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Augmented mitochondrial energy metabolism is an early response to chronic glucose stress in human pancreatic beta cells – 22/09/2020

Isabelle Chareyron, Stefan Christen, Sofia Moco, Armand Valsesia, Steve Lassueur, Loïc Dayon, Claes B. Wollheim, Jaime Santo Domingo, Andreas Wiederkehr

Type 2 diabetes causes mitochondrial dysfunction in pancreatic beta cells. In this issue, Chareyron et al ( studied whether glucose stress alone results in gradual loss of mitochondrial function in human beta cells in vitro. Unexpectedly, at early stages, chronic glucose stress (4 day exposure to 11 mmol/l glucose) was found to over-activate mitochondria. Basal mitochondrial respiration and the cytosolic ATP/ADP ratio remained markedly elevated when human islets were returned to resting glucose conditions. The inability of mitochondria to return to a resting state was associated with metabolic dysregulation, including the accumulation of glycerol-3-phosphate and elevation of tricarboxylic acid (TCA) cycle and pentose phosphate pathway metabolites. This resulted in a slight elevation of basal insulin secretion and poor glucose-induced beta cell activation. Inhibition of mitochondrial pyruvate transport partially reversed the negative effects of chronic glucose overload. The authors propose that protecting mitochondria from nutrient overload may allow beta cells to return to a resting state and regain nutrient responsiveness in a way that may prevent the conversion from impaired fasting glucose and/or glucose tolerance to overt type 2 diabetes.

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