Obesity causes mitochondrial damage and β-cell dysfunction due to increased mitochondrial metabolism and the buildup of oxidative stress. β-cells, in particular, express antioxidant enzymes at low quantities and are extremely sensitive to oxidative stress. To compensate for insulin resistance, β-cells secrete more glucose-stimulated insulin early in the development of obesity.
An increase in β-cell activity in the presence of higher metabolic stress implies that β-cells have a defensive mechanism against increased oxidative damage, which may become inadequate or deteriorate with the onset of type 2 diabetes. For a study, researchers showed that metabolic stress activates the β-cell hypoxia-inducible factor 2α (HIF-2α) gene, which increases antioxidant gene expression (e.g., Sod2 and Cat) and protects against mitochondrial reactive oxygen species (ROS) and consequent mitochondrial damage.
By raising mitochondrial ROS levels, HIF-2α knockdown in Min6 cells enhanced chronic high glucose-induced mitochondrial damage and -cell dysfunction. Furthermore, on a high-fat diet, inducible β-cell HIF-2α mutant animals had more severe β-cell dysfunction and glucose intolerance, as well as higher ROS levels and reduced islet mitochondrial mass. The findings revealed a previously undiscovered method by which β-cells protect themselves against increased metabolic load in order to enhance β-cell compensation in obesity.
