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

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.