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.
Highlights
The splanchnic territory is physiologically exposed to high concentrations of glucose and fructose during the postprandial period.[5]
We have examined the involvement of permeability transition pore (PTP) opening in INS-1 cell death induced by high levels of glucose or fructose
We have reported that in INS-1 insulinoma cells (i) both Cyclosporin A (CsA) and metformin inhibited PTP opening, (ii) high glucose and high fructose led to PTP opening, (iii) PTP inhibitors hampered high glucose- and high fructose-induced cell death
Summary
The splanchnic territory is physiologically exposed to high concentrations of glucose and fructose during the postprandial period.[5]. Chronic exposure to elevated glucose or fructose concentrations impairs b-cells survival[13,14] by a mechanism that may involve oxidative stress.[13,15,16] Hyperglycemia-induced oxidative stress has been shown to induce mitochondrial permeability transition and subsequent cell death in human endothelial cells.[11] Concerning pancreatic-derived cells, CsA has been shown to inhibit Ca2 þ -induced PTP opening in permeabilized INS-1 and MIN-6 cells.[17] It has been proposed that cytokine-induced apoptosis may be due to PTP opening in pancreatic RINm5F cells[18] whereas CsA has been reported to prevent PK11195-induced cell death in isolated human pancreatic islets.[19] it has recently been shown that. CsA protects MIN-6 cells against Pdx[1] insufficiency-induced cell death, genetic ablation of the endogenous PTP-inducers cyclophilin D prevents diabetes in Pdx[1] þ /À mice.[20] Whether metformin regulates PTP opening in b-cells and whether hyperglycemia or hyperfructosemia induces PTP opening in pancreatic-derived cells has not been studied yet
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