Abstract

Background：The International Diabetes Federation (IDF) data shows that the number of people with diabetes continues to grow globally, with approximately 537 million adults worldwide having diabetes in 2023, accounting for 10.5% of the adult population in that age group. It is projected that this number will increase to 783 million by 2045, with nearly 90% of undiagnosed cases concentrated in low and middle income countries. Diabetes imposes a significant health burden and is closely associated with various microvascular and macrovascular complications. Therefore,it is crucial to explore new prevention and treatment strategies for diabetes. Gastrin, primarily secreted by G cells in the gastric antrum, regulates gastric acid secretion by acting on the CCKBR receptor. Recent studies have shown that gastrin/CCKBR has potential benefits in regulating β cell function in the pancreas and protecting diabetic mice. However, there is currently no research establishing whether gastrin regulates blood glucose levels through CCKBR in the kidneys. This study aims to elucidate the role of renal CCKBR in the pathogenesis of type 2 diabetes and its underlying mechanism involving SGLT2-mediated glucose reabsorption, thereby providing new therapeutic targets for the treatment of type 2 diabetes mellitus (T2DM).

Methods：Renal tubule-specific Cckbr-knockout mice (Cckbr^CKO) and their littermate control mice (Cckbr^fl/fl) were utilized to investigate the effect of renal CCKBR on SGLT2 and systemic glucose homeostasis under normal diet, high fat diet (HFD), and HFD with a subsequent injection of a low dose of streptozotocin. The regulation of SGLT2 expression by gastrin/CCKBR and the underlying mechanism was explored using HK-2 cells.

Results: CCKBR was downregulated in kidneys of diabetic mice. Compared with Cckbr^fl/fl mice, CckbrCKO mice exhibited a greater susceptibility to obesity and diabetes when subjected to HFD. In vitro experiments using HK-2 cells revealed an upregulation of glucose transporters after incubation with high glucose, a response that was significantly attenuated following gastrin intervention. The glucose uptake from the culture medium of cells was altered accordingly. Moreover, gastrin administration effectively mitigated hyperglycemia in WT diabetic mice by inhibition of SGLT2 mediated glucose reabsorption, but this effect was compromised in the absence of CCKBR, as seen in Cckbr^CKO mice. Mechanistically, gastrin/CCKBR substantially reduced SGLT2 expression in HK-2 cells exposed to high glucose, via modulating Erk/NF-κB pathway.

Conclusion: Renal gastrin/CCKBR plays a key role in regulating SGLT2 expression and glucose resorption. In diabetic mice, the expression of renal CCKBR is downregulated, and Cckbr^CKO mice fed a high-fat diet are more prone to obesity and diabetes. Our study results indicate that renal CCKBR has the potential to become a new target for T2DM treatment.

Furthermore, future studies could investigate the interactions between renal CCKBR and other glucose transporters, as well as their impact on lipid metabolism, to provide a more comprehensive foundation for diabetes treatment.