Intestinal Gastrin/CCKBR Axis Protects against Type 2 Diabetes by Reducing Intestinal Glucose Absorption through the PI3K/Akt/eIF4B Signaling Pathway

Xue Liu, Institute of Laboratory Animal Sciences (CAMS & PUMC), National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, 100021, Beijing, China.
Xing Liu, Institute of Laboratory Animal Sciences (CAMS & PUMC), National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, 100021, Beijing, China.
Yunpeng Liu, Institute of Laboratory Animal Sciences (CAMS & PUMC), National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, 100021, Beijing, China.
Anxiong Long, Institute of Laboratory Animal Sciences (CAMS & PUMC), National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, 100021, Beijing, China.
Wei Liu, Graduate School of Hebei North University, Zhangjiakou, Hebei, 075031, China.
Shiyun Sun, Institute of Laboratory Animal Sciences (CAMS & PUMC), National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, 100021, Beijing, China.
Shuaibing Lu, Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
Xianxian Wu, Institute of Laboratory Animal Sciences (CAMS & PUMC), National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, 100021, Beijing, China.
Xiaodi Jia, Taihe County People's Hospital, The Taihe Hospital of Wannan Medical College, 21 Jiankang Road, Taihe County, Anhui Province, 236600, China.
Pedro A. Jose, Department of Pharmacology and Physiology, The George Washington University School of Medicine & Health Sciences, Washington, DC, 20052, USA.
Qiang Wei, Institute of Laboratory Animal Sciences (CAMS & PUMC), National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, 100021, Beijing, China.
Xiaoliang Jiang, Institute of Laboratory Animal Sciences (CAMS & PUMC), National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, 100021, Beijing, China.
Haizeng Zhang, Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
Zhiwei Yang, Institute of Laboratory Animal Sciences (CAMS & PUMC), National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, 100021, Beijing, China.

Document Type

Journal Article

Publication Date

2-14-2025

Journal

Advanced science (Weinheim, Baden-Wurttemberg, Germany)

DOI

10.1002/advs.202410032

Keywords

Gastrin‐SiO2 microspheres; cholecystokinin B receptor; glucose transporter type 2; sodium/glucose cotransporter 1; type 2 diabetes

Abstract

The Gastrin/CCKBR axis is essential for inhibiting intestinal sodium absorption, but its effects on intestinal glucose metabolism remain elusive. This study aims to determine the role of intestinal Gastrin/CCKBR on glucose absorption in the development of type 2 diabetes (T2D). Intestinal epithelial cell-specific Cckbr knockout mice and control wild-type mice are fed normal diet (ND, 10% fat) or high fat diet (HFD, 60% fat) to study the effect of intestinal Gastrin/CCKBR on blood glucose levels. Gastrin-SiO microspheres (20 mg kg d) are designed so that gastrin specifically stimulates intestinal CCKBR, without its absorption into the circulation. Mice with silenced intestinal Cckbr has pre-diabetes mellitus (Pre-DM) that rapidly progressed into T2D when fed HFD. Moreover, Gastrin-SiO microspheres markedly reduce glucose absorption in duodenum obtained from patients with T2D. In mice with HFD-induced T2D, Gastrin-SiO microspheres reduce intestinal glucose absorption by down-regulating intestinal SGLT1 and GLUT2 expressions and stimulating incretin secretion. This study shows the important role of intestinal Gastrin/CCKBR in intestinal glucose absorption. Gastrin-SiO microspheres may be a promising strategy for the treatment of patients with T2D.

Department

Pharmacology and Physiology

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