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Bcl-xL protects pancreatic beta-cells from high glucose-induced failure by dampening mitochondrial metabolism

University of British Columbia

Chronic nutrient oversupply, such as seen in obesity, increases metabolic load and oxidative stress in the insulin-secreting β-cells. This progressively impairs β-cell function and survival, contributing to the development of type 2 diabetes. Bcl-xL is an antiapoptotic protein of the Bcl-2 family. Recent studies have shown additional non-apoptotic functions of Bcl-xL in suppressing glucose signaling of non-diabetic β-cells. Conceivably, this metabolic dampening may be beneficial to counter β-cell dysfunction during nutrient excess of type 2 diabetes. To test the hypothesis that Bcl-xL protects β-cell function during metabolic stress via regulation of mitochondrial physiology, we examined the effects of gene deletion and overexpression of Bcl-xL in β-cells. In normal conditions, islets of β-cell-specific Bcl-x knockout (BclxβKO) mice tend to be metabolically more active compared to BclxβWT islets. This metabolic effect of Bcl-xL is further enhanced after prolonged high glucose culture, where BclxβKO islets display a pre-toxic state of metabolic amplification with dysregulated intracellular Ca²+ and insulin secretion. Islets overexpressing Bcl-xL display suppressed intracellular Ca²+ responses, in agreement with our knockout studies. Interestingly, cells expressing Bcl-xL at high levels have increased mitochondrial aggregates. We also demonstrated that Bcl-xL suppresses superoxide levels and cell death induced by ribose, but not islet-cell death under glucolipotoxic conditions. In conclusion, we propose that endogenous Bcl-xL protects β-cells from high glucose-induced failure by dampening mitochondrial activity, as well as suppressing oxidative stress-induced cell death.

Text

2015-04-20

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/52873

Cell and Developmental Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/