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

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.