IAPP toxicity activates HIF1?/PFKFB3 signaling delaying ?-cell loss at the expense of ?-cell function.

ABSTRACT: 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 ?-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?/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, ?-cells in adult humans are minimally replicative, and therefore fail to execute the second pro-regenerative phase of the HIF1?/PFKFB3 injury pathway. Instead, ?-cells in T2D remain trapped in the pro-survival first phase of the HIF1? injury repair response with metabolism and the mitochondrial network adapted to slow the rate of cell attrition at the expense of ?-cell function.

SUBMITTER: Montemurro C 

PROVIDER: S-EPMC6581914 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature