Schematic of the pleiotropic effects of PGC-1α and PGC-1β. Changes in PGC-1α and PGC-1β expression levels in different tissues may explain many of the metabolic abnormalities that accompany T2DM. In muscle: decreased PGC-1α may cause decreased formation of mitochondria-rich oxidative type 1 myofibers and decreased glucose oxidation. Decreased PGC-1β expression may cause decreased fat influx and oxidation and decreased nonoxidative glucose metabolism. Subjects with the Gly482Ser PGC-1α variant appear to be more susceptible to age-related decreases in PGC-1α and PGC-1β. In the β cell: increased PGC-1α expression or function, which is observed in several animal models of diabetes, would be expected to decrease β cell dysfunction and decrease insulin secretion. In liver: increases in PGC-1α expression or function would be expected to cause increased hepatic gluconeogenesis. In fat: decreases in PGC-1α expression or function would be expected to cause decreased mitochondrial biogenesis and defective adaptive thermogenesis, possibly leading to positive energy balance and obesity. Other factors, i.e., physical activity, diet, and other gene variants, may affect PGC-1α and PGC-1β expression or function and thus susceptibility to T2DM.