Pancreatic Islet Cell Crosstalk: Insight Into α-/β-Cell Compensatory Mechanisms

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. A β-cell-specific Nox4 knockout mouse (Nox4^βKO) displays defective glucose-stimulated insulin secretion and develops a prediabetic phenotype. To uncover the adaptive changes, we ran a detailed analysis of Nox4^βKO pancreatic islets. We analyzed their composition, hormone secretion dynamics, receptor expression profiles, and downstream signaling pathways by immunocytochemistry, flow cytometry, RNA sequencing, cAMP assays, and insulin or glucagon secretion assays using both isolated islets and pancreatic slices across different glucose levels and receptor-modulating conditions. Prediabetic Nox4^βKO 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 engagement: whereas GLP-1R dominated in wild-type islets, GCGR signaling gained prominence in Nox4^βKO islets. This functional rebalancing is consistent with an adaptive response to emerging β-cell dysfunction. Functional assays demonstrated that insulin secretion in prediabetic islets became increasingly reliant on glucagon-driven potentiation 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. α-cell remodeling and flexible engagement of glucagon and GLP-1 receptors act as key compensatory mechanisms that may help to sustain insulin secretion during early β-cell stress. The context-dependent plasticity of intra-islet receptor activation highlights a coordinated multicellular adaptation in prediabetes and suggests that targeting intra-islet endocrine crosstalk may help preserve β-cell function in prediabetes.