Review Note

Pathogenesis of Type 2 Diabetes Mellitus (T2DM) and Insulin Resistance

• Autoantibodies: Not present (unlike in Type 1 diabetes).
• Relative Insulin Deficiency:
  • Decreased insulin secretion throughout the disease.
  • Less inhibition of gluconeogenesis in the liver → increased gluconeogenesis.
• Central Obesity:
  • Increased fat cells → increased free fatty acids (FFAs) in plasma.
  • Dyslipidemia: Abnormal lipid levels often present.
• Insulin Resistance: A key feature in the development of T2DM.

1. Peripheral Insulin Resistance:
   • Results from numerous genetic and environmental factors.
   • Central obesity → increased plasma levels of FFAs → impaired insulin-dependent glucose uptake into hepatocytes, myocytes, and adipocytes.
   • Increased serine kinase activity in liver, fat, and skeletal muscle cells → phosphorylation of insulin receptor substrate (IRS) → decreased affinity of the receptor → decreased expression of GLUT4 channels, reducing glucose uptake.
2. Pancreatic β-cell Dysfunction:
   • Accumulation of pro-amylin (islet amyloid polypeptide) in the pancreas → decreased endogenous insulin production.
   • Initially, insulin resistance is compensated by increased insulin and amylin secretion.
   • Over time, insulin resistance progresses, while insulin secretion capacity declines.

• Definition: Inability of cells to respond adequately to insulin, resulting in:
  • Inhibited glucose uptake from the bloodstream into muscle and other tissues.
  • Impaired anabolic metabolism → elevated blood glucose levels.
• Compensation:
  • Higher levels of insulin are required for cells to uptake glucose and maintain normoglycemia → leads to hyperinsulinemia.
  • This can cause increased feelings of hunger, weight gain, and worsening obesity, perpetuating the cycle of insulin resistance and T2DM progression.