IAPP toxicity activates HIF1α/PFKFB3 signaling delaying β-cell loss at the expense of β-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 β-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 HIF1α/PFKFB3 signaling, this increases glycolysis disengaged from oxidative phosphorylation with mitochondrial fragmentation and perinuclear clustering, considered a protective posture against increased cytosolic Ca 2+ characteristic of toxic oligomer stress. In contrast to tissues with the capacity to regenerate, β-cells in adult humans are minimally replicative, and therefore fail to execute the second pro-regenerative phase of the HIF1α/PFKFB3 injury pathway. Instead, β-cells in T2D remain trapped in the pro-survival first phase of the HIF1α injury repair response with metabolism and the mitochondrial network adapted to slow the rate of cell attrition at the expense of β-cell function.

Activation of the HIF1α/PFKFB3 stress response pathway in beta cells in type 1 diabetes

“…ab181861; RRID: not available) at 1:400 for immunofluorescence, 1:1000 for western blotting and 1 μg for immunoprecipitation. We have confirmed the specificity of this antibody previously [5]. Other antibodies used in the study were: rabbit anti-HIF1α (Abcam; catalogue no.…”

“…Taken together these data suggest that HIF1α-mediated stress signalling is activated in beta cells exposed to cytokines implicated in type 1 diabetes, mirroring the stress response induced by protein misfolding in type 2 diabetes [5]. Given that the most prominent downstream target of HIF1α remodelled metabolism is PFKFB3, we next sought to establish if the PFKFB3 protein levels are increased in beta cells in type 1 diabetes.…”

“…We recently established that the slow time course of beta cell loss in type 2 diabetes, along with a predominant defect in glucose-stimulated insulin secretion, is at least partially attributable to activation of a highly conserved stress-induced prosurvival hypoxia inducible factor 1 α (HIF1α)/ 6phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) signalling pathway [5]. Deletion of Hif1a increases vulnerability of beta cells to viral infections and toxins and increases the incidence of autoimmune diabetes in the NOD mouse model [6].…”

Amyloid damage to islet β-cells in type 2 diabetes: hypoxia or pseudo-hypoxia?

“…Montemurro et al 1 have recently shown that in vitro exposure to oligomeric human islet amyloid polypeptide (IAPP) triggers the hypoxia response in islets of Langerhans from diabetic IAPP transgenic rats. In the absence of actual hypoxia, this response was considered pseudo-hypoxic.…”

“…In the absence of actual hypoxia, this response was considered pseudo-hypoxic. The metabolic shift of β-cells toward aerobic glycolysis and depression of Krebs cycle in type 2 diabetes, attributed to mitochondrial toxicity of IAPP oligomers, was suggested to resemble the Warburg effect in tumours 1,2 . There is also transcriptomic and proteomic evidence of hypoxia in islets of Langerhans in type 2 diabetes.…”