Metformin enhances insulin signalling in insulin‐dependent and ‐independent pathways in insulin resistant muscle cells

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Abstract
Metformin lowers blood glucose levels in type 2 diabetic patients. To evaluate the insulin sensitizing action of metformin on skeletal muscle cells, we have used C2C12 skeletal muscle cells differentiated in chronic presence or absence of insulin. Metformin was added during the last 24 h of differentiation of the C2C12 myotubes. Insulin‐stimulated tyrosine phosphorylation of insulin receptor (IR) and insulin receptor substrate‐1 (IRS‐1) was determined. Chronic insulin treatment resulted in 60 and 40% reduction in insulin‐stimulated tyrosine phosphorylation of IR and IRS‐1, respectively. Treatment with metformin was able to increase the tyrosine phosphorylation of IR and IRS‐1 by 100 and 90% respectively. Chronic insulin treatment drastically reduced (45%) insulin‐stimulated phosphatidyl inositol 3‐kinase (PI 3‐kinase) activity. Metformin treatment restored PI 3‐kinase activity in insulin‐resistant myotubes. Insulin‐stimulated glucose uptake was impaired in chronically insulin‐treated myotubes. Metformin increased basal glucose uptake to significant levels (PBritish Journal of Pharmacology (2002) 137, 329–336. doi:10.1038/sj.bjp.0704878