Clinical meaning
Type 2 diabetes mellitus involves progressive beta-cell dysfunction and insulin resistance in hepatic, muscle, and adipose tissue. Metformin acts primarily by suppressing hepatic gluconeogenesis via activation of AMP-activated protein kinase (AMPK) and improving peripheral insulin sensitivity. SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin) block the sodium-glucose cotransporter 2 in the proximal convoluted tubule, preventing reabsorption of approximately 70-80g glucose daily, producing glycosuria and osmotic diuresis. This mechanism provides cardiovascular and renal benefits independent of glycemic control through natriuresis, reduced preload, and improved cardiac energetics. GLP-1 receptor agonists (semaglutide, liraglutide) mimic incretin hormones, stimulating glucose-dependent insulin secretion, suppressing glucagon, delaying gastric emptying, and promoting satiety via hypothalamic receptors. DPP-4 inhibitors (sitagliptin) prevent degradation of endogenous GLP-1, providing a more modest incretin effect. Insulin therapy becomes necessary when beta-cell function declines to the point where oral and injectable non-insulin agents cannot maintain glycemic targets.