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Titolo:
Diabetogenic effect of cyclosporin A is mediated by interference with mitochondrial function of pancreatic B-cells
Autore:
Dufer, M; Krippeit-Drews, P; Lembert, N; Idahl, LA; Drews, G;
Indirizzi:
Univ Tubingen, Inst Pharm, Dept Pharmacol, D-72076 Tubingen, Germany Univ Tubingen Tubingen Germany D-72076 rmacol, D-72076 Tubingen, Germany
Titolo Testata:
MOLECULAR PHARMACOLOGY
fascicolo: 4, volume: 60, anno: 2001,
pagine: 873 - 879
SICI:
0026-895X(200110)60:4<873:DEOCAI>2.0.ZU;2-L
Fonte:
ISI
Lingua:
ENG
Soggetto:
STIMULATED INSULIN RELEASE; BETA-CELLS; TRANSPLANT RECIPIENTS; INDUCED INHIBITION; WISTAR RATS; CALCIUM; ISLETS; SECRETION; GLUCOSE; OSCILLATIONS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
42
Recensione:
Indirizzi per estratti:
Indirizzo: Krippeit-Drews, P Univ Tubingen, Inst Pharm, Dept Pharmacol, Morgenstelle 8, D-72076 Tubingen, Germany Univ Tubingen Morgenstelle 8 Tubingen GermanyD-72076 y
Citazione:
M. Dufer et al., "Diabetogenic effect of cyclosporin A is mediated by interference with mitochondrial function of pancreatic B-cells", MOLEC PHARM, 60(4), 2001, pp. 873-879

Abstract

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 muM 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+]. Thiseffect 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 causedby 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 Delta Psi was affected by CsA by inhibiting the oscillations in Delta Psi. 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 insulinsecretion. Thus, CsA acts on different targets to induce the immunosuppressive and the diabetogenic effect.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/01/20 alle ore 12:58:06