Effects on insulin secretion and insulin action of a 48-h reduction of plasma free fatty acids with acipimox in nondiabetic subjects genetically predisposed to type 2 diabetes

Elevated plasma FFA cause beta-cell lipotoxicity and impair insulin secretion in nondiabetic subjects predisposed to type 2 diabetes mellitus [ T2DM; i. e., with a strong family history of T2DM ( FH+)] but not in nondiabetic 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 48 h. Plasma glucose/ insulin/ C- peptide concentrations were measured from 0800 to 2400. On day 3, insulin secretion rates ( ISRs) were assessed during a + 125 mg/ dl hyperglycemic clamp. Acipimox reduced 48- h plasma FFA by 36% ( P < 0.001) and increased the plasma C- peptide relative to the plasma glucose concentration or Delta C- peptide/ Delta glucose AUC ( + 177%, P = 0.02), an index of improved beta-cell function. Acipimox improved insulin sensitivity ( M/I) 26.1 +/- 5% ( P < 0.04). First- (+ 19 +/- 6%, P = 0.1) and second- 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 first- and second- 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 first- phase ISR ( r(2) = 0.31, P < 0.02) and acute ( 2 - 4 min) glucose- induced insulin release after acipimox ( r(2) = 0.52, P < 0.04). In this proof-of-concept study in FH + individuals predisposed to T2DM, a 48-h 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.