  5. Insulin action stimulates lipid synthesis and inhibits fatty acid breakdown to ketone bodies

  6. Insulin action stimulates protein synthesis
• Mechanism of Insulin Action

  1. Binding of insulin to specific receptors in the plasma membrane

  2. Binding of insulin to the extracellular α-subunit of the insulin receptor induces autophosphorylation of the β-subunit of the receptor and phosphorylation of selected intracellular proteins, the insulin-receptor substrate (IRS) family

  3. These latter phosphoproteins interact with other targets, thereby activating phosphorylation cascades, which result in glucose uptake, enzymes regulation, enhanced gene expression, cell growth, and differentiation
• Insulin and glucose uptake

  • Insulin enhances glucose uptake via GLUT4 receptor in insulin dependant tissue (heart, skeletal muscle and adipose tissue)
  • Binding of insulin to its receptor mediate Glute4 that embedded in the cytoplasm to move to the cell membrane
• Clinical Types of Diabetes

  • Type 1 DM (Insulin Dependent DM / Juvenile onset DM)
  • Type 2 DM (Noninsulin Dependent DM / Adult onset DM)
  • Gestational Diabetes Mellitus (GDM)
  • Other types (Secondary DM, Mature onset of Diabetes mellitus (MODY))
• Type 1 DM


  The disease is characterized by an absolute deficiency of insulin caused by an autoimmune attack on the β cells of the pancreas leads to gradual depletion of the β-cell population
• Type 2 DM


  It is a combined insulin resistance and relative deficiency in insulin secretion
• Gestational Diabetes Mellitus (GDM)

  Developing during some cases of pregnancy but usually disappears after pregnancy
• Other types of Diabetes

  • Secondary DM (Endocrine disorders, Pancreatic disease, Drugs)
  • Mature onset of Diabetes mellitus (MODY)
• MODY


  There are a small number of families showing a clear pattern of dominant inheritance of diabetes. The diabetes develops in early childhood, but insulin is secreted in near-normal amounts
• Pathogenesis of Type 1 Diabetes Mellitus

  1. Autoimmune destruction of the insulin-secreting cells of pancreatic β-cells

  2. 80 to 90% reduction in the volume of β-cells is required to induce symptomatic type 1 diabetes

  3. Susceptibility to type 1 diabetes is inherited but the mode of inheritance is complex and has not been defined

  4. Environmental factor can contribute: As viral infection
• Pathogenesis of Type 2 Diabetes Mellitus

  1. Decreased ability of insulin to act on peripheral tissue (insulin resistance)

  2. β-cell dysfunction, which is an inability of the pancreas to produce sufficient insulin to compensate for the insulin resistance

  3. Type 2 diabetes mellitus is an extremely heterogeneous disease, result from combination of environmental and genetic factors
• Causes of insulin resistance

  • Insulin resistance increases with weight gain and decreases with weight loss
  • Adipose tissue secretion of proinflammatory cytokines such as interleukin 6
  • Increased lipolysis and production of FFAs
  • Internalization of insulin receptors
  • Mutation that affect insulin signaling molecules
• Insulin resistance syndrome


  A collection of associated clinical and laboratory findings, consisting of insulin resistance, hyperinsulinemia, obesity, dyslipidemia, and hypertension
• Clinical presentation and Biochemical Correlations

  Insufficient insulin or decreased insulin sensitivity disturb carbohydrate, protein and lipid metabolism
• Presentation Diabetes Mellitus


  • Some may present with all classical symptoms like thirst, 3p symptoms (polydypsia, Polyuria, Polyphagia), loss of weight
  • Some women present during pregnancy (stress)
  • A few specially Type-1 cases may present as fulminant ketoacidosis and a few with complications
• Altered CHO Metabolism


  • Insulin stimulates glucose utilization, glycogenolysis
  • Hyperglycemia
  • Glucosuria (osmotic diuresis)
  • Polyuria (and electrolyte imbalance)
  • Polydipsia
• Renal threshold


  When blood glucose is greater than 180 mg/dl, the ability of the kidneys to reabsorp glucose is impaired. This results in glucose "spilling" into the urine. The loss of glucose is accompanied by the loss of water, resulting in the characteristic polyuria (with dehydration) and polydipsia of diabetes
• Altered Protein Metabolism


  • Insulin stimulates protein catabolism, gluconeogenesis (amino acids → glucose)
  • Hyperglycemia
  • Weight Loss and Fatigue
• Altered Fat Metabolism


  • Insulin stimulates lipolysis, free fatty acids + ketones
  • Acidosis + Weight Loss
• Characteristics of Diabetes Types

  • Type 1: 5-10% of diabetic pop, usually < 30 yr, no pancreatic function, autoimmune, uncommon obesity, often severe symptoms, treated with insulin
  • Type 2: 90% of diabetic pop, usually > 40 yr, normal/high/low insulin, insulin resistance and deficiency, common obesity, mild symptoms, treated with diet, exercise, oral antidiabetics, insulin
• Complications of Diabetes Mellitus

  • Acute: Diabetic ketoacidosis and coma
  • Chronic: Microvascular (retinopathy, nephropathy, neuropathy)
  • Chronic: Macrovascular (atherosclerosis, stroke, gangrene, coronary artery disease)
• Diabetic Ketoacidosis


  1. Develops when body doesn't have enough insulin, liver breaks down fat for fuel, enhances ketogenesis pathway

  2. Causes: Illness (infection), missing insulin shots, clogged insulin pump, wrong insulin dose

  3. Increased ketone bodies leads to acidosis, hyperventilation, fruity breath odor

  4. Anorexia, nausea, vomiting, dehydration, drowsiness, diabetic coma
• Chronic Complications


  1. Increased polyol pathway flux (osmotic disturbances)

  2. Increased intracellular formation of advanced glycation end-products (AGEs) (glycation of enzymes and structural proteins, modifications in basement membranes)