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


METHODS
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.
Division of Endocrinology and Metabolism, Department of Internal Medicine and General Clinical Research Center, University of Virginia Health System, P.O. Box 801410, Charlottesville, Virginia 22908, USA.
Jia
J
Liu
Linda A
LA
Jahn
Dale E
DE
Fowler
Eugene J
EJ
Barrett
Wenhong
W
Cao
Zhenqi
Z
Liu
D000328:Adult; D001794:Blood Pressure / Q000502:physiology; D002196:Capillaries / Q000502:physiology*; D005217:Fat Emulsions, Intravenous / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005260:Female; D005542:Forearm / Q000098:blood supply; D006321:Heart / Q000502:physiology*; D006801:Humans; D006946:Hyperinsulinism / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008055:Lipids / Q000097:blood; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply / Q000502:physiology*; D009206:Myocardium; D012039:Regional Blood Flow / Q000502:physiology
D005217:Fat Emulsions, Intravenous; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids