Infusing lipid raises plasma free fatty acids and induces insulin resistance in muscle microvasculature

Abstract

Context: Insulin recruits muscle microvasculature, which increases the endothelial exchange surface area to facilitate substrate delivery. Elevated plasma concentrations of free fatty acids (FFAs) cause insulin resistance.

Objectives: The aim of the study was to examine whether FFAs cause insulin resistance in human muscle microvasculature.

Setting: The study was conducted at the General Clinical Research Center at the University of Virginia.

Methods: Twenty-two healthy subjects were studied under two protocols designed to raise plasma insulin concentrations to postprandial levels using either an insulin infusion or a mixed meal challenge. Within each protocol, subjects were studied twice. In random order, they received a 5-h systemic infusion of either saline or Intralipid/heparin. Three hours into the infusion, baseline muscle microvascular blood volume (MBV), microvascular flow velocity, and microvascular blood flow (MBF) were measured. Each subject was then given either the mixed meal or a 1 mU/kg x min insulin clamp for 2 h. Microvascular parameters were again obtained 2 h after the meal or at the end of insulin infusion.

Results: Meal feeding and insulin infusion raised plasma insulin concentrations to approximately 200 pm, and each significantly increased muscle MBV (P = 0.03 and P < 0.01, respectively). MBF trended up after meal feeding (P = 0.08) and increased significantly after insulin infusion (P = 0.02). In the presence of Intralipid, neither the meal nor the insulin infusion increased muscle MBV and MBF.

Conclusions: Compared to saline, lipid infusion raises plasma FFA concentrations and blocks the ability of insulin or meal to recruit muscle microvasculature. High plasma FFA concentrations may contribute to muscle insulin resistance and the microvascular complications of diabetes.

Figures

Figure 1

Changes in biochemical parameters after meal ingestion in protocol 1 subjects. Open circles, Saline infusion; closed circles, Intralipid infusion. *, P < 0.04; **, P = 0.01, compared with saline infusion. Data are presented as mean ± sem.

Figure 2

Muscle MBV (top), MFV (middle), and MBF (bottom) at baseline and at 120 min after a mixed meal ingestion in the presence of Intralipid + heparin infusion or saline infusion. *, P = 0.03, compared with baseline (n = 10). Data are presented as mean ± sem.

Figure 3

Changes in biochemical parameters during insulin clamp in protocol 2 subjects. Open circles, Saline infusion; closed circles, Intralipid infusion. *, P = 0.003, compared with saline infusion. Data are presented as mean ± sem.

Figure 4

Muscle MBV (top), MFV (middle), and MBF (bottom) at baseline and at end of 120 min insulin infusion in the presence of Intralipid/heparin infusion or saline infusion. *, P < 0.01; **, P < 0.003; ***, P = 0.02, compared with baseline (n = 12). Data are presented as mean ± sem.