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

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

  • Adv Sci (Weinh). 2025 Feb 14:e2410032. doi: 10.1002/advs.202410032.
Xue Liu 1 2,  Xing Liu 1,  Yunpeng Liu 1,  Anxiong Long 1,  Wei Liu 3,  Shiyun Sun 1,  Shuaibing Lu 4 5,  Xianxian Wu 1,  Xiaodi Jia 6,  Pedro A Jose 7 8,  Qiang Wei 1,  Xiaoliang Jiang 1,  Haizeng Zhang 4 5,  Zhiwei Yang 1
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Cardiology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory Zhejiang Province, 310009, Hangzhou, China.
  • 3 Graduate School of Hebei North University, Zhangjiakou, Hebei, 075031, China.
  • 4 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.
  • 5 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
  • 6 Taihe County People's Hospital, The Taihe Hospital of Wannan Medical College, 21 Jiankang Road, Taihe County, Anhui Province, 236600, China.
  • 7 Department of Pharmacology and Physiology, The George Washington University School of Medicine & Health Sciences, Washington, DC, 20052, USA.
  • 8 Department of Medicine, Division of Kidney Diseases & Hypertension, The George Washington University School of Medicine & Health Sciences, Washington, DC, 20052, USA.
PMID: 39950948 DOI: 10.1002/advs.202410032
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-SiO2 microspheres (20 mg kg-1 d-1) 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-SiO2 microspheres markedly reduce glucose absorption in duodenum obtained from patients with T2D. In mice with HFD-induced T2D, Gastrin-SiO2 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-SiO2 microspheres may be a promising strategy for the treatment of patients with T2D.

Keywords

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

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