Effects of acute lipid overload on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance

Abstract

We hypothesized that acute lipid-induced insulin resistance would be attenuated in high-oxidative muscle of lean trained (LT) endurance athletes due to their enhanced metabolic flexibility and mitochondrial capacity. Lean sedentary (LS), obese sedentary (OS), and LT participants completed two hyperinsulinemic euglycemic clamp studies with and without (glycerol control) the coinfusion of Intralipid. Metabolic flexibility was measured by indirect calorimetry as the oxidation of fatty acids and glucose during fasted and insulin-stimulated conditions, the latter with and without lipid oversupply. Muscle biopsies were obtained for mitochondrial and insulin-signaling studies. During hyperinsulinemia without lipid, glucose infusion rate (GIR) was lowest in OS due to lower rates of nonoxidative glucose disposal (NOGD), whereas state 4 respiration was increased in all groups. Lipid infusion reduced GIR similarly in all subjects and reduced state 4 respiration. However, in LT subjects, fat oxidation was higher with lipid oversupply, and although glucose oxidation was reduced, NOGD was better preserved compared with LS and OS subjects. Mitochondrial performance was positively associated with better NOGD and insulin sensitivity in both conditions. We conclude that enhanced mitochondrial performance with exercise is related to better metabolic flexibility and insulin sensitivity in response to lipid overload.

Keywords: lipids; mitochondria; skeletal muscle.

Fig. 1.

Study design. MBx, muscle biopsy.

Fig. 2.

Insulin sensitivity and glucose metabolism. A: total glucose disposal as determined by the glucose infusion rate (GIR), normalized to fat-free mass (FFM), during steady-state was determined by the hyperinsulinemic euglycemic clamp described in methods. B and C: glucose oxidation (B) and nonoxidative glucose disposal (NOGD; C), calculated as %total glucose disposal. Black bars, lean trained; gray bars, lean sedentary; open bars, obese sedentary. ^A,BP < 0.05, group difference; noncorresponding letters are different. *P < 0.05 different from control. Data are means ± SE.

Fig. 3.

Mitochondrial respiration. Skeletal muscle fiber bundles were prepared from biopsy samples, as described in methods. Mean O₂ flux, normalized to dry tissue weight (mg), for preinfusion (black bars) and postinfusion (open bars) is presented for the control (A–C) and lipid oversupply (D–F) conditions. ^A,BP < 0.05, group difference; noncorresponding letters are different. *P < 0.05 different from preinfusion. Data are means ± SE. LT, lean trained; LS, lean sedentary; OS, obese sedentary.

Fig. 4.

Skeletal muscle proteins related to insulin sensitivity and metabolic flexibility. Akt phosphorylation (p-Akt; A and C), and p-GSK-3β (B and D) measured by Western blot, as described in methods. Data represent preinfusion (black bars) and insulin-stimulated (open bars) quantified values for control (A and C) and lipid (C and D) infusions, respectively. Representative immunoblots arranged to coincide with figures. ^A,BP < 0.05, group difference; noncorresponding letters are different. *P < 0.05 different from preinfusion. Data are means ± SE. Black lines through immunoblots represent spliced images to follow group and treatment order.