Cellular oxygen levels are determined by oxygen supply and oxygen consumption. Pancreatic β-cells, a mitochondria rich tissue consume a lot of oxygen to produce ATP for insulin secretion, which renders them severely hypoxic even when surrounding oxygen level slightly becomes lower (JBC 2011). Besides hypoxia response gene expression (glycolytic genes etc.) was upregulated in a HIF-1α dependent manner and functional β-cell gene expression (such as Mafa and Slc2a2) was downregulated in a HIF-1α independent manner under hypoxic conditions (PLoSONE 2014,  JBC 2017).
　Acute or chronic hypoxia lowers insulin secretion from pancreatic β-cells while insulin secretion defect becomes a trigger of hyperglycemia, leading to further increase of insulin demand. This vicious cycle of increased oxygen consumption due to high insulin demand can eventually compromise β-cell function and systemic glucose homeostasis. We hypothesize that "β-cell hypoxia" could be a trigger of onset or progression of diabetes, and try to uncover this β-cell deterioration mechanism by hypoxia.
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