Effects of Acute Changes of Plasma Free Fatty Acids on Intramyocellular Fat Content and Insulin Resistance in Healthy Subjects
- 1Division of Endocrinology/Diabetes/Metabolism, the General Clinical Research Center, and the
- 2Department of Radiology, Temple University School of Medicine, Philadelphia, Pennsylvania
Abstract
The reason for the 3- to 4-h delay between a rise in plasma free fatty acid (FFA) levels and the development of insulin resistance remains unknown. In the current study, we have tested the hypothesis that the delay may be caused by the need for plasma FFAs to first enter muscle cells and to be re-esterified there before causing insulin resistance. To this end, we have determined intramyocellular triglyceride (IMCL-TG) content with proton nuclear magnetic resonance (1H-NMR) spectroscopy in healthy volunteers before and 4 h after lowering of plasma FFAs (with euglycemic-hyperinsulinemic clamping) or after increasing plasma FFAs (with lipid plus heparin infusions). Increasing plasma FFAs (from 516 to 1,207 μmol/l or from 464 to 1,857 μmol/l, respectively) was associated with acute increases in IMCL-TG from 100 to 109 ± 5% (P < 0.05) or to 133 ± 11% (P < 0.01), respectively, and with a significant increase in insulin resistance (P < 0.05 after 3.5 h). Lowering of plasma FFAs from 560 to 41 μmol/l was associated with a tendency for IMCL-TG to decrease (from 100 to 95 ± 3%). Changes in plasma FFAs correlated linearly with IMCL-TG (r = 0.74, P < 0.003). The demonstration that acute changes in plasma FFAs were accompanied by corresponding changes in IMCL-TG and with the development of insulin resistance, taken together with previous reports of a close correlation between IMCL-TG and insulin resistance, supported the notion that accumulation of IMCL-TG is a step in the development of FFA-induced insulin resistance.
Footnotes
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Address correspondence and reprint requests to Guenther Boden, Temple University Hospital, 3401 North Broad St., Philadelphia, PA 19140. E-mail: bodengh{at}tuhs.temple.edu.
Received for publication 26 December 2000 and accepted in revised form 10 April 2001.
ANOVA, analysis of variance; EMCL, extramyocellular; FFA, free fatty acid; fov, field of vision; GIR, glucose infusion rate; 1H-NMR, proton nuclear magnetic resonance; IMCL, intramyocellular; IRS-1, insulin receptor substrate-1; LC-CoA, long-chain acyl-CoA; MRI, magnetic resonance imaging; npRQ, nonprotein respiratory quotient; PKC, protein kinase C; TE, echo time; TG, triglyceride; TR, repetition time.
