Tacrolimus and Sirolimus Cause Insulin Resistance in Normal Sprague Dawley Rats

Abstract

Tacrolimus-sirolimus immunosuppression has improved islet graft survival but may affect islet function. We studied the effects of tacrolimus, sirolimus, or both in normal adult male Sprague Dawley rats. Glucose and insulin response to oral glucose load and pancreas pathology were evaluated after two weeks of daily tacrolimus (1-8 mg/kg/day), sirolimus (0.08-8 mg/kg/day), or low-dose sirolimus (0.08 mg/kg/day) plus tacrolimus (1 mg/kg/day) treatment compared to controls. Tacrolimus and sirolimus each caused dose-dependent hyperglycemia with hyperinsulinemia in response to oral glucose compared to controls, suggesting insulin resistance. At the highest doses of sirolimus, fasting insulin concentrations were high and did not increase with oral glucose suggesting loss of first phase insulin release. The combination of low doses of tacrolimus and sirolimus, at concentrations used in clinical transplantation, resulted in hyperglycemia without hyperinsulinemia after oral glucose administration. The combination of tacrolimus and sirolimus decreased islet size, and increased islet apoptosis more than either medication alone, or controls. In summary, short-term therapy with either tacrolimus or sirolimus causes insulin resistance in normal rats. Combination tacrolimus-sirolimus causes greater islet changes suggesting early islet failure.