Seven classes of FDA-approved T2D drugs are widely used: Biguanides. Several hypotheses have been proposed for metformin’s mechanism of action: (i) activation of AMPK (102, 103); (ii) inhibition of hepatic adenylyl cyclase (104); (iii) inhibition of mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) (105); (iv) increasing levels of GDF15 (106, 107); and (v) alteration of intracellular protein-bound iron levels (108). Metformin decreases hepatic glucose production (109). Its action may be exerted in the gut independent of absorption into the circulation (110). Sulfonylureas bind to sulfonylurea receptor-1 (SUR-1) in pancreatic β cells, leading to closure of the ATP-inhibitable K⁺ channel K_ir6.1, thereby initiating electrophysiological changes that trigger insulin secretion (111). Thiazolidinediones (TZDs) activate PPARγ, an adipose tissue transcription factor (112). TZDs promote triglyceride storage in adipose tissue while decreasing deposition of triglycerides in liver and muscle, thereby increasing insulin sensitivity (113, 114). GLP1RAs bind to the GLP1 receptor on pancreatic β cells, augmenting glucose-stimulated insulin secretion. GLP1RAs also delay gastric emptying, decrease glucagon levels, and decrease food intake (115). DPP4is protect GLP1 from degradation, thereby potentiating endogenous GLP1 activity. SGLT2is promote glucosuria and natriuresis by inhibiting proximal tubular glucose reabsorption. Glucosuria decreases HbA1c levels and promotes weight loss. Natriuresis decreases blood pressure, and may also protect against congestive heart failure (41). Insulin binds to its receptor in liver, skeletal muscle, and adipose tissue, triggering intracellular signaling pathways that mediate the various biological actions of insulin — including increased glucose transport into skeletal muscle and adipocytes, regulation of several key metabolic enzymes, and regulation of gene expression (116). Five other classes of approved drugs are less widely used: meglitinides, α-glucosidase inhibitors, amylinomimetics, bile acid sequestrants, and bromocriptine (a D2/D3 dopaminergic agonist).