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β-Cell dysfunction is a hallmark of type 2 diabetes (T2DM) and comprises insulin secretory dysfunction and/or reduced β-cell mass (1). Normal β-cell function requires tight coupling of glucose metabolism with insulin secretion via a well-defined pathway utilizing oxidative metabolism and ATP production (2). Moreover, β-cell gene expression and metabolism are tuned to suppress pathways that would otherwise disrupt glucose-stimulated insulin secretion (GSIS), such as lactate production (3,4). Oversupply of glucose during T2DM can disrupt GSIS (glucotoxicity) via excessive generation of reactive oxygen species (ROS) causing oxidative stress: β-cells are particularly susceptible due to relatively low expression of antioxidant enzymes (5). Therefore, understanding the mechanisms by which ROS contribute to β-cell dysfunction during T2DM is an important research goal.The new study by Sasaki et al. (6) identifies a novel mechanism by which ROS impair β-cell function during T2DM: by activating hypoxia-inducible factor 1α (Hif1α), switching on lactate production and impairing glucose oxidation and insulin secretion (Fig. 1). The authors studied Goto-Kakizaki (GK) rats, an inbred, polygenic model of nonobese T2DM with β-cell dysfunction, originally derived from Wistar rats, and found that dual antioxidant treatment significantly improved GSIS in vivo and in vitro, consistent with previous studies using the GK rat and other diabetic models such as Zucker diabetic fatty rats and db / db mice (5). Taken together, these findings reinforce the role of glucotoxicity and oxidative stress in β-cell dysfunction during T2DM. Furthermore, …

Sweet and Sour β-Cells: ROS and Hif1α Induce Warburg-Like Lactate Production During Type 2 Diabetes