Lec 4 two

• 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

  
• Insulin action


  • Stimulates glucose uptake by the tissues
  • Stimulates liver glycogen formation and inhibits glycogen breakdown
  • Stimulates lipid synthesis and inhibits fatty acid breakdown to ketone bodies
  • Stimulates protein synthesis

  
• The 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 phosphoproteins interact with other targets, thereby activating phosphorylation cascades, which result in glucose uptake (in adipose tissue and skeletal muscle), enzymes regulation (glucose metabolism, synthesis of glycogen, lipid, and proteins), 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 (IDDM)/ Juvenile onset DM
  • Type 2 DM: Noninsulin Dependent DM (NIDDM) Adult onset DM
  • Gestational Diabetes Mellitus (GDM)
  • 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
• Causes of Secondary DM

  • Endocrine disorders: acromegally, Cushing`s syndrome, pheochromocytoma and thyrotoxicosis
  • Pancreatic disease: as in chronic pancreatitis
  • Drugs: as estrogen-containing oral contraceptives and thiazide diuretics
• Mature onset of Diabetes mellitus (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 [high triglyceride and low high-density lipoprotein (HDL) cholesterol], 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

  
• Hyperglycemia


  Glucosuria (osmotic diuresis), Polyuria, Polydipsia
• Insulin


  Decreased protein catabolism, Decreased gluconeogenesis from amino acids

  
• Insulin


  Decreased lipolysis, Decreased free fatty acids and ketones

  
• Characteristics


  • Type 1 DM
  • Type 2 DM
• Diabetic ketoacidosis (DKA) is a serious complication of diabetes that can be life-threatening. DKA is most common among people with type 1 diabetes.

  
• Diabetic ketoacidosis


  Develops when your body doesn't have enough insulin to allow blood sugar into your cells for use as energy. Liver breaks down fat for fuel, enhancing ketogenesis pathway.

  
• Causes of DKA


  • Illness (Infection)
  • Missing insulin shots, a clogged insulin pump, or the wrong insulin dose

  
• Increased ketone bodies leads to acidosis, which leads to hyperventilation ("air-hunger"). If ketosis is severe, acetone will be breathed out, giving characteristic "fruity" smell in breath (due to acetone).
• Continued loss of water and electrolytes increases dehydration. Ketoacidosis produces increasing drowsiness, leading to diabetic coma in untreated cases.
• Hypotheses for how hyperglycemia causes chronic complications

  • Increased aldose reductase (or polyol pathway) flux
  • Enhanced formation of advanced glycation end products (AGE)
  • Increased intracellular formation of advanced glycation end-products (AGEs)
  • Modifications (glycation) in the basement membranes of capillaries in the eye and other tissues

  
• 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

  
• Insulin action


  • Stimulates glucose uptake by the tissues
  • Stimulates liver glycogen formation and inhibits glycogen breakdown
  • Stimulates lipid synthesis and inhibits fatty acid breakdown to ketone bodies
  • Stimulates protein synthesis

  
• The 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 phosphoproteins interact with other targets, thereby activating phosphorylation cascades, which result in glucose uptake (in adipose tissue and skeletal muscle), enzymes regulation (glucose metabolism, synthesis of glycogen, lipid, and proteins), 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 (IDDM)/ Juvenile onset DM
  • Type 2 DM: Noninsulin Dependent DM (NIDDM) Adult onset DM
  • Gestational Diabetes Mellitus (GDM)
  • 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

  
• Causes of Secondary DM

  • Endocrine disorders: acromegally, Cushing`s syndrome, pheochromocytoma and thyrotoxicosis
  • Pancreatic disease: as in chronic pancreatitis
  • Drugs: as estrogen-containing oral contraceptives and thiazide diuretics
• Mature onset of Diabetes mellitus (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