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.
| Original language | English |
|---|---|
| Journal | Diabetes |
| Volume | 55 |
| Issue number | 3 |
| Pages (from-to) | 785-91 |
| Number of pages | 7 |
| ISSN | 0012-1797 |
| Publication status | Published - Mar 2006 |
Keywords
- 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
