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Peer-reviewedCC BY-NCScience Advances

Carbonic anhydrase VIII regulates IP3R1-dependent Ca ²⁺ signaling to coordinate insulin secretion and hepatic glucose production

  • Muhammad Fauzi1
  • Takaaki Murakami1
  • Ryota Usui2
  • Ainur Botagarova1
  • Daisuke Otani1
  • Kentarou Sakaki1
  • Shinsuke Tokumoto1
  • Toshinori Imaizumi1
  • Hisato Tatsuoka3
  • Masahito Ogura4
  • Jonathan Campbell5
  • Nobuya Inagaki6
1 more authors
  • Daisuke Yabe1
6 affiliations
  1. 1Department of Diabetes, Endocrinology, and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  2. 2Center for Diabetes, Endocrinology and Metabolism, Kansai Electric Power Hospital, Osaka, Japan.
  3. 3Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Kyoto, Japan.
  4. 4Department of Diabetes, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
  5. 5Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
  6. 6Medical Research Institute KITANO HOSPITAL, PIIF Tazuke-kofukai, Osaka, Japan.
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Abstract

Intracellular Ca 2+ signaling is essential for glucose-induced insulin secretion (GIIS) and hepatic glucose production (HGP), yet how Ca 2+ 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 Ca 2+ 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 IP 1 , indicating heightened IP3R1 sensitivity rather than increased IP 3 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 Ca 2+ signaling with translational relevance to diabetes.

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Cite

BibTeXRIS
BibTeX
@article{fauzi2026carbonic,
  title = {{Carbonic anhydrase VIII regulates IP3R1-dependent Ca ²⁺ signaling to coordinate insulin secretion and hepatic glucose production}},
  author = {Muhammad Fauzi and Takaaki Murakami and Ryota Usui and Ainur Botagarova and Daisuke Otani and Kentarou Sakaki and Shinsuke Tokumoto and Toshinori Imaizumi and Hisato Tatsuoka and Masahito Ogura and Jonathan Campbell and Nobuya Inagaki and Daisuke Yabe},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aeh4948},
  url = {https://www.science.org/doi/10.1126/sciadv.aeh4948},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - Carbonic anhydrase VIII regulates IP3R1-dependent Ca ²⁺ signaling to coordinate insulin secretion and hepatic glucose production
AU  - Muhammad Fauzi
AU  - Takaaki Murakami
AU  - Ryota Usui
AU  - Ainur Botagarova
AU  - Daisuke Otani
AU  - Kentarou Sakaki
AU  - Shinsuke Tokumoto
AU  - Toshinori Imaizumi
AU  - Hisato Tatsuoka
AU  - Masahito Ogura
AU  - Jonathan Campbell
AU  - Nobuya Inagaki
AU  - Daisuke Yabe
PY  - 2026
DA  - 2026/10/09
JO  - Science Advances
DO  - 10.1126/sciadv.aeh4948
UR  - https://www.science.org/doi/10.1126/sciadv.aeh4948
AB  - Intracellular Ca 2+ signaling is essential for glucose-induced insulin secretion (GIIS) and hepatic glucose production (HGP), yet how Ca 2+ 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 Ca 2+ 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 IP 1 , indicating heightened IP3R1 sensitivity rather than increased IP 3 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 Ca 2+ signaling with translational relevance to diabetes.
SN  - 2375-2548
ER  -