Free fatty acids induce insulin resistance in both cardiac and skeletal muscle microvasculature in humans

Abstract

Context: Insulin recruits microvasculature in both cardiac and skeletal muscle, which increases the endothelial exchange surface area. Plasma concentrations of free fatty acids (FFAs) are elevated in patients with diabetes, which impairs insulin-mediated skeletal muscle microvascular recruitment.

Objective: The objective of the study was to examine whether elevated FFAs likewise cause insulin resistance in cardiac muscle microvasculature.

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

Methods: Twenty-two healthy, young adults were studied twice in random order after an overnight fast. Each subject received a 5-h systemic infusion of either saline or Intralipid/heparin with a 1 mU/min · kg euglycemic insulin clamp superimposed for the last 2 h. Cardiac and forearm skeletal muscle microvascular blood volume (MBV) and flow velocity were measured and microvascular blood flow (MBF) calculated before and at the end of the insulin infusion.

Results: Insulin significantly increased MBV and MBF in both cardiac (P < 0.0001 for both) and skeletal (P = 0.008 and < 0.03, respectively) muscle. Microvascular flow velocity increased slightly but significantly in the skeletal (P = 0.04) but not in cardiac muscle. Lipid infusion lowered insulin-stimulated whole-body glucose disposal and abolished insulin-mediated increases in MBV and MBF in both cardiac and skeletal muscle. Whole-body insulin sensitivity predicted skeletal but not cardiac muscle microvascular responses to insulin. Insulin even decreased skeletal muscle MBV during lipid infusion in subjects who were moderately sensitive to insulin metabolically.

Conclusions: In conclusion, high plasma concentrations of FFAs cause insulin resistance in cardiac as well as skeletal muscle microvasculature in healthy humans. This may contribute to the association of cardiac complications with metabolic insulin resistance in diabetes.

Figures

Fig. 1.

Myocardial MBV (A), MFV (B), and MBF (C) at baseline and at the end of the 120-min insulin infusion. The P values were derived with two-way, repeated-measures ANOVA with Holm-Sidak post hoc analysis. P < 0.001 for MBV, P = 0.101 for MFV, and P < 0.001 for MBF. *, P < 0.0001 compared with control baseline; #, P < 0.02 compared with control baseline.

Fig. 2.

Skeletal muscle MBV (A), MFV (B), and MBF (C) at baseline and at the end of the 120-min insulin infusion. The P values were derived with two-way, repeated-measures ANOVA with Holm-Sidak post hoc analysis. P < 0.001 for MBV, P <0.001 for MFV, and P = 0.001 for MBF. *, P = 0.008 compared with control baseline; **, P = 0.04 compared with control baseline; ***, P < 0.03 compared with control baseline; #, P < 0.02 compared with lipid baseline; ##, P = 0.006 compared with lipid baseline.

Fig. 3.

Regression analysis of insulin-induced changes in MBV between cardiac and skeletal muscle microvascular beds.

Fig. 4.

Effect of lipid infusion on steady-state, whole-body glucose disposal based on whole-body metabolic insulin sensitivity. L, Lower tertile (GIR 7 mg/min · kg, n = 6). *, P < 0.0001 compared with control L; **, P = 0.001 compared with control M; #, P = 0.05 compared with control M; ##, P = 0.001 compared with control H; @, P < 0.003 compared with lipid L; @@, P < 0.0002 compared with lipid L; @@, P < 0.0002 compared with lipid M.

Fig. 5.

Cardiac muscle MBV based on whole-body metabolic insulin sensitivity in the absence or presence of lipid infusion. A, Lower tertile (GIR 7 mg/min · kg, n = 6). P values were derived with two-way, repeated-measures ANOVA with Holm-Sidak post hoc analysis. P = 0.172 for lower tertile, P < 0.001 for middle tertile, and P < 0.03 for upper tertile. *, P = 0.005 compared with control baseline; **, P = 0.05 compared with control baseline; #, P = 0.007 compared with control baseline.

Fig. 6.

Skeletal muscle MBV based on whole-body metabolic insulin sensitivity in the absence or presence of lipid infusion. A, Lower tertile (GIR 7 mg/min · kg, n = 6). P values were derived with two-way, repeated-measures ANOVA with Holm-Sidak post hoc analysis. P = 0.15 for lower tertile, P < 0.02 for middle tertile, and P < 0.01 for upper tertile. *, P < 0.03 compared with control baseline; #, P = 0.009 compared with control baseline.