Calcineurin inhibitors acutely improve insulin sensitivity without affecting insulin secretion in healthy human volunteers

Abstract

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. AIMThe 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. METHODSTen 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. RESULTSClamp 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 Ϯ 23.5 mg l -1 for CsA and 12.8 Ϯ 0.5 mg l -1 for Tac. CONCLUSIONSAcute 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.

Steroid Withdrawal in Pediatric Kidney Transplant Allows Better Growth, Lipids and Body Composition: A Randomized Controlled Trial

“…On the other hand, new-onset diabetes after transplantation related to treatment with immunosuppressive medications is an important complication. In fact, the acute effects of intravenous calcineurin inhibitors (CsA) and TAC infusions in healthy volunteers include increased IS [22]. However, chronic use of TAC impairs insulin secretion at multiple distal sites in stimulus-secretion coupling [23].…”

Post-Transplant Diabetes Mellitus: Causes, Treatment, and Impact on Outcomes

“…In 10 healthy human volunteers with normal BMI (24.7 Ϯ 0.5 kg/m 2 ), Øzbay et al (69) showed that an acute infusion of CNIs over 5 hours increased insulin sensitivity as determined by hyperinsulinemic-euglycemic clamp. A greater increase in sensitivity was observed with cyclosporine (25%) than tacrolimus (13%), but there was no change in first-phase insulin secretion or insulin pulsatility.…”

An Update of Liver Transplantation for Nonalcoholic Steatohepatitis

“…Corticosteroids, for example, induce insulin resistance in a dose-dependent manner by decreased beta-cell insulin production, increased gluconeogenesis, and decreased peripheral glucose utilization [38]. Calcineurin inhibitors inhibit insulin synthesis and secretion by pancreatic beta-cells [39]. mTOR inhibitors block B-cell proliferation, theoretically increasing the risk for diabetes, but also increases GLUT-4 signaling in insulin-responsive cells [40].…”