Effects of cyclosporine on glucose metabolism

Cyclosporine may have deleterious effects on glucose metabolism. This study was designed to characterize more precisely cyclosporine-induced alterations in glucose homeostasis in a large animal model with hyperglycemic and euglycemic clamp studies in addition to simple bolus glucose (IVGTT) and insulin (IVITT) tolerance tests. In experiment 1, IVGTTs and hyperglycemic clamp studies were performed in eight ewes before and after 4 weeks of cyclosporine treatment. Studies were repeated 4 weeks after cessation of therapy. In experiment 2, IVITTs and euglycemic clamp studies were performed in seven ewes before and after 4 weeks of cyclosporine treatment. Fasting glucose and insulin levels were not affected by cyclosporine treatment. In experiment 1 cyclosporine did not alter IVGTTs; however, during sustained hyperglycemia, cyclosporine caused a 37% decrease in net glucose disposal (p < 0.001) and a 39% decrease in plateau plasma insulin levels (p < 0.05). In experiment 2 cyclosporine had no effect on IVITTs. Plateau insulin values in euglycemic clamp studies were lowered by 27% (p < 0.05) after cyclosporine treatment. In addition, the metabolic clearance rate of insulin was increased by 25% (p < 0.05), and the steady-state insulin clearance rate was increased by 16% (p < 0.003). Measurements of insulin sensitivity were unchanged by cyclosporine. These experiments suggest that cyclosporine treatment results in impairment of sustained synthesis and secretion of insulin, increased insulin clearance, and unaltered insulin sensitivity.