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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

¹Diabetes Division, Department of Medicine; and ²Audie L. Murphy Veterans Administration Medical Center, The University of Texas Health Science Center at San Antonio, San Antonio, Texas

Submitted 17 November 2006 ; accepted in final form 6 February 2007

Elevated plasma FFA cause -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 C-peptide/glucose AUC (+177%, P = 0.02), an index of improved -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 (r² = 0.31, P < 0.02) and acute (2–4 min) 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 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.

insulin resistance; lipotoxicity; -cell; family history of T2DM

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