Acute enhancement of insulin secretion by FFA in humans is lost with prolonged FFA elevation

The in vivo effect of elevated free fatty acids (FFA) on p-cell function in humans remains extremely controversial. We examined, in healthy young men, the acute (90 min) and chronic (48 h) effects of an approximately twofold elevation of plasma FFA vs. control on glucose-stimulated insulin secretion (GSIS). GSIS was studied in response to a graded intravenous glucose infus ion (peak plasma glucose, similar to 10 mmol/l, n = 8) and a two-step hyper glycemic clamp (10 and 20 mmol/l, n = 8). In the acute studies, GSIS was si gnificantly higher, insulin sensitivity index (S-I) was lower, and disposit ion index (DI = insulin sensitivity x insulin secretion) was unchanged with elevated FFA vs. control [2-step clamp: DI = 8.9 +/- 1.4 x 10(-3) l(2) . k g(-1) . min(-2) in control vs. 10.0 +/- 1.9 x 10(-3) l(2). kg(-1) . min(-2) with high FFA, P = nonsignificant (NS)]. In the chronic studies, there was no difference in absolute GSIS between control and high FFA studies, but t here was a reduction in SI and a loss of the expected compensatory increase in insulin secretion as assessed by the DI (2-step clamp: DI = 10.0 +/- 1. 2 x 10(-3) l(2) . kg(-1) . min(-2) in control vs. 6.1 +/- 0.7 x 10(-3) l(2) . kg(-1) min(-2) with high FFA, P = 0.01). In summary, 1) acute and chroni c FFA elevation induces insulin resistance; 2) with acute FFA elevation, th is insulin resistance is precisely countered by an FFA-induced increase in insulin secretion, such that DI does not change; and 3) chronic FFA elevati on disables this beta-cell compensation.