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Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT
Valborg Gudmundsdottir1, Helle Krogh Pedersen1, Karla Viviani Allebrandt2
1Department of Bio and Health Informatics, Technical University of Denmark, Kongens Lyngby, Denmark.
Plos One
|January 3, 2018
Summary
Genetic factors influence glucagon-like peptide 1 (GLP-1) stimulated insulin secretion. This study identified key genes and pathways in beta-cells, offering insights into GLP-1 action and potential therapeutic targets.
Area of Science:
- Genetics
- Endocrinology
- Molecular Biology
Background:
- Glucagon-like peptide 1 (GLP-1) stimulated insulin secretion has a significant heritable component.
- Few genetic variants influencing this trait have been identified previously.
Purpose of the Study:
- To identify genetic variants associated with GLP-1 stimulated insulin secretion.
- To explore the underlying biological mechanisms using a network-based approach.
Main Methods:
- Genome-wide association study (GWAS) in non-diabetic individuals.
- Tissue-specific protein-protein interaction network analysis.
- Polygenic risk score analysis in independent cohorts and validation in mouse models.
Main Results:
- Identified a beta-cell protein-protein interaction module enriched for genes related to GLP-1 secretion.
- A polygenic risk score derived from network-prioritized SNPs associated with glucose-stimulated insulin secretion.
- Network genes are involved in focal adhesion, extracellular-matrix receptor interaction, and PI3K-Akt signaling pathways.
- Similar regulatory networks were observed in mouse adipose tissue after GLP-1 receptor agonist treatment.
Conclusions:
- The study provides biological insights into GLP-1 action modulation.
- Highlights potential roles for RYR2, GDI2, KIAA0232, COL4A1, and COL4A2 in GLP-1 stimulated insulin secretion.
- Suggests conserved molecular mechanisms across human beta-cells and mouse adipose tissue.
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