Pancreatic Gα _s ablation disrupts tissue architecture and YAP signaling and unveils a compensatory regenerative response

Diabetes mellitus is characterized by chronic hyperglycemia and loss of pancreatic β-cell function and mass. Current therapies focus on β-cell protection and regeneration, led by GLP-1 receptor agonists. The G protein α-subunit (Gα _s ) acts as a key signaling node downstream of numerous GPCRs, integrating diverse signals that impact β-cell mass and function. Elucidating the integrative role of pancreatic Gα _s signaling is thus crucial for understanding β-cell biology. Our map of the pancreatic Gα _s -coupled GPCR landscape reveals sophisticated, cell-type-specific networks, positioning Gα _s as a central hub for intra-pancreatic communication. Previous studies in mice with β-cell-specific or whole-pancreatic Gα _s deletion demonstrated reduced β-cell mass, impaired insulin secretion, and glucose intolerance. The stronger phenotype in the whole-pancreas model—marked by α-cell expansion and abnormal distribution—points to a crucial role for Gα _s in differential control of postnatal α- and β-cell proliferation. Here, we analyze the organ-wide consequences of Gα _s deletion using pancreas-specific Gα _s knockout mice (PGsKO). Consistent with prior findings, PGsKO mice exhibit reduced weight gain from four weeks and severe diabetes due to decreased β-cell mass and concomitant α-cell expansion. Furthermore, Gα _s loss induces profound architectural and functional defects in the exocrine pancreas, linked to YAP reactivation in acinar cells. Importantly, we observed attempted β-cell regeneration in PGsKO mice. Although insufficient to reverse diabetes, our results delineate the full pancreatic phenotype that may facilitate these regenerative efforts and suggest that strategically biasing GPCR signaling network away from Gα _s could be a viable strategy to promote β-cell regeneration from other pancreatic cell types.