IRS-1 serine phosphorylation and insulin resistance in skeletal muscle from pancreas transplant recipients
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Diabetes |
Volume | 55 |
Issue number | 3 |
Pages (from-to) | 785-91 |
Number of pages | 7 |
ISSN | 0012-1797 |
Publication status | Published - Mar 2006 |
- Adult, Extracellular Signal-Regulated MAP Kinases, Fatty Acids, Nonesterified, Female, Glucose, Humans, Immunosuppressive Agents, Insulin Receptor Substrate Proteins, Insulin Resistance, Kidney Transplantation, Male, Muscle, Skeletal, Pancreas Transplantation, Phosphatidylinositol 3-Kinases, Phosphoproteins, Phosphorylation, Proto-Oncogene Proteins c-akt, Serine, Signal Transduction, Journal Article, Research Support, Non-U.S. Gov't
Research areas
ID: 174866417