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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

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

Montemurro Chiara C Nomoto Hiroshi H Pei Lina L Parekh Vishal S VS Vongbunyong Kenny E KE Vadrevu Suryakiran S Gurlo Tatyana T Butler Alexandra E AE Subramaniam Rohan R Ritou Eleni E Shirihai Orian S OS Satin Leslie S LS Butler Peter C PC Tudzarova Slavica S

Nature communications 20190618 1

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 m ...[more]

PMID: 31213603

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Project description:Aims/hypothesisType 2 diabetes is characterised by islet amyloid and toxic oligomers of islet amyloid polypeptide (IAPP). We posed the questions, (1) does IAPP toxicity induce an islet response comparable to that in humans with type 2 diabetes, and if so, (2) what are the key transcriptional drivers of this response?MethodsThe islet transcriptome was evaluated in five groups of mice: beta cell specific transgenic for (1) human IAPP, (2) rodent IAPP, (3) human calpastatin, (4) human calpastatin and human IAPP, and (5) wild-type mice. RNA sequencing data was analysed by differential expression analysis and gene co-expression network analysis to establish the islet response to adaptation to an increased beta cell workload of soluble rodent IAPP, the islet response to increased expression of oligomeric human IAPP, and the extent to which the latter was rescued by suppression of calpain hyperactivation by calpastatin. Rank-rank hypergeometric overlap analysis was used to compare the transcriptome of islets from human or rodent IAPP transgenic mice vs humans with prediabetes or type 2 diabetes.ResultsThe islet transcriptomes in humans with prediabetes and type 2 diabetes are remarkably similar. Beta cell overexpression of soluble rodent or oligomer-prone human IAPP induced changes in islet transcriptome present in prediabetes and type 2 diabetes, including decreased expression of genes that confer beta cell identity. Increased expression of human IAPP, but not rodent IAPP, induced islet inflammation present in prediabetes and type 2 diabetes in humans. Key mediators of the injury responses in islets transgenic for human IAPP or those from individuals with type 2 diabetes include STAT3, NF-κB, ESR1 and CTNNB1 by transcription factor analysis and COL3A1, NID1 and ZNF800 by gene regulatory network analysis.Conclusions/interpretationBeta cell injury mediated by IAPP is a plausible mechanism to contribute to islet inflammation and dedifferentiation in type 2 diabetes. Inhibition of IAPP toxicity is a potential therapeutic target in type 2 diabetes.

Dataset Information

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

Publications

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

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