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Role of glycogen content in insulin resistance in human muscle cells

Lookup NU author(s): Dr Gary Litherland, Dr Nick Morris, Professor Mark Walker, Emeritus Professor Steve Yeaman


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We have used primary human muscle cell cultures to investigate the role of glycogen loading in cellular insulin resistance. Insulin pre-treatment for 2 h markedly impaired insulin signaling, as assessed by protein kinase B (PKB) phosphorylation. In contrast, insulin-dependent glycogen synthesis, glycogen synthase (GS) activation, and GS sites 3 de-phosphorylation were impaired only after 5 h of insulin pre-treatment, whereas 2-deoxyglucose transport was only decreased after 18 h pre-treatment. Insulin-resistant glycogen synthesis was associated closely with maximal glycogen loading. Both glucose limitation and 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) treatment during insulin pre-treatment curtailed glycogen accumulation, and concomitantly restored insulin-sensitive glycogen synthesis and GS activation, although GS de-phosphorylation and PKB phosphorylation remained impaired. Conversely, glycogen super-compensation diminished insulin-sensitive glycogen synthesis and GS activity. Insulin acutely promoted GS translocation to particulate subcellular fractions; this was abolished by insulin pre-treatment, as was GS dephosphorylation therein. Limiting glycogen accumulation during insulin pre-treatment re-instated GS dephosphorylation in particulate fractions, whereas glycogen super-compensation prevented insulin-stimulated GS translocation and dephosphorylation. Our data suggest that diminished insulin signaling alone is insufficient to impair glucose disposal, and indicate a role for glycogen accumulation in inducing insulin resistance in human muscle cells. © 2006 Wiley-Liss, Inc.

Publication metadata

Author(s): Litherland GJ, Morris NJ, Walker M, Yeaman SJ

Publication type: Article

Publication status: Published

Journal: Journal of Cellular Physiology

Year: 2007

Volume: 211

Issue: 2

Pages: 344-352

ISSN (print): 0021-9541

ISSN (electronic): 1097-4652

Publisher: John Wiley & Sons, Inc.


DOI: 10.1002/jcp.20942

PubMed id: 17167773


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Funder referenceFunder name
066495/Z/01/AWellcome Trust