Lipid-Induced Insulin Resistance Is Not Mediated by Impaired Transcapillary Transport of Insulin and Glucose in Humans
- Julia Szendroedi1,2,
- Martin Frossard3,4,
- Nikolas Klein3,
- Christian Bieglmayer3,4,
- Oswald Wagner4,
- Giovanni Pacini5,
- Janette Decker1,
- Peter Nowotny1,
- Markus Müller3 and
- Michael Roden1,2⇓
- 1Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Düsseldorf, Germany
- 2Department of Metabolic Diseases, Heinrich Heine University, Düsseldorf, Germany
- 3Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
- 4Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
- 5Metabolic Unit, ISIB-CNR, Corso Stati Uniti, Padova, Italy
- Corresponding author: Michael Roden, .
J.S. and M.F. contributed equally to this study.
Increased lipid availability reduces insulin-stimulated glucose disposal in skeletal muscle, which is generally explained by fatty acid–mediated inhibition of insulin signaling. It remains unclear whether lipids also impair transcapillary transport of insulin and glucose, which could become rate controlling for glucose disposal. We hypothesized that lipid-induced insulin resistance is induced by inhibiting myocellular glucose uptake and not by interfering with the delivery of insulin or glucose. We measured changes in interstitial glucose and insulin in skeletal muscle of healthy volunteers during intravenous administration of triglycerides plus heparin or glycerol during physiologic and supraphysiologic hyperinsulinemia, by combining microdialysis with oral glucose tolerance tests and euglycemic-hyperinsulinemic clamps. Lipid infusion reduced insulin-stimulated glucose disposal by ∼70% (P < 0.05) during clamps and dynamic insulin sensitivity by ∼12% (P < 0.05) during oral glucose loading. Dialysate insulin and glucose levels were unchanged or even transiently higher (P < 0.05) during lipid than during glycerol infusion, whereas regional blood flow remained unchanged. These results demonstrate that short-term elevation of free fatty acids (FFAs) induces insulin resistance, which in skeletal muscle occurs primarily at the cellular level, without impairment of local perfusion or transcapillary transport of insulin and glucose. Thus, vascular effects of FFAs are not rate controlling for muscle insulin-stimulated glucose disposal.
- Received January 29, 2012.
- Accepted June 18, 2012.
- © 2012 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.