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Improved skeletal muscle oxidative enzyme activity and restoration of PGC-1α and PPARβ/δ gene expression upon rosiglitazone treatment in obese patients with type 2 diabetes mellitus

International Journal of Obesity volume 31, pages 1302–1310 (2007)Cite this article

Abstract

Objective:

To examine whether rosiglitazone alters gene expression of some key genes involved in mitochondrial biogenesis and oxidative capacity in skeletal muscle of type 2 diabetic patients, and whether this is associated with alterations in skeletal muscle oxidative capacity and lipid content.

Design:

Skeletal muscle gene expression, mitochondrial protein content, oxidative capacity and lipid accumulation were measured in muscle biopsies obtained from diabetic patients, before and after 8 weeks of rosiglitazone treatment, and matched controls. Furthermore, whole-body insulin sensitivity and substrate utilization were assessed.

Subjects:

Ten obese type 2 diabetic patients and 10 obese normoglycemic controls matched for age and BMI.

Methods:

Gene expression and mitochondrial protein content of complexes I–V of the respiratory chain were measured by quantitative polymerase chain reaction and Western blotting, respectively. Histochemical staining was used to quantify lipid accumulation and complex II succinate dehydrogenase (SDH) activity. Insulin sensitivity and substrate utilization were measured during a hyperinsulinemic–euglycemic clamp with indirect calorimetry.

Results:

Skeletal-muscle mRNA of PGC-1α and PPARβ/δ – but not of other genes involved in glucose, fat and oxidative metabolism – was significantly lower in diabetic patients (P<0.01). Rosiglitazone significantly increased PGC-1α (∼2.2-fold, P<0.01) and PPARβ/δ (∼2.6-fold, P<0.01), in parallel with an increase in insulin sensitivity, SDH activity and metabolic flexibility (P<0.01). Surprisingly, none of the measured mitochondrial proteins was reduced in type 2 diabetic patients, nor affected by rosiglitazone treatment. No alterations were seen in muscular fat accumulation upon treatment.

Conclusion:

These results suggest that the insulin-sensitizing effect of rosiglitazone may involve an effect on muscular oxidative capacity, via PGC-1α and PPARβ/δ, independent of mitochondrial protein content and/or changes in intramyocellular lipid.

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Acknowledgements

This work was financially supported by a grant from Glaxo SmithKline (GSK). Dr P Schrauwen was supported by a grant from the Royal Netherlands Academy of Arts and Sciences, and Dr M Hesselink is supported by a VIDI grant for innovative research from The Netherlands Organization for Scientific Research (Grant 917.66.359).

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Authors and Affiliations

  1. Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands

    M Mensink & P Schrauwen

  2. Department of Movement Sciences, Maastricht University, Maastricht, The Netherlands

    M K C Hesselink & G Schaart

  3. Centre for Physical Activity and Nutrition (C-PAN), School of Exercise and Nutrition Sciences, Deakin University, Melbourne, Australia

    A P Russell

  4. Department of Internal Medicine, Academic Hospital Maastricht, Maastricht, The Netherlands

    J-P Sels

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  1. M Mensink
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  2. A P Russell
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  3. G Schaart
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  4. J-P Sels
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  5. P Schrauwen
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Correspondence to M Mensink.

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Mensink, M., Hesselink, M., Russell, A. et al. Improved skeletal muscle oxidative enzyme activity and restoration of PGC-1α and PPARβ/δ gene expression upon rosiglitazone treatment in obese patients with type 2 diabetes mellitus. Int J Obes 31, 1302–1310 (2007). https://doi.org/10.1038/sj.ijo.0803567

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