Diabetogenicity of Cyclosporine and Tacrolimus
Condition: Complications of Transplanted Organs and Tissue; Diabetes Mellitus Nos New Onset
MeSH terms: Diabetes Mellitus
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): cyclosporine; tacrolimus; Capsules and isotonic saline
Intervention type(s): Drug; Drug; Other
Intervention description(s): For Healthy volunteers (study 1) and Dialysis patients (study 2): Single intravenous infusion of 0.155 mg/kg over a maximum duration of 5 hours.
For Dialysis Patients (study 2): Oral intake of 4 mg/kg 2 times daily for 8-11 days.; For Healthy volunteers (study 1) and Dialysis patients (study 2): Single intravenous infusion of 0.0012 mg/kg over a maximum duration of 5 hours.
For Dialysis Patients (study 2): Oral intake of 0.1 mg/kg 2 times daily for 8-11 days.; For Healthy volunteers (study 1) and Dialysis patients (study 2): Single intravenous infusion of 0.06 ml/kg isotonic saline over a maximum duration of 5 hours.
For Dialysis patients (study 2): Placebo capsules 2 times daily for 8-11 days.
Other intervention name(s): Sandimmun; Prograf; Saline; NaCl
Intervention MeSH terms: Cyclosporine; Tacrolimus; Cyclosporins
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Insulin pulsatility; Insulin secretion; Insulin sensitivity; Calcineurin inhibitor; Cyclosporine; Tacrolimus