Abstract
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.Graphical abstract
Highlights
The islet in type 2 diabetes is characterised by islet amyloid derived from islet amyloid polypeptide (IAPP), a protein coexpressed with insulin by beta cells that when misfolded and in aggregate form may contribute to beta cell failure [1,2,3,4]
The synthesis, folding and processing of insulin is close to the limit of the biosynthetic capacity of beta cells [46]. Human IAPP (hIAPP) is highly oligomer prone and readily assembles into membrane permeant toxic oligomers if the rate of expression exceeds the capacity of the cell to fold and traffic newly expressed protein
These observations suggest protein misfolding may contribute to beta cell failure leading to type 2 diabetes under conditions of insulin resistance (Fig. 9)
Summary
The islet in type 2 diabetes is characterised by islet amyloid derived from islet amyloid polypeptide (IAPP), a protein coexpressed with insulin by beta cells that when misfolded and in aggregate form may contribute to beta cell failure [1,2,3,4]. While numerous hypotheses have been put forward to explain the wide-ranging changes in islets in type 2 diabetes [7], there is a consensus that misfolded protein stress induced by toxic oligomers of amyloidogenic proteins initiate these changes in neurodegenerative diseases. Risk factors for type 2 diabetes include insulin resistance [8] and low birthweight [9]. Beta cell misfolded protein stress is induced when expression of hIAPP per cell exceeds the cellular threshold for clearing misfolded proteins [12]. This threshold declines with ageing [13], a risk factor for both type 2 diabetes and neurodegenerative diseases. This threshold declines with ageing [13], a risk factor for both type 2 diabetes and neurodegenerative diseases. hIAPP overexpression in isolated mouse islets in vitro can modify islet gene expression with relevance to type 2 diabetes [14]
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