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

• Published in: Diabetes (New York, N.Y.) Vol. 55; no. 3; pp. 785 - 791
• Main Authors: Bouzakri, Karim, Karlsson, Håkan K.R., Vestergaard, Henrik, Madsbad, Sten, Christiansen, Erik, Zierath, Juleen R.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.03.2006
• Subjects: Adult; Biological and medical sciences; Biopsy; Diabetes; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Extracellular Signal-Regulated MAP Kinases - metabolism; Fatty Acids, Nonesterified - blood; Female; Fundamental and applied biological sciences. Psychology; Glucose; Glucose - metabolism; Health aspects; Humans; Immunosuppressive Agents - therapeutic use; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Kidney Transplantation; Kidney transplants; Kinases; Male; Medical sciences; Metabolism; Muscle, Skeletal - metabolism; Musculoskeletal system; Pancreas; Pancreas Transplantation; Pancreas transplants; Phosphatidylinositol 3-Kinases - metabolism; Phosphoproteins - metabolism; Phosphorylation; Plasma; Proto-Oncogene Proteins c-akt - metabolism; Serine - metabolism; Signal transduction; Signal Transduction - physiology; Striated muscle. Tendons; Transplantation; Vertebrates: osteoarticular system, musculoskeletal system; Endocrinopathy; Phosphorylation; Aminoacid; Diabetes mellitus; Serine; Insulin resistance; Transplantation; Striated muscle; Pancreas; Insulin receptor substrate protein
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.55.03.06.db05-0796

IRS-1 Serine Phosphorylation and Insulin Resistance in Skeletal Muscle From Pancreas Transplant Recipients Karim Bouzakri 1 , Håkan K.R. Karlsson 1 , Henrik Vestergaard 2 , Sten Madsbad 3 , Erik Christiansen 4 and Juleen R. Zierath 1 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 Abstract 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. ERK, extracellular signal–regulated kinase IRS, insulin receptor substrate MAPK, mitogen-activated protein kinase NEFA, nonesterified free fatty acid PI, phosphatidylinositol Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted November 28, 2005. Received June 22, 2005. DIABETES