Alpha-to-beta cell crosstalk: Adaptive mechanisms shaping islet function.

Abstract

The pancreatic islet, historically described as a binary system of insulin-secreting beta cells and glucagon-secreting alpha cells, is increasingly recognized as a complex paracrine network contributing to glucose homeostasis. Alpha-to-beta cell communication is not merely modulatory but a decisive mechanism sustaining islet function under metabolic stress. Alpha cell distribution, structural specializations at the alpha-beta interface, and adaptations in signaling pathways collectively shape glycemic set points and beta cell resilience. Recent studies highlight the context-dependent nature of this intra-islet crosstalk. Visa et al. demonstrated that prediabetic stress in Western diet-fed mice remodels islet cytoarchitecture in a sex-dependent manner, enhancing alpha-to-beta signaling and Ca²⁺ dynamics, and thereby preserving insulin secretion more effectively in females than in males. Experiments using a glucagon receptor antagonist in human islets confirmed that glucagon paracrine signaling is essential for this adaptive enhancement, particularly the increased Ca²⁺ dynamics in female islets under high metabolic demand. Mechanistic studies further revealed that the GLP-1 receptor forms specialized nanodomains at the alpha-beta junction that undergo pre-internalization, priming beta cells for rapid Ca²⁺ influx and heightened metabolic responsiveness. Collectively, these findings highlight intra-islet communication as a critical determinant of adaptation or failure in diabetes progression. However, conflicting evidence from beta cell-only islets, which display enhanced glucose-stimulated insulin secretion, together with reports that long-term exposure to the GLP-1 analog liraglutide can compromise beta cell function, presents a paradox that challenges current models of intra-islet regulation. Understanding these nuances is crucial for translating intra-islet signaling into targeted therapeutic strategies and regenerative tissue engineering.