RT Journal Article
SR Electronic
T1 Diabetogenic Effect of Cyclosporin A Is Mediated by Interference with Mitochondrial Function of Pancreatic B-Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 873
OP 879
VO 60
IS 4
A1 Düfer, Martina
A1 Krippeit-Drews, Peter
A1 Lembert, Nicolas
A1 Idahl, Lars-Åke
A1 Drews, Gisela
YR 2001
UL http://molpharm.aspetjournals.org/content/60/4/873.abstract
AB Treatment of patients after organ transplantation with the immunosuppressive drug cyclosporin A (CsA) is often accompanied by impaired glucose tolerance, thus promoting the development of diabetes mellitus. In the present article we show that 2 to 5 μM CsA diminishes glucose-induced insulin secretion of isolated mouse pancreatic islets in vitro by inhibiting glucose-stimulated oscillations of the cytoplasmic free-Ca2+ concentration [Ca2+]c. This effect is not due to an inhibition of calcineurin, which mediates the immunosuppressive effect of CsA, because other calcineurin inhibitors, deltamethrin and tacrolimus, did not affect the oscillations in [Ca2+]c of the B-cells. 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 we recently suggested to be involved in the regulation of oscillations. Consequently, CsA also inhibited the oscillations of the cell membrane potential, and it is shown that these effects could not be ascribed to cellular ATP depletion. However, the mitochondrial membrane potential ΔΨ was affected by CsA by inhibiting the oscillations in ΔΨ. Interestingly, the observed reduction in [Ca2+]c could be counteracted by the K+ATP channel blocker tolbutamide, indicating that the stimulus-secretion coupling was interrupted before the closure of K+ATP channels. It is concluded that CsA alters B-cell function by inhibiting the mitochondrial PTP. This terminates the oscillatory activity that is indispensable for adequate insulin secretion. Thus, CsA acts on different targets to induce the immunosuppressive and the diabetogenic effect. The American Society for Pharmacology and Experimental Therapeutics