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Calcineurin inhibitors acutely improve insulin sensitivity without affecting insulin secretion in healthy human volunteers
Author(s) -
Øzbay Lara Aygen,
Møller Niels,
Juhl Claus,
Bjerre Mette,
Carstens Jan,
Rungby Jørgen,
Jørgensen Kaj Anker
Publication year - 2012
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2011.04118.x
Subject(s) - ciclosporin , calcineurin , tacrolimus , medicine , insulin , diabetes mellitus , transplantation , endocrinology , crossover study , glucose clamp technique , pharmacology , insulin resistance , pancreatic hormone , pathology , alternative medicine , placebo
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • New onset diabetes after transplantation is related to treatment with immunosuppressive medications. Clinical studies have shown that risk of new onset diabetes is greater with tacrolimus compared with ciclosporin. The diabetogenicity of ciclosporin and tacrolimus has been attributed to both beta cell dysfunction and impaired insulin sensitivity. WHAT THIS STUDY ADDS • This is the first trial to investigate beta cell function and insulin sensitivity using gold standard methodology in healthy human volunteers treated with clinically relevant doses of ciclosporin and tacrolimus. We document that both drugs acutely increase insulin sensitivity, while first phase and pulsatile insulin secretion remain unaffected. This study demonstrates that ciclosporin and tacrolimus have similar acute effects on glucose metabolism in healthy humans. AIM The introduction of calcineurin inhibitors (CNIs) ciclosporin (CsA) and tacrolimus (Tac) has improved the outcome of organ transplants, but complications such as new onset diabetes mellitus after transplantation (NODAT) cause impairment of survival rates. The relative contribution of each CNI to the pathogenesis and development of NODAT remains unclear. We sought to compare the impact of CsA and Tac on glucose metabolism in human subjects. METHODS Ten healthy men underwent 5 h infusions of CsA, Tac and saline in a randomized, double‐blind, crossover study. During infusion glucose metabolism was investigated using following methods: a hyperinsulinaemic‐euglycemic clamp, an intravenous glucose tolerance test (i.v.GTT), glucose‐stimulated insulin concentration–time series and indirect calorimetry. RESULTS Clamp derived insulin sensitivity was increased by 25% during CsA (P < 0.0001) and 13% during Tac administration (P = 0.047), whereas first phase and pulsatile insulin secretion were unaffected. Coinciding with the CNI induced improved insulin sensitivity, glucose oxidation rates increased, while insulin clearance rates decreased, only non‐significantly. Tac singularly lowered hsCRP concentrations, otherwise no changes were observed in circulating glucagon, FFA or adiponectin concentrations. Mean blood concentrations of CNIs were 486.9 ± 23.5 µg l −1 for CsA and 12.8 ± 0.5 µg l −1 for Tac. CONCLUSIONS Acute effects of i.v. CsA, and to a lesser degree Tac infusions, in healthy volunteers include increased insulin sensitivity, without any effect on first phase or pulsatile insulin secretion.