The effect of muraglitazar on adiponectin signalling, mitochondrial function and fat oxidation genes in human skeletal muscle in vivo

D. K. Coletta, M. Fernandez, E. Cersosimo, A. Gastaldelli, N. Musi, R. A. Defronzo

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Aims: The molecular mechanisms by which muraglitazar (peroxisome proliferator-activated receptor γ/α agonist) improves insulin sensitivity in Type 2 diabetes mellitus are not fully understood. We hypothesized that muraglitazar would increase expression of 5′-monophosphate-activated protein kinase and genes involved in adiponectin signalling, free fatty acid oxidation and mitochondrial function in skeletal muscle. Methods: Sixteen participants with Type 2 diabetes received muraglitazar, 5 mg/day (n = 12) or placebo (n = 4). Before and after 16 weeks, participants had vastus lateralis muscle biopsy followed by 180 min euglycaemic hyperinsulinaemic clamp. Results: Muraglitazar increased plasma adiponectin (9.0 ± 1.1 to 17.8 ± 1.5 μg/ml, P < 0.05), while no significant change was observed with placebo. After 16 weeks with muraglitazar, fasting plasma glucose declined by 31%, fasting plasma insulin decreased by 44%, insulin-stimulated glucose disposal increased by 81%, HbA1c decreased by 21% and plasma triglyceride decreased by 39% (all P < 0.05). Muraglitazar increased mRNA levels of 5′-monophosphate-activated protein kinase, adiponectin receptor 1, adiponectin receptor 2, peroxisome proliferator-activated receptor gamma coactivator-1 alpha and multiple genes involved in mitochondrial function and fat oxidation. In the placebo group, there were no significant changes in expression of these genes. Conclusions: Muraglitazar increases plasma adiponectin, stimulates muscle 5′-monophosphate-activated protein kinase expression and increases expression of genes involved in adiponectin signalling, mitochondrial function and fat oxidation. These changes represent important cellular mechanisms by which dual peroxisome proliferator-activated receptor agonists improve skeletal muscle insulin sensitivity.

Original languageEnglish (US)
Pages (from-to)657-664
Number of pages8
JournalDiabetic Medicine
Volume32
Issue number5
DOIs
StatePublished - May 1 2015

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ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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