Diabetogenic effect of cyclosporin A is mediated by interference with mitochondrial function of pancreatic B-cells

Treatment of patients after organ transplantation with the immunosuppressiv e drug cyclosporin A (CsA) is often accompanied by impaired glucose toleran ce, thus promoting the development of diabetes mellitus. In the present art icle we show that 2 to 5 muM CsA diminishes glucose-induced insulin secreti on of isolated mouse pancreatic islets in vitro by inhibiting glucose-stimu lated oscillations of the cytoplasmic free-Ca2+ concentration [Ca2+]. This effect is not due to an inhibition of calcineurin, which mediates the immun osuppressive effect of CsA, because other calcineurin inhibitors, deltameth rin and tacrolimus, did not affect the oscillations in [Ca2+](c) of the B-c ells. The CsA-induced decrease in [Ca2+](c) to basal values was not caused by a direct inhibition of L-type Ca2+ channels. CsA is known to be a potent inhibitor of the mitochondrial permeability transition pore (PTP), which w e recently suggested to be involved in the regulation of oscillations. Cons equently, CsA also inhibited the oscillations of the cell membrane potentia l, and it is shown that these effects could not be ascribed to cellular ATP depletion. However, the mitochondrial membrane potential Delta Psi was aff ected by CsA by inhibiting the oscillations in Delta Psi. Interestingly, th e observed reduction in [Ca2+](c) could be counteracted by the K-ATP(+) cha nnel blocker tolbutamide, indicating that the stimulus-secretion coupling w as interrupted before the closure of K-ATP(+) channels. It is concluded tha t CsA alters B-cell function by inhibiting the mitochondrial PTP. This term inates the oscillatory activity that is indispensable for adequate insulin secretion. Thus, CsA acts on different targets to induce the immunosuppress ive and the diabetogenic effect.