title: Protection of pancreatic INS-1 β-cells from glucose- and fructose-induced cell death by inhibiting mitochondrial permeability transition with cyclosporin A or metformin.
abstract: Hyperglycemia is detrimental to β-cell viability, playing a major role in the progression of β-cell loss in diabetes mellitus. The permeability transition pore (PTP) is a mitochondrial channel involved in cell death. Recent evidence suggests that PTP inhibitors prevent hyperglycemia-induced cell death in human endothelial cells. In this work, we have examined the involvement of PTP opening in INS-1 cell death induced by high levels of glucose or fructose. PTP regulation was studied by measuring the calcium retention capacity in permeabilized INS-1 cells and by confocal microscopy in intact INS-1 cells. Cell death was analyzed by flow cytometry. We first reported that metformin and cyclosporin A (CsA) prevented Ca²+-induced PTP opening in permeabilized and intact INS-1 cells. We then showed that incubation of INS-1 cells in the presence of 30 mM glucose or 2.5 mM fructose induced PTP opening and led to cell death. As both metformin and CsA prevented glucose- and fructose- induced PTP opening, and hampered glucose- and fructose- induced cell death, we conclude that PTP opening is involved in high glucose- and high fructose- induced INS-1 cell death. We therefore suggest that preventing PTP opening might be a new approach to preserve β-cell viability.
authors: Inserm, U1055, Grenoble F-38041, France.
authors: S
authors: S
authors: Lablanche
authors: C
authors: C
authors: Cottet-Rousselle
authors: F
authors: F
authors: Lamarche
authors: P-Y
authors: PY
authors: Benhamou
authors: S
authors: S
authors: Halimi
authors: X
authors: X
authors: Leverve
authors: E
authors: E
authors: Fontaine
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D005632:Fructose / Q000378:metabolism / Q000633:toxicity*; D005947:Glucose / Q000378:metabolism / Q000633:toxicity*; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008687:Metformin / Q000494:pharmacology*; D008928:Mitochondria / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats
chemical_list: D020011:Protective Agents; D005632:Fructose; D016572:Cyclosporine; D008687:Metformin; D005947:Glucose; D002118:Calcium