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

Michele Solimena,Carolin Wegbrod,Anne Jörns,Jürgen Weitz,Frédéric Burdet,Manon Von Bülow,Jörn Meinel,Anke Sönmez,Robert Grützmann,Lorella Marselli,Bernard Thorens,Hans–Detlev Saeger ,Sigurd Lenzen,Raphaël Scharfmann ,Marco Bugliani,Gustavo Baretton ,Florian Ehehalt,Anne Friedrich,Marius Distler,Ioannis Xénarios ,Enrico Petretto,Manuela Kleeberg,Katja Pfriem,Everson Nogoceke,Leonore Wigger,Krister Bokvist,Franco Filipponi,Andreas Dahl,Mathias Lesche,Dorothèe Sturm ,Hassan Mziaut,Julia Parnis,Daniela Richter,Daniel Margerie,Claes B Wollheim,Ezio Bonifacio,Birgit Meyer‐Puttlitz ,Afshan Siddiq,Mario Falchi,Ugo Boggi,Anke M Schulte,Aida Moreno‐Moral ,Farooq Syed,Klaus-Peter Knoch,Robin Liechti,Paolo Meda,Guy A Rutter,Mara Suleiman,Mark Ibberson,Philippe Froguel,Piero Marchetti

doi:10.1007/s00125-017-4500-3

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.

Highlights

The interplay of genetic and environmental factors leads to impaired beta cell function and viability, which are the ultimate and possibly primary causes of type 2 diabetes [1,2,3]
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
In our phenotyped pancreatectomised patients (PPP) cohort, the prevalence of pancreatitis and benign or malignant pancreatic tumours was comparable between the non-diabetic and type 2 diabetic PPP. None of these disorders was associated with islet transcriptome changes (ESM Fig. 10), while PPP and organ donors (OD) islets were equivalent in terms of the presence of ‘contaminating’ acinar and ductal cell markers

Summary

Introduction

The interplay of genetic and environmental factors leads to impaired beta cell function and viability, which are the ultimate and possibly primary causes of type 2 diabetes [1,2,3]. Groop and collaborators correlated the transcriptome of islets from 54 non-diabetic and nine type 2 diabetic organ donors with ex vivo insulin secretion and clinical features, including HbA1c [15]. The same group compared the islet transcriptome of 51 non-diabetic individuals, 12 type 2 diabetic individuals and 15 people with an HbA1c of 6.0–6.5% (42– 48 mmol/mol) [16]. These studies found several genes to be differentially expressed in type 2 diabetic islets, including some related to insulin secretion and/or HbA1c [15, 16], beta cell apoptosis [17] and beta cell proliferation [18, 19]. In type 2 diabetic islets, they described upregulation of SFRP4, which might link islet inflammation to beta cell dysfunction [20]

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Results

Conclusion