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

Valborg Guðmundsdóttir ,Andreas Fritsche,Mark H H Kramer,Adem Y Dawed,Martijn Van De Bunt,Christopher J Groves,Jorge Ferrer,Gonneke Willemsen,Anubha Mahajan,Harald Staiger,Joris Deelen,Dorret I Boomsma,Karina Banasik,Thomas Hübschle,Ramneek Gupta,Nienke Van Leeuwen,Søren Brunak,Caroline Brorsson,Eco J C De Geus,Mark I Mccarthy,Ewan R Pearson,Elisabeth M W Eekhoff,Hans‐Ulrich Häring ,A.j.j Dietrich ,Helle Pedersen ,Karla V Allebrandt ,Annemarie M Simonis-Bik ,Leen M ’T Hart

doi:10.1371/journal.pone.0189886

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.

Highlights

Glucagon-like petide-1 (GLP-1) receptor agonists and DPP4-inhibitors are increasingly used therapeutic agents for type 2 diabetes, as they stimulate insulin secretion from the pancreatic beta-cells by potentiating glucose-dependent insulin secretion
No single nucleotide polymorphism (SNP) association reached genome-wide significance in the Netherlands twin register (NTR) cohort association analysis adjusted for age, gender, BMI, glucose tolerance status and insulin sensitivity (S1 and S2 Figs), while six independent signals were identified with P < 1.0 × 10−5 (S1 Table)
A more detailed analysis flowchart is shown in S3 Fig. As tissue-specific PPI networks have previously been shown to perform better for gene prioritization than global networks [12], we mapped gene significance values for Glucagon-like peptide 1 (GLP-1) stimulated insulin secretion onto a PPI network containing 8,457 genes that are expressed in pancreatic beta-cells [13]

Summary

Introduction

Glucagon-like petide-1 (GLP-1) receptor agonists and DPP4-inhibitors are increasingly used therapeutic agents for type 2 diabetes, as they stimulate insulin secretion from the pancreatic beta-cells by potentiating glucose-dependent insulin secretion. A large part of this variability is expected to be explained by underlying genetic differences as GLP-1 stimulated insulin secretion has an estimated heritability of 0.53 (95% CI, 0.33–0.70) [2]. Identification of these genetic determinants may aid patient stratification with regard to treatment response and shed light on the differential properties of the complex signaling networks controlling GLP-1 stimulated insulin secretion, which to date are not well understood. Among the loci nominally associated with GLP-1 stimulated insulin secretion are variants in the TCF7L2 [3], GLP1R [4], WFS1 [5] and CTRB1/2 loci [6] (all P < 0.05), which highlights the potential of further genetic studies of GLP-1 stimulated insulin secretion

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Conclusion