Diabetes Mellitus-pathogenesis

Etiology and Pathogenesis

Causes

  • type 2 diabetes is caused by insulin resistance and progressive insulin secretory defects related to inflammation and metabolic stress, likely in combination with other contributing factors, such as genetic predisposition
    • results in variable combinations of
      • resistance to insulin action
      • inadequate compensatory insulin secretory response
    • patients have peripheral insulin resistance with a relative, rather than absolute, insulin deficiency
    • etiology of secretory defect unclear, but not due to autoimmune beta-cell destruction (as in diabetes mellitus type 1)
    • insulin resistance often caused by obesity or an increased percentage of body fat

Pathogenesis

  • pathogenesis unclear, but multiple genetic, lifestyle, environmental, metabolic, and other risk factors suggest a multifactorial process
  • pathophysiology of type 2 diabetes2
    • insulin resistance and inadequate insulin secretion result in deficient action of insulin on target tissues
    • deficient action of insulin on target tissues results in abnormal carbohydrate, fat, and protein metabolism
    • abnormal metabolism results in hyperglycemia
    • acute hyperglycemia can cause metabolic emergencies such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state
    • chronic hyperglycemia can cause vascular complications such as nephropathy, retinopathy, and cardiovascular disease
  • pathophysiology of vascular complications
    • likely multifactorial, involving prolonged exposure to hyperglycemia combined with other risk factors such as genetic susceptibility, hypertension, and dyslipidemia
    • mechanisms leading to micro-and macrovascular complications include
      • high intracellular glucose concentration activates protein kinase C (PKC), which causes structural and functional changes in vasculature, including alterations in cellular permeability, inflammation, angiogenesis, cell growth, extracellular matrix expansion, and apoptosis
      • insulin resistance contributes to endothelial dysfunction and produces a prothrombotic state – increased cellular synthesis of plasminogen activator inhibitor-1 and fibrinogen, and decreased synthesis of tissue plasminogen activator, result in reduced inhibition of platelet aggregation and thrombosis