Peripheral and hepatic insulin sensitivity in non-insulin-dependent diabetes mellitus: Effect of nonesterified fatty acids

Abstract

Plasma nonesterified fatty acid (NEFA) levels are increased in the insulin-stimulated state in non-insulin-dependent diabetes mellitus (NIDDM) and may contribute to the decrease in peripheral and hepatic insulin sensitivity. To test this hypothesis and to avoid the confounding effect of obesity, we examined the effect of decreasing plasma NEFA levels on peripheral and total glucose metabolism in eight non-obese, NIDDM patients. Each received 250 mg Acipimox (a nicotinic acid analogue) or placebo at 0 and 120 minutes on separate occasions. [6,6- 2H 2]-glucose (0 to 300 minutes) and insulin (120 to 300 minutes) were infused in each study, and isoglycemia was maintained. Plasma NEFA levels (140 ± 30 v 600 ± 70 μmol/L [SEM]; P < .001) and forearm NEFA uptake measured with [1- 14C]-palmitate (+93 ± 21 v +313 ± 42 nmol · 100 mL forearm −1; P < .001) were decreased with acipimox during the basal period (90 to 120 minutes), with no change in forearm glucose uptake (+334 ± 80 and +330 ± 60 nmol · 100 mL forearm −1 · min −1) and hepatic glucose output ([HGO] 13.6 ± 0.9 and 13.4 ± 0.7 μmol · kg −1 · min −1). Serum insulin (256 ± 12 and 266 ± 18 pmol/L) and plasma glucose (9.5 ± 0.6 and 9.4 ± 0.5 mmol/L) levels were comparable during the clamp period (270 to 300 minutes). Plasma NEFA levels (65 ± 12 v 150 ± 20 μmol/L; P < .005) and forearm uptake (+39 ± 8 v +81 ± 14 nmol · 100 mL forearm −1 · min −1; P < .01) remained lower with acipimox, but with no significant effect on forearm glucose uptake (+1,087 ± 300 and +1,414 ± 520 nmol · 100 mL forearm −1 · min −1). However, HGO was decreased (1.0 ± 0.4 v 2.1 ± 0.5 μmol · kg −1 · min −1; P = .02). Therefore, short-term decreases of plasma NEFA levels do not improve peripheral insulin sensitivity at low insulin levels in NIDDM, but increase the suppressive action of insulin on HGO.