Figure 6.

Speculation of how UCP2 activity and quantity is altered in T2D. In healthy individuals: UCP2 levels are basal, UCP2 is glutathionylated, ROS levels are low enough so that they do not cause cell damage but the levels are sufficient so that these molecules can amplify insulin secretion, and proton leak exists (~55% of islet beta cells’ metabolism is wasted due to proton leak which is not caused by UCP2) but is minimal, so enough of the protons can move down the gradient through ATP synthase to generate sufficient ATP levels. In T2D, UCP2 is deglutathionylated (due to increased ROS levels) and upregulated allowing for much greater proton leak. Consequently, the majority of the protons prematurely leak through the inner mitochondrial membrane and do not pass through ATP synthase, although there is likely a period before the UCP2 deglutathionylation where ATP production occurs, it is unlikely that enough ATP is generated during this time to promote adequate insulin secretion. Hence, overall ATP production is impaired in the cell resulting in the inadequate insulin secretion observed in T2D during both the postprandial period and fasting. ROS levels are likely too high (leading to cytotoxic damage) during the postprandial period as a result of severe nutrient oversupply to islet beta-cells, due to the enhanced hyperglycaemia and hyperlipidaemia in T2D during this period. The excess ROS levels result in UCP2 deglutathionylation and a subsequent dissipated PMF, meaning that ROS formation during fasting is impaired and insulin secretion is not amplified by ROS to alleviate the chronic hyperglycaemia and hyperlipidaemia in fasting T2D subjects. Although UCP2 may become glutathionylated upon ROS levels decreasing during fasting, this likely reverses during subsequent feeding as ROS levels once again become undesirably high, restarting this cycle. This figure and information in its legend are with data adapted from these studies.^{32,175,178,179,189,190,329,330}