INHIBITION OF INSULIN RELEASE BY CYCLOSPORINE AND PRODUCTION OF PERIPHERAL INSULIN RESISTANCE IN THE DOG

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Abstract
Cyclosporine has been shown to cause glucose intolerance in both humans and animals. This can result from alterations in insulin release, insulin metabolism, the sensitivity of peripheral or hepatic tissues to insulin, or a combination of these factors. The present study was designed to simultaneously evaluate the effect of CsA on these variables. A group of chronically catheterized dogs were administered oral CsA (20 mg/kg/day) for a period of 10 weeks. The glucagon stimulation test (GST) and the euglycemic glucose clamp technique, using a primed continuous infusion of 3H-3-glucose and a continuous insulin infusion (0.8 mU/kg/min), were employed to evaluate pancreatic insulin release, peripheral glucose disposal rate (Rd), hepatic glucose output (HGO), and metabolic clearance rate (MCR) of insulin. The dogs were tested before and after 2, 6, and 10 weeks of CsA administration. Serum CsA levels were 358 .+-. 85, 244 .+-. 48, and 355 .+-. 81 ng/ml at 2, 6, and 10 weeks, respectively (P = NS). Elevated fasting glucose and an abnormal glucose response to an i.v. bolus of glucagon (0.25 U) were noted after 2, 6, and 10 weeks of CsA administration. The areas under the glucose curve (AUCG) for 0-60 min were 9605 .+-. 773, 1163 .+-. 1226, 12380 .+-. 719, and 12626 .+-. 1560 mg/min/dl at 0, 2, 6, and 10 weeks, P(F3, 15=5.1)=0.012, demonstrating a CsA-induced disturbance of glucose homeostasis. The areas under the insulin curve (AUC1) for 0-20 min of the insulin response curve were 2033 .+-. 203, 1089 .+-. 187, 1038 .+-. 179, and 972 .+-. 161 uU/min/dl at 0, 2, 6, and 10 weeks, P (F3, 15 = 13.1) < 0.001, indicating a 50% reduction during CsA treatment. CsA did not affect basal Rd, but peripheral insulin resistance was noted in the insulin-stimulated state. Rd during the third hour of the insulin infusion decreased from 6.72 .+-. 0.69 to 4.42 .+-. 0.44, 5.02 .+-. 0.64, 4.47 .+-. 0.52 mg/kg/min at 0, 2, 6, and 10 weeks, respectively, P (F3, 15 = 6.94) < 0.004. HGO suppression by insulin and MCR of insulin were not altered by CsA. Similarly, glucagon secretion did not appear to be influenced by CsA. In conclusion, this study has simultaneously evaluated the effect of CsA on several aspects of glucose and insulin metabolism in the dog. CsA administration produces abnormal glucose homeostasis by reducing pancreatic insulin release, in addition to inducing peripheral insulin resistance. This may be a useful model to study non-insulin-dependent diabetes, since the combination of elevated fasting glucose, abnormal insulin response, peripheral insulin resistance, and a normal fasting insulin level are present.