190: Single-Cell Networks Reveal Cell Type–Specific Mechanisms in Type 2 Diabetes

️ Episode 190: Single-Cell Networks Reveal Cell Type–Specific Mechanisms in Type 2 Diabetes In this episode of PaperCast Base by Base, we explore how a network-based analysis of single-cell RNA sequencing from human pancreatic islets uncovers cell type–specific gene-regulatory changes that help explain type 2 diabetes pathophysiology. Study Highlights:The authors develop differential Gene Coordination Network Analysis (dGCNA) to compare gene–gene coordination between non‑T2D and T2D donors in Smart‑seq2 datasets covering >8,000 islet cells from 32 individuals. In beta cells, dGCNA resolves eleven networks with strong ontological specificity, revealing de‑coordination of mitochondria, glycolysis, cytoskeleton, cell cycle, unfolded protein response, and glucose‑response programs, while insulin secretion, lysosomal regulation, and ribosome-related programs show hyper‑coordination. Functional experiments validate predictions by showing that CEBPG modulates the unfolded protein response and insulin production/secretion, and that TMEM176A/B influences actin microfilaments and cAMP‑amplified exocytosis, with supportive phenotypes in knockout mice and human islets. Results replicate across independent datasets and outperform differential expression (DESeq2) in cross‑dataset reproducibility, and analysis of alpha cells reveals distinct T2D‑linked coordination changes involving secretory granules, glycolysis, mitochondria, and ribosomes. Conclusion:By focusing on networks of differentially coordinated genes rather than expression alone, dGCNA provides a robust framework to pinpoint cell type–specific mechanisms and nominate actionable targets for preserving islet function in type 2 diabetes. Reference:Nature Communications (2025). Single-cell mRNA-regulation analysis reveals cell type-specific mechanisms of type 2 diabetes. https://doi.org/10.1038/s41467-025-65060-z License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/ Episode Slug:  Keywords: single-cell RNA-seq, differential network analysis, pancreatic islets, beta cells, type 2 diabetes

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