Acute elevation of plasma free fatty acid (FFA) levels causes insulin resistance to rise dose dependently in pregnant and nonpregnant women. Plasma FFA levels are commonly elevated during late pregnancy, partly due to rising blood levels of lipolytic placental hormones, and are a likely cause for much of the increase in insulin resistance occurring at that time in all pregnant women. Plasma FFA levels are similar or higher and the insulin resistance is comparable or more severe in women with gestational diabetes mellitus (GDM) than in nondiabetic pregnant women. In contrast to healthy pregnant women, insulin secretion in women with GDM is defective and, therefore, is unable to rise adequately to compensate for the insulin resistance; the result is hyperglycemia. The mechanism by which elevated plasma FFA levels cause insulin resistance in skeletal muscle includes intramyocellular accumulation of diacylglycerol, which activates protein kinase C (the β II and δ isoforms). This results in reduction of tyrosine phosphorylation of the insulin receptor substrate-1 and inhibits activation of phosphoinositol-3 kinase, an enzyme that is essential for normal insulin-stimulated glucose uptake.