Carbonic anhydrase VIII regulates IP3R1-dependent Ca2+ signaling to coordinate insulin secretion and hepatic glucose production.

Intracellular Ca2+ signaling is essential for glucose-induced insulin secretion (GIIS) and hepatic glucose production (HGP), yet how Ca2+ dynamics are coordinated across organs remains unclear. Carbonic anhydrase VIII (CA8), an endogenous inhibitor of inositol 1,4,5-trisphosphate receptor 1 (IP3R1), was identified as a shared regulator of pancreatic and hepatic glucose metabolism. Using Car8wdl mice, we showed that CA8 deficiency enhanced GIIS and HGP in vivo and ex vivo. In islets and hepatocytes, CA8 loss augments Ca2+ oscillations, an effect abolished by IP3R inhibition or Car8 reexpression. Enhanced HGP persists independently of glucagon receptor, PLC, or PKA signaling and occurs without increased IP1, indicating heightened IP3R1 sensitivity rather than increased IP3 production. In hepatocytes, chronic glucagon exposure attenuated acute glucagon responsiveness in a CA8-dependent manner. In obese diabetic mice, CA8 increased in islets but decreased in hepatocytes; hepatic CA8 restoration reduced excessive HGP. Collectively, these findings identify CA8 as a cross-organ regulator of IP3R1-dependent Ca2+ signaling with translational relevance to diabetes.