Mitochondrial Substrate Availability and Its Role in Lipid-Induced Insulin Resistance and Proinflammatory Signaling in Skeletal Muscle

  1. Harinder S. Hundal1
  1. 1Division of Cell Signalling and Immunology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee, U.K.
  2. 2Division of Endocrinology, Diabetology, Angiology, Nephrology, Pathobiochemistry and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, Tübingen, Germany
  3. 3Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany (Paul Langerhans Institute Tübingen), Member of the German Centre for Diabetes Research
  4. 4Department of Physiology, Medical University of Bialystok, Bialystok, Poland
  5. 5Glasgow Polyomics Metabolomics Facility, University of Glasgow, Glasgow, U.K.
  1. Corresponding author: Harinder S. Hundal, h.s.hundal{at}dundee.ac.uk.

Abstract

The relationship between glucose and lipid metabolism has been of significant interest in understanding the pathogenesis of obesity-induced insulin resistance. To gain insight into this metabolic paradigm, we explored the potential interplay between cellular glucose flux and lipid-induced metabolic dysfunction within skeletal muscle. Here, we show that palmitate (PA)-induced insulin resistance and proinflammation in muscle cells, which is associated with reduced mitochondrial integrity and oxidative capacity, can be attenuated under conditions of glucose withdrawal or glycolytic inhibition using 2-deoxyglucose (2DG). Importantly, these glucopenic-driven improvements coincide with the preservation of mitochondrial function and are dependent on PA oxidation, which becomes markedly enhanced in the absence of glucose. Intriguingly, despite its ability to upregulate mitochondrial PA oxidation, glucose withdrawal did not attenuate PA-induced increases in total intramyocellular diacylglycerol and ceramide. Furthermore, consistent with our findings in cultured muscle cells, we also report enhanced insulin sensitivity and reduced proinflammatory tone in soleus muscle from obese Zucker rats fed a 2DG-supplemented diet. Notably, this improved metabolic status after 2DG dietary intervention is associated with markedly reduced plasma free fatty acids. Collectively, our data highlight the key role that mitochondrial substrate availability plays in lipid-induced metabolic dysregulation both in vitro and in vivo.

Footnotes

  • Received February 15, 2013.
  • Accepted May 29, 2013.

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  1. Diabetes vol. 62 no. 10 3426-3436
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