ROLE OF FATTY-ACIDS IN THE PATHOGENESIS OF INSULIN-RESISTANCE AND NIDDM (VOL 46, PG 3, 1997)

Evidence is reviewed that free fatty acids (FFAs) are one important li nk between obesity and insulin resistance and NIDDM. First, plasma FFA levels are elevated in most obese subjects. Second, physiological ele vations in plasma FFA concentrations inhibit insulin stimulated periph eral glucose uptake in a dose-dependent manner in normal controls and in patients with NIDDM. Two possible mechanisms are identified: 1) a f at-related inhibition of glucose transport or phosphorylation, which a ppears after 3-4 h of fat infusion, and 2) a decrease in muscle glycog en synthase activity, which appears after 4-6 h of fat infusion. Third , FFAs stimulate insulin secretion in nondiabetic individuals. Some of this insulin is transmitted in the peripheral circulation and is able to compensate for FFA-mediated peripheral insulin resistance. FFA-med iated portal hyperinsulinemia counteracts the stimulation of FFAs on h epatic glucose production (HGP) and thus prevents hepatic glucose over production. We speculate that, in obese individuals who are geneticall y predisposed to develop NIDDM, FFAs will eventually fail to promote i nsulin secretion. The stimulatory effect of FFAs on HGP would then bec ome unchecked, resulting in hyperglycemia. Hence, continuously elevate d levels of plasma FFAs may play a key role in the pathogenesis of NID DM in predisposed individuals by impairing peripheral glucose utilizat ion and by promoting hepatic glucose overproduction.