膵臓と肝臓をつなぐ血糖調節のしくみを解明―2型糖尿病の複雑な病態から新治療へ―

2026-10-13 京都大学

膵臓と肝臓が協調して血糖を維持する仕組みと、2型糖尿病モデルでみられた臓器間の逆方向の変化。（作成：研究グループ／図版作成支援：OpenAI ChatGPT［GPT-5.6 Sol］）

＜関連情報＞

• https://www.kyoto-u.ac.jp/ja/research-news/2026-10-13-0
• https://www.science.org/doi/10.1126/sciadv.aeh4948

炭酸脱⽔酵素VIII は IP3R1 依存性カルシウムシグナルを調節し、インスリン分泌と肝糖産⽣を協調制御する Carbonic anhydrase VIII regulates IP3R1-dependent Ca2+ signaling to coordinate insulin secretion and hepatic glucose production

Muhammad Fauzi, Takaaki Murakami, Ryota Usui, Ainur Botagarova, […] , and Daisuke Yabe
Science Advances  Published:9 Oct 2026
DOI:https://doi.org/10.1126/sciadv.aeh4948

Abstract

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 Car8^wdl 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.