Acipimox increases glucose disposal in normal man independent of changes in plasma nonesterified fatty acid concentration and whole-body lipid oxidation rate

Abstract

The short-term administration of a nicotinic acid analogue (acipimox) increases insulin sensitivity and consequently glucose disposal, both in patients with non-insulin-dependent diabetes mellitus (NIDDM) and in patients with cirrhosis. This effect has been attributed to a decrease in plasma nonesterified fatty acid (NEFA) levels and fatty acid oxidation rates, and a corresponding increase in carbohydrate oxidation. The aim of the present study was to determine whether acipimox influenced glucose disposal independent of changes in lipid metabolism. Seven normal men (age, 31 ± 4 years; body mass index, 23.2 ± 1.8 kg · m −2; fat-free mass [FFM], 66.8 ± 4.2 kg) were studied on two separate occasions with hyperinsulinemic (0.06 U · kg FFM −1 · h −1) euglycemic clamps (duration, 150 minutes). A primed (150 U), continuous (0.4 U · kg −1 · min −1) infusion of heparin together with 10% intralipid (25 mL · h −1) was infused in both studies from −90 to 150 minutes to maintain comparable levels of plasma NEFA and lipid oxidation rates. Acipimox (500-mg capsules) or placebo were administered orally in a double-blind random fashion at t = −90 and t = 0 minutes. Whole-body lipid and carbohydrate oxidation were measured in the last 30 minutes of both the basal (preclamp) period (−30 to 0 minutes) and the clamp period (120 to 150 minutes). Mean plasma NEFA concentrations were similar throughout both studies (−90 to 0 minutes, 0.84 ± 0.08 v 0.85 ± 0.11 mmol · L −1; 30 to 60 minutes, 0.58 ± 0.03 v 0.58 ± 0.03 mmol · L −1; 120 to 150 minutes, 0.48 ± 0.05 v 0.51 ± 0.11 mmol · L −1; all NS), as were whole-body lipid oxidation rates (−30 to 0 minutes acipimox v placebo 0.71 ± 0.11 v 0.69 ± 0.07 mg · kg FFM −1 · min −1, NS; 120 to 150 minutes, 0.17 ± 0.08 v 0.21 ± 0.07 mg · kg FFM −1 · min −1, NS). Steady-state mean blood glucose levels were the same (120 to 150 minutes, 4.3 ± 0.2 v 4.3 ± 0.1 mmol · L −1). Despite this, there was a significant increase in glucose disposal following acipimox treatment (9.00 ± 0.8 v 7.96 ± 0.8 mg · kg FFM −1 · min −1, P < .01), which could be attributed to a significant increase in nonoxidative glucose disposal (5.36 ± 0.81 v 4.36 ± 0.64 mg · kg FFM −1 · min −1, P = .01). These data suggest that acipimox has a direct (pharmacological) effect on glucose disposal that is not mediated through changes in plasma NEFA concentrations or total-body lipid oxidation rates.