Pathophysiology
Clinical meaning
Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder characterized by the 'ominous octet' โ eight distinct pathophysiological defects that contribute to hyperglycemia (as described by DeFronzo): 1. Insulin resistance in muscle: impaired glucose uptake due to defective GLUT4 translocation and post-receptor signaling abnormalities 2. Hepatic insulin resistance: failure to suppress gluconeogenesis and glycogenolysis, leading to excessive hepatic glucose output (the primary cause of fasting hyperglycemia) 3. Beta-cell dysfunction: progressive loss of insulin secretory capacity โ beta-cell function is already reduced ~50% at the time of T2DM diagnosis and continues to decline at ~4% per year 4. Adipocyte insulin resistance: impaired lipogenesis and increased lipolysis release FFAs that worsen hepatic and muscle insulin resistance (lipotoxicity) 5. Incretin deficiency/resistance: reduced GLP-1 secretion and impaired GIP action reduce the 'incretin effect' (normally responsible for 50-70% of meal-stimulated insulin secretion) 6. Alpha-cell dysregulation: inappropriate glucagon secretion (normally suppressed by postprandial hyperglycemia) drives hepatic gluconeogenesis 7. Renal glucose reabsorption: upregulated SGLT2 transporters in the proximal tubule increase the renal threshold for glucosuria, reabsorbing more glucose back into the blood 8. CNS neurotransmitter dysfunction:...