BL5 Biochemical Changes in Diabetes Mellitus

• Diabetes mellitus


  A heterogeneous group of multifactorial, polygenic syndromes characterized by an elevated fasting blood glucose

  
• Type 1 diabetes

  • Characterized by an absolute deficiency of insulin
  • Caused by an autoimmune attack on the β cells of the pancreas
  • Symptoms appear abruptly when 80%–90% of the β cells are destroyed

  
• Type 2 diabetes


  • Typically develops gradually without obvious symptoms
  • Patients have a combination of insulin resistance and dysfunctional β cells
  • Do not require insulin to sustain life, but insulin eventually will be required to control hyperglycemia

  
• Metabolic changes in type 1 diabetes

  1. Hyperglycemia and ketoacidosis

  2. Hypertriacylglycerolemia

  3. Hypoglycemia

  
• Hyperglycemia in type 1 diabetes

  Caused by increased hepatic production of glucose via gluconeogenesis combined with diminished peripheral utilization (due to lack of insulin)

  
• Ketosis in type 1 diabetes

  Results from increased mobilization of fatty acids from adipose tissue, combined with accelerated hepatic fatty acid β-oxidation & synthesis of ketone bodies

  
• Hypertriacylglycerolemia in type 1 diabetes


  Excess fatty acids are converted to triacylglycerol and packaged and secreted in VLDLs

  
• Hypoglycemia in type 1 diabetes

  Caused by excess insulin (most common complication of insulin therapy)<|>Patients develop a deficiency of glucagon and epinephrine secretion, creating a symptom-free condition ("hypoglycemia unawareness")

  
• Contraindications for tight control of blood glucose in type 1 diabetes

  
• Insulin resistance in type 2 diabetes

  • Decreased ability of target tissues (liver, adipose & muscle) to respond properly to insulin
  • Characterized by increased hepatic glucose production, decreased glucose uptake by muscle & adipose tissue, and increased adipose lipolysis with production of free fatty acids

  
• Insulin resistance alone will not lead to type 2 diabetes

  
• Insulin resistance and obesity

  Insulin resistance increases with weight gain and decreases with weight loss<|>Excess adipose tissue secretes proinflammatory factors that result in insulin resistance

  
• Effect of insulin resistance

  Increased lipolysis and production of FFAs, which decrease use of glucose and increase deposition of TAG in liver

  
• Progression of type 2 diabetes

  Initially, the pancreas retains β-cell capacity but over time the β cells become increasingly dysfunctional and fail to secrete enough insulin

  
• Metabolic changes in type 2 diabetes

  1. Hyperglycemia

  2. Dyslipidemia

  
• Hyperglycemia in type 2 diabetes


  Caused by increased hepatic production of glucose, combined with diminished peripheral use

  
• Dyslipidemia in type 2 diabetes

  Elevated plasma chylomicron and VLDL levels due to decreased lipoprotein degradation by lipoprotein lipase<|>Low levels of HDL

  
• Treatment of type 2 diabetes

  1. Weight reduction, exercise, and medical nutrition therapy often correct hyperglycemia

  2. Hypoglycemic agents or insulin therapy may be required to achieve satisfactory plasma glucose levels

  
• Glycation


  The nonenzymic attachment of sugars (mainly glucose) to amino groups of proteins (and also to other molecules including DNA and lipids)

  
• Advanced glycation end-products (AGEs)

  Formed from the initial ketoamine product of glucose and protein, through further reactions<|>Underlie tissue damage in poorly controlled diabetes mellitus

  
• Consistently elevated blood glucose

  Increased glycation of proteins, including collagen and other proteins in the extracellular matrix

  
• AGEs and tissue damage in diabetes mellitus

  AGEs appear to be involved in both microvascular and macrovascular damage<|>Uptake of glycated proteins by endothelial cells and macrophages can activate NF-kB, generating cytokines and proinflammatory molecules

  
• HbA1c

  Nonenzymic attachment glycation of hemoglobin A, increased in patients with diabetes mellitus with poor glycemic control

  
• Measurement of HbA1c is an important part of the management of patients with diabetes mellitus