Mitochondrial substrate availability and its role in lipid-induced insulin resistance and proinflammatory signaling in skeletal muscle

Lipina, C., Macrae, K., Suhm, T., Weigert, C., Blachnio-Zabielska, A., Baranowski, M., Gorski, J., Burgess, K. and Hundal, H. S. (2013) Mitochondrial substrate availability and its role in lipid-induced insulin resistance and proinflammatory signaling in skeletal muscle. Diabetes, 62(10), pp. 3426-3436. (doi:10.2337/db13-0264) (PMID:23733201) (PMCID:PMC3781443)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Burgess, Dr Karl
Authors: Lipina, C., Macrae, K., Suhm, T., Weigert, C., Blachnio-Zabielska, A., Baranowski, M., Gorski, J., Burgess, K., and Hundal, H. S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Diabetes
Publisher:American Diabetes Association
ISSN:0012-1797
ISSN (Online):1939-327X
Copyright Holders:Copyright © 2013 e American Diabetes Association
First Published:First published in Diabetes 62(10):3426-3436
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
620261Metabolomic characterisation of clinical biofilms: monitoring of their formation and dispersal on different nanoscale patterned surfaces (ISSF Catalyst)Karl BurgessWellcome Trust (WELLCOME)097821/Z/11/ZIII - PARASITOLOGY