Diabetogenicity of Cyclosporine and Tacrolimus

Overview

Cyclosporine (CsA) and Tacrolimus (Tac) are immunosuppressive agents comprising the cornerstone of treatment among organ transplant recipients. Unfortunately diabetes is a known complication after transplantation, yet the underlying mechanisms of this type of diabetes are still unresolved. A direct comparison of the diabetogenic effects of CsA and Tac, without interference of corticosteroid treatment, has not yet been investigated using a hyperinsulinemic euglycemic glucose clamp technique, which is the best method for estimating insulin sensitivity. Randomized, investigator-blinded cross-over studies will be carried out, studying 10 healthy subjects and 10 hemodialysis patients. Each participant will receive treatment with CsA, Tac and placebo respectively in a random order. The results will be of relevance to the choice and monitoring of immunosuppressive regimens in kidney transplant recipients as well as the development of better treatment modalities for diabetes.

Background: Post-transplantation diabetes mellitus (PTDM) is a complication of the calcineurin inhibitors (CI) cyclosporine (CsA) and Tacrolimus (Tac), but much controversy still exists regarding the mechanism leading to this disorder. Several studies using intravenous (IVGTT) or oral glucose tolerance tests have shown that CsA and Tac tend to reduce insulin release, while corticosteroids increase insulin resistance. Decreased insulin secretion may be the result of beta-cell toxicity, apoptosis or inhibition of calcineurin signaling cessating insulin gene transcription. Comparing the drug using IVGTT has shown that long-term glucose metabolism is not significantly different between the two. Reviewing the literature brings forth that some of these data and the observed higher incidence of PTDM in Tac-treated recipients are conflicting. To or knowledge, comparison of the diabetogenic effects of CsA and Tac, without concomitant corticosteroids, has never been investigated using the gold standard to estimate insulin sensitivity; a hyperinsulinemic euglycemic glucose clamp (HEGC). Hypotheses: CsA and Tac are able to induce diabetes, by exerting acute and chronic effects on pancreas beta-cell performance and insulin sensitivity. The hypothesized effects will be investigated during following studies: 1. Acute effect in 10 healthy subjects undergoing HEGC 2. Chronic effect in 10 pre-transplant uremic patients undergoing HEGC Methods: The studies are randomized, double-blinded (Study 1) and investigator blinded (Study 2) cross-over designs. Each study subject participates in three experimental study days with an interval of 4-6 weeks. A HEGC is carried out on the study days, where treatment includes CsA, Tac and placebo respectively in random order. Following an overnight fast the healthy subject / uremic patient arrives in the research laboratory, where a catheter is implanted in each arm for blood sampling and infusion purposes. Pulse induction: Glucose 6 mg/kg/min is infused every 10 minutes followed by a 9 minute pause. From 30 to 90 min blood is drawn every minute for insulin and every 10th minute for glucose measurements. First phase insulin secretion: After 120 minutes glucose 0.3 g/kg (maximally 25 g) is infused over 2 min and the catheter is flushed with 50 ml of isotonic saline. Insulin, glucose and c-peptide are measured with a few minutes intervals. Insulin infusion/HEGC: 1.0 mU/kg/min insulin infusion is initiated at the 165th minute and blood glucose levels are kept at 5.0 mmol/L, using variable infusion of a 20% glucose dilution throughout the following 120 minutes. The final 30 min of the clamp is considered the hyperinsulinaemic steady state period. Aside from glucose, insulin and other endocrinological parameters, measurements of drug concentration and CaN will also be performed. Perspectives: The studies are expected to give valuable insight into the diabetogenic effects of CI, and to show whether or not CsA and Tac are comparable in their Diabetogenicity. The results will be of relevance to the choice and monitoring of immunosuppressive regimens in kidney transplant recipients as well as the development of better treatment modalities for diabetes.