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Temporal Single-Cell Transcriptional Dynamics of Murine Pancreatic Islet Remodeling During Hyperglycaemia Progression

ABSTRACT: Pancreatic islets undergo coordinated cellular remodeling during obesity-induced insulin resistance. However, longitudinal changes across endocrine and non-endocrine compartments remain largely unexplored. We present a comprehensive high-resolution atlas using longitudinal single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) on islets from C57BL/6 mice subjected to high-fat diet (HFD) feeding for 8, 16, and 24 weeks, along with age-matched controls on regular chow (RC). We mapped dynamic changes in islet cell composition and transcriptional states. Trajectory inference indicated diversification of beta-cell programs into adaptive and inflammatory states under HFD. Progression of insulin resistance induced shrinkage and transcriptional remodeling of glucagon-secreting alpha-cells, marked by upregulation of genes related to intracellular transport and oxidative stress, accompanied by the emergence of a polyhormonal alpha-cell subpopulation. Similarly, we identified delta-cell subpopulations exhibiting beta-like transcriptional signatures and polyhormonal identity under nutritional stress, suggesting adaptive delta-cell plasticity that may partially compensate for beta-cell loss during insulin resistance. The islet microenvironment exhibited robust expansion of proinflammatory M1 macrophages, reaching a plateau by 16 weeks of HFD, indicating niche saturation. Cell-cell communication analyses revealed disruption of key signaling pathways within endocrine and between endocrine and non-endocrine cells under HFD conditions. Notably, CCL27a–chemokine receptor signaling between beta-cells and M1 macrophages was significantly reduced in HFD islets, likely driven by reduced Ccl27a expression and chromatin accessibility in a distinct beta cell subpopulation, which we further validated using INS-1 cells exposed to HFD-like conditions. Comparative analysis with scRNA seq of human islets confirmed conserved stress signatures. Furthermore, genetic variants at the CCL27 locus were associated with increased T2D risk and HOMA-IR in human populations, establishing a novel link between beta-cell stress and systemic inflammation. This resource provides a hierarchical framework for understanding islet failure and identifies potential therapeutic nodes for type 2 diabetes.

ORGANISM(S): Mus musculus

PROVIDER: GSE329967 | GEO | 2026/05/25

REPOSITORIES: GEO

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Project description:Aim: To investigate the compensatory role of α-cell-derived paracrine signaling through glucagon and GLP-1 receptors in maintaining β-cell function when insulin secretion is compromised. Methods: A β-cell-specific Nox4 knockout mouse (Nox4βKO), which displays defective glucose-stimulated insulin secretion, was used to assess adaptive changes in pancreatic islets. We analyzed islet composition, hormone secretion dynamics, receptor expression profiles, and downstream signaling pathways. Methodologies included immunocytochemistry, flow cytometry, RNA sequencing, cAMP assays, and functional insulin/glucagon secretion assays using both isolated islets and pancreatic slices across different glucose levels and receptor-modulating conditions. Results: Prediabetic Nox4βKO islets showed increased α-cell numbers, expansion of bihormonal cells, and elevated production of glucagon and GLP-1. Receptor profiling revealed a shift in receptor usage: whereas GLP-1R dominated in wild-type islets, GCGR signaling gained prominence in Nox4βKO islets. This restructuring appears to reflect an adaptive response to emerging β-cell dysfunction. Functional assays demonstrated that insulin secretion in prediabetic islets became increasingly reliant on glucagon-driven activation of GLP-1R and cAMP-dependent pathways. Transcriptomic and signaling data confirmed enhanced expression of cAMP-related intermediates and calcium-handling components, indicating partial preservation of insulin secretory capacity despite underlying defects. Conclusion: α-cell remodeling and flexible engagement of glucagon and GLP-1 receptors act as key compensatory mechanisms that help maintain insulin secretion during early β-cell stress. The context-dependent reordering of intra-islet receptor dominance highlights a coordinated multicellular adaptation in prediabetes and suggests that targeting intra-islet endocrine crosstalk may help preserve β-cell function in prediabetes and early type 2 diabetes.

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Temporal Single-Cell Transcriptional Dynamics of Murine Pancreatic Islet Remodeling During Hyperglycaemia Progression

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