Elevated plasma free fatty acids (FFA) cause -cell lipotoxicity and impair insulin secretion in non-diabetic subjects predisposed to type 2 diabetes (T2DM) (i.e., with a strong family history of T2DM [FH+]), but not in non-diabetic subjects without a family history of T2DM. To determine whether lowering plasma FFA with acipimox, an antilipolytic nicotinic acid derivative, may enhance insulin secretion, nine FH+ volunteers were admitted twice and received in random order either acipimox or placebo (double-blind) for 48h. Plasma glucose/insulin/C-peptide concentrations were measured from 0800-2400h. On Day 3, insulin secretion rates (ISR) were assessed with a +125mg/dl hyperglycemic clamp. Acipimox reduced 48h plasma FFA by 36%(P<0.001) and postprandial glucose by 46%(P<0.001), and increased the plasma C-peptide relative to the plasma glucose concentration or ?C-peptide/?glucose AUC (+177%, P=0.02), an index of improved beta-cell function. Acipimox improved insulin sensitivity (M/I) 29±5% (p<0.04). First (+19±6%, p=0.1) and 2nd phase (+31±6%, p=0.05) ISRs during the hyperglycemic clamp also improved. This was particularly evident when examined relative to the prevailing insulin resistance (1/[M/I]), as both 1st and 2nd phase ISR markedly increased by 29±7% (P<0.05) and 41±8% (P=0.02). There was an inverse correlation between fasting FFA and 1st phase ISR(r2=0.31,p<0.02) and acute (2-4 minute) glucose-induced insulin release after acipimox (r2=0.52,p<0.04). In this proof-of-concept study in FH+ individuals predisposed to T2DM, a 48h reduction of plasma FFA improves day-long meal and glucose-stimulated insulin secretion. These results provide additional evidence for the important role that plasma FFA play regarding insulin secretion in FH+ subjects predisposed to T2DM.