Complications of Transplanted Organs and Tissue Clinical Trial
Official title:
Diabetogenicity of Cyclosporine and Tacrolimus
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.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT01976689 -
New-onset Diabetes and Left Ventricular Hypertrophy in Renal Transplantation
|
N/A |