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p38 MAPK activation upregulates proinflammatory pathways in skeletal muscle cells from insulin-resistant type 2 diabetic patients

Lookup NU author(s): Dr Audrey Brown, Dr Peter Avery, Emeritus Professor Steve Yeaman, Professor Mark Walker

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Abstract

Skeletal muscle is the key site of peripheral insulin resistance in type 2 diabetes. Insulin-stimulated glucose uptake is decreased in differentiated diabetic cultured myotubes, which is in keeping with a retained genetic/epigenetic defect of insulin action. We investigated differences in gene expression during differentiation between diabetic and control muscle cell cultures. Microarray analysis was performed using skeletal muscle cell cultures established from type 2 diabetic patients with a family history of type 2 diabetes and clinical evidence of marked insulin resistance and nondiabetic control subjects with no family history of diabetes. Genes and pathways upregulated with differentiation in the diabetic cultures, compared with controls, were identified using Gene Spring and Gene Set Enrichment Analysis. Gene sets upregulated in diabetic myotubes were associated predominantly with inflammation. p38 MAPK was identified as a key regulator of the expression of these proinflammatory gene sets, and p38 MAPK activation was found to be increased in the diabetic vs. control myotubes. Although inhibition of p38 MAPK activity decreased cytokine gene expression from the cultured diabetic myotubes significantly, it did not improve insulin-stimulated glucose uptake. Increased cytokine expression driven by increased p38 MAPK activation is a key feature of cultured myotubes derived from insulinresistant type 2 diabetic patients. p38 MAPK inhibition decreased cytokine expression but did not affect the retained defect of impaired insulin action in the diabetic muscle cells.

Publication metadata

Author(s): Brown AE, Palsgaard J, Borup R, Avery P, Gunn DA, De Meyts P, Yeaman SJ, Walker M

Publication type: Article

Publication status: Published

Journal: American Journal of Physiology Endocrinology and Metabolism

Year: 2015

Volume: 308

Issue: 1

Pages: E63-E70

Print publication date: 01/01/2015

Acceptance date: 30/10/2014

ISSN (print): 0193-1849

ISSN (electronic): 1522-1555

Publisher: American Physiological Society

URL: http://dx.doi.org/10.1152/ajpendo.00115.2014

DOI: 10.1152/ajpendo.00115.2014

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