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Diabetes 55:785-791, 2006
DOI: 10.2337/diabetes.55.03.06.db05-0796
© 2006 by the American Diabetes Association
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Pathophysiology

IRS-1 Serine Phosphorylation and Insulin Resistance in Skeletal Muscle From Pancreas Transplant Recipients

Karim Bouzakri1, Håkan K.R. Karlsson1, Henrik Vestergaard2, Sten Madsbad3, Erik Christiansen4, and Juleen R. Zierath1

1 Section of Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
2 Division of Endocrinology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
3 Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
4 Department of Medicine, Division of Endocrinology, Roskilde County Hospital, Copenhagen, Denmark

Address correspondence and reprint requests to Professor Juleen R. Zierath, Karolinska Institute, Department of Molecular Medicine and Surgery, Section of Integrative Physiology, von Eulers väg 4, 4th floor, S-171 77 Stockholm, Sweden. E-mail: juleen.zierath{at}ki.se

Abbreviations: ERK, extracellular signal–regulated kinase; IRS, insulin receptor substrate; MAPK, mitogen-activated protein kinase; NEFA, nonesterified free fatty acid; PI, phosphatidylinositol

Insulin-dependent diabetic recipients of successful pancreas allografts achieve self-regulatory insulin secretion and discontinue exogenous insulin therapy; however, chronic hyperinsulinemia and impaired insulin sensitivity generally develop. To determine whether insulin resistance is accompanied by altered signal transduction, skeletal muscle biopsies were obtained from pancreas-kidney transplant recipients (n = 4), nondiabetic kidney transplant recipients (receiving the same immunosuppressive drugs; n = 5), and healthy subjects (n = 6) before and during a euglycemic-hyperinsulinemic clamp. Basal insulin receptor substrate (IRS)-1 Ser (312) and Ser (616) phosphorylation, IRS-1–associated phosphatidylinositol 3-kinase activity, and extracellular signal–regulated kinase (ERK)-1/2 phosphorylation were elevated in pancreas-kidney transplant recipients, coincident with fasting hyperinsulinemia. Basal IRS-1 Ser (312) and Ser (616) phosphorylation was also increased in nondiabetic kidney transplant recipients. Insulin increased phosphorylation of IRS-1 at Ser (312) but not Ser (616) in healthy subjects, with impairments noted in nondiabetic kidney and pancreas-kidney transplant recipients. Insulin action on ERK-1/2 and Akt phosphorylation was impaired in pancreas-kidney transplant recipients and was preserved in nondiabetic kidney transplant recipients. Importantly, insulin stimulation of the Akt substrate AS160 was impaired in nondiabetic kidney and pancreas-kidney transplant recipients. In conclusion, peripheral insulin resistance in pancreas-kidney transplant recipients may arise from a negative feedback regulation of the canonical insulin-signaling cascade from excessive serine phosphorylation of IRS-1, possibly as a consequence of immunosuppressive therapy and hyperinsulinemia.


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