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The Journal of Experimental Biology 205, 3739-3746 (2002)
Copyright © 2002 The Company of Biologists Limited

Gliclazide increases insulin receptor tyrosine phosphorylation but not p38 phosphorylation in insulin-resistant skeletal muscle cells

Naresh Kumar and Chinmoy S. Dey^*

Signal Transduction Research Laboratory, Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Punjab, India

^* Author for correspondence (e-mail: csdey{at}niper.ac.in)

Accepted 23 August 2002

Sulfonylurea drugs are used in the treatment of type 2 diabetes. The mechanism of action of sulfonylureas is to release insulin from pancreatic cells and they have been proposed to act on insulin-sensitive tissues to enhance glucose uptake. The goal of the present study was to test the hypothesis that gliclazide, a second-generation sulfonylurea, could enhance insulin signaling in insulin-resistant skeletal muscle cells. We demonstrated that gliclazide enhanced insulin-stimulated insulin receptor tyrosine phosphorylation in insulin-resistant skeletal muscle cells. Although insulin receptor substrate-1 tyrosine phosphorylation was unaffected by gliclazide treatment, phosphatidylinositol 3-kinase activity was partially restored by treatment with gliclazide. No increase in 2-deoxyglucose uptake in insulin-resistant cells by treatment with gliclazide was observed. Further investigations into the mitogen-activated protein kinase (MAPK) pathway revealed that insulin-stimulated p38 phosphorylation was impaired, as compared with extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), which were phosphorylated normally in insulin-resistant cells. Treatment with gliclazide could not restore p38 phosphorylation in insulin-resistant cells. We propose that gliclazide can regulate part of the insulin signaling in insulin-resistant skeletal muscle, and p38 could be a potential therapeutic target for glucose uptake to treat insulin resistance.

Key words: insulin resistance, skeletal muscle, insulin signaling, glucose uptake, gliclazide, p38

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