Systems biology of the IMIDIA biobank from organ donors and pancreatectomised patients defines a novel transcriptomic signature of islets from individuals with type 2 diabetes

Abstract

Aims/hypothesisPancreatic islet beta cell failure causes type 2 diabetes in humans. To identify transcriptomic changes in type 2 diabetic islets, the Innovative Medicines Initiative for Diabetes: Improving beta-cell function and identification of diagnostic biomarkers for treatment monitoring in Diabetes (IMIDIA) consortium (www.imidia.org) established a comprehensive, unique multicentre biobank of human islets and pancreas tissues from organ donors and metabolically phenotyped pancreatectomised patients (PPP).MethodsAffymetrix microarrays were used to assess the islet transcriptome of islets isolated either by enzymatic digestion from 103 organ donors (OD), including 84 non-diabetic and 19 type 2 diabetic individuals, or by laser capture microdissection (LCM) from surgical specimens of 103 PPP, including 32 non-diabetic, 36 with type 2 diabetes, 15 with impaired glucose tolerance (IGT) and 20 with recent-onset diabetes (<1 year), conceivably secondary to the pancreatic disorder leading to surgery (type 3c diabetes). Bioinformatics tools were used to (1) compare the islet transcriptome of type 2 diabetic vs non-diabetic OD and PPP as well as vs IGT and type 3c diabetes within the PPP group; and (2) identify transcription factors driving gene co-expression modules correlated with insulin secretion ex vivo and glucose tolerance in vivo. Selected genes of interest were validated for their expression and function in beta cells.ResultsComparative transcriptomic analysis identified 19 genes differentially expressed (false discovery rate ≤0.05, fold change ≥1.5) in type 2 diabetic vs non-diabetic islets from OD and PPP. Nine out of these 19 dysregulated genes were not previously reported to be dysregulated in type 2 diabetic islets. Signature genes included TMEM37, which inhibited Ca2+-influx and insulin secretion in beta cells, and ARG2 and PPP1R1A, which promoted insulin secretion. Systems biology approaches identified HNF1A, PDX1 and REST as drivers of gene co-expression modules correlated with impaired insulin secretion or glucose tolerance, and 14 out of 19 differentially expressed type 2 diabetic islet signature genes were enriched in these modules. None of these signature genes was significantly dysregulated in islets of PPP with impaired glucose tolerance or type 3c diabetes.Conclusions/interpretationThese studies enabled the stringent definition of a novel transcriptomic signature of type 2 diabetic islets, regardless of islet source and isolation procedure. Lack of this signature in islets from PPP with IGT or type 3c diabetes indicates differences possibly due to peculiarities of these hyperglycaemic conditions and/or a role for duration and severity of hyperglycaemia. Alternatively, these transcriptomic changes capture, but may not precede, beta cell failure.Electronic supplementary materialThe online version of this article (10.1007/s00125-017-4500-3) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Patterns of differential gene expression in a cellular model of human islet development, and relationship to type 2 diabetes predisposition

“…This pathway is important for islet development and is targeted in many in vitro differentiation protocols [8,9]. These data therefore indicate that REST is likely to be an important transcriptional regulator of human islet development, both in intermediate (pancreatic endoderm, endocrine progenitor) and later (endocrine-like cell, beta-like cell) [40] stages of differentiation, as has also been recently suggested by studies in mice and humans [41,42].…”

Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure

“…However, as pointed out by the IMIDIA collaboration, there is no consensus on a diabetic gene expression signature, in view of the large variations observed in different datasets [44]. In this regard, it should be noted that the vast majority of genes whose biological function in human islets is beyond question don't show changes to mRNA levels in these databases (e.g., all MODY genes except PDX1, glucokinase, sulfonylurea receptor, insulin processing enzymes, and others) [43][44][45]. In addition, CYB5R3 is expressed in both α− and β-cells; and a key point of our theory is that CYB5R3 levels drop only in those β-cells with advanced cellular pathology.…”

Organ donor pancreases for the study of human islet cell histology and pathophysiology: a precious and valuable resource

“…1d, e) [24][25][26][27][28][29][30]. Further, islets isolated by enzymatic digestion or acquired by laser capture microdissection may be obtained from the same glands that are used for histology and can, therefore, be characterised in terms of functional, ultrastructural and molecular features for association studies [31,32].…”