AbstractThe 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.