IAPP toxicity activates HIF1α/PFKFB3 signaling delaying β-cell loss at the expense of β-cell function

The islet in type 2 diabetes (T2D) is characterized by amyloid deposits derived from islet amyloid polypeptide (IAPP), a protein co-expressed with insulin by beta-cells. In common with amyloidogenic proteins implicated in neurodegeneration, human IAPP (hIAPP) forms membrane permeant toxic oligomers implicated in misfolded protein stress. Here, we establish that hIAPP misfolded protein stress activates HIF1 alpha/PFKFB3 signaling, this increases glycolysis disengaged from oxidative phosphorylation with mitochondrial fragmentation and perinuclear clustering, considered a protective posture against increased cytosolic Ca2+ characteristic of toxic oligomer stress. In contrast to tissues with the capacity to regenerate, beta-cells in adult humans are minimally replicative, and therefore fail to execute the second pro-regenerative phase of the HIF1 alpha/PFKFB3 injury pathway. Instead, beta-cells in T2D remain trapped in the pro-survival first phase of the HIP1 alpha injury repair response with metabolism and the mitochondrial network adapted to slow the rate of cell attrition at the expense of beta-cell function.