Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study

Valborg Gudmundsdottir, Helle Krogh Pedersen, Karla Viviani Allebrandt, Caroline Brorsson, Nienke van Leeuwen, Karina Banasik, Anubha Mahajan, Christopher J. Groves, Martijn van de Bunt, Adem Y. Dawed, Andreas Fritsche, Harald Staiger, Annemarie M.C. Simonis-Bik, Joris Deelen, Mark H.H. Kramer, Axel Dietrich, Thomas Hübschle, Gonneke Willemsen, Hans Ulrich Häring, Eco J.C. de GeusDorret I. Boomsma, Elisabeth M.W. Eekhoff, Jorge Ferrer, Mark I. McCarthy, Ewan R. Pearson, Ramneek Gupta, Søren Brunak, Leen M. t Hart*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Glucagon-like peptide 1 (GLP-1) stimulated insulin secretion has a considerable heritable component as estimated from twin studies, yet few genetic variants influencing this phenotype have been identified. We performed the first genome-wide association study (GWAS) of GLP-1 stimulated insulin secretion in non-diabetic individuals from the Netherlands Twin register (n = 126). This GWAS was enhanced using a tissue-specific protein-protein interaction network approach. We identified a beta-cell protein-protein interaction module that was significantly enriched for low gene scores based on the GWAS P-values and found support at the network level in an independent cohort from Tübingen, Germany (n = 100). Additionally, a polygenic risk score based on SNPs prioritized from the network was associated (P < 0.05) with glucose-stimulated insulin secretion phenotypes in up to 5,318 individuals in MAGIC cohorts. The network contains both known and novel genes in the context of insulin secretion and is enriched for members of the focal adhesion, extracellular-matrix receptor interaction, actin cytoskeleton regulation, Rap1 and PI3K-Akt signaling pathways. Adipose tissue is, like the beta-cell, one of the target tissues of GLP-1 and we thus hypothesized that similar networks might be functional in both tissues. In order to verify peripheral effects of GLP-1 stimulation, we compared the transcriptome profiling of ob/ob mice treated with liraglutide, a clinically used GLP-1 receptor agonist, versus baseline controls. Some of the upstream regulators of differentially expressed genes in the white adipose tissue of ob/ob mice were also detected in the human beta-cell network of genes associated with GLP-1 stimulated insulin secretion. The findings provide biological insight into the mechanisms through which the effects of GLP-1 may be modulated and highlight a potential role of the beta-cell expressed genes RYR2, GDI2, KIAA0232, COL4A1 and COL4A2 in GLP-1 stimulated insulin secretion.

Original languageEnglish
Article numbere0189886
JournalPLoS ONE
Volume13
Issue number1
DOIs
Publication statusPublished - Jan 2018

Bibliographical note

Funding Information:
The work leading to this publication has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n115317 (DIRECT), resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. Sanofi (an EFPIA member) provided support in the form of salaries for authors [KA, TH, and AD] and funding of the experimentation conducted in mice. Beyond the contribution of these authors, Sanofi did not have any additional role in the study design, data collection and analysis that pertain to this manuscript, as well as on the decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the’author contributions’ section. The study received funding from the Netherlands Organization for Health Research and Development (Priority Medicines Elderly Program 113102006); by BBMRI-NL, a Research Infrastructure financed by the Dutch government (NWO 184.021.007). The Netherlands Twin Register acknowledges funding from the Netherlands Organization for Scientific Research (NWO: Netherlands Twin Registry Repository: researching the interplay between genome and environment). The department of internal medicine section Endocrinology and Diabetic Center VUmc acknowledges funding from ZonMw. We are very grateful to all participants who took part in these studies. Data on glycaemic traits have been contributed by MAGIC investigators and have been downloaded from www.magicinvestigators.org.

Publisher Copyright:
© 2018 Gudmundsdottir et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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