Type II Diabetes II: Pathophysiology

Pathophysiology

Type 2 diabetes mellitus (T2DM ) is a chronic metabolic disorder characterized by insulin resistance and progressive pancreatic β-cell dysfunction, leading to impaired glucose homeostasis. It results from interactions among genetic predisposition, environmental factors, and metabolic stressors, such as overnutrition and a sedentary lifestyle.

Insulin Resistance and Glucose Dysregulation

Early T2DM involves insulin resistance in skeletal muscle, adipose tissue, and the liver. Skeletal muscle shows reduced glucose uptake despite normal or high insulin levels. The liver fails to suppress gluconeogenesis and glycogenolysis, causing excess glucose production. Hyperglucagonemia further increases hepatic glucose output, leading to fasting and postprandial hyperglycemia.

β-cell Dysfunction and Metabolic Stress

Initially, β-cells compensate with hyperinsulinemia. Over time, glucotoxicity, lipotoxicity, oxidative stress, and inflammation impair β-cell function and reduce β-cell mass via apoptosis, leading to inadequate insulin secretion. Adipose insulin resistance increases lipolysis, elevating free fatty acids, which worsen hepatic insulin resistance and β-cell damage. Reduced lipoprotein lipase activity contributes to diabetic dyslipidemia (high triglycerides, low HDL, small dense LDL).

Systemic Effects and Complications

Muscle insulin resistance alters protein metabolism, increasing the release of amino acids that fuel gluconeogenesis. Stress hormones (cortisol, catecholamines, glucagon) worsen hyperglycemia and may trigger hyperosmolar hyperglycemic state (HHS) or, rarely, diabetic ketoacidosis (DKA). Chronic hyperglycemia leads to protein glycation, oxidative stress, and inflammation, causing macrovascular (CAD, stroke) and microvascular complications such as neuropathy, nephropathy, and retinopathy.