背景：2 型糖尿病（T2DM）是一种高发的慢性代谢性疾病，全球约有 5.37 亿 20-79 岁的成年人患有糖尿病。T2DM 引发的一系列的大血管和微血管并发症显著影响患 者预后。阐明 T2DM 的发病机制并开发有效干预手段至关重要。既往研究表明，胃 泌素及其受体 CCKBR（胆囊收缩素 B 受体）在糖代谢中发挥重要作用，然而肾脏 CCKBR 是否影响血糖稳态以及糖尿病发生发展尚不明确。本研究旨在探讨肾脏 CCKBR 在糖代谢调控的功能，并揭示其在 T2DM 中的具体作用机制。 方法：采用肾小管特异性 Cckbr 敲除小鼠（CckbrCKO）和同窝对照小鼠（Cckbrfl/fl）， 通过正常饮食、高脂饮食（HFD）和糖尿病模型诱导（HFD 联合低剂量链脲佐菌素） 等方式进行造模，检测小鼠血糖、葡萄糖耐量和血生化等指标，评估肾脏 CCKBR 对全身葡萄糖代谢稳态的影响。通过 Western blot、RT-qPCR 和免疫荧光染色等方法 探究 CCKBR 对肾脏 SGLT2（钠-葡萄糖共转运体）表达的影响。在体外实验中，通 过高糖、高糖+胃泌素、高糖+胃泌素+CCKBR siRNA 处理人肾近曲小管上皮细胞 （HK2 细胞），研究胃泌素/CCKBR 对细胞葡萄糖吸收的调节作用， 利用分子生 物学手段探讨胃泌素/CCKBR 对 SGLT2 表达的调控作用及机制。 结果：糖尿病小鼠肾脏中 CCKBR 表达明显下调。与 Cckbrfl/fl 小鼠相比，CckbrCKO 小鼠更容易受到高脂饮食和糖尿病诱导饮食的影响，表现为更显著的体重增加以及 血糖稳态受损。体外实验结果显示，在高糖培养条件下，HK2 细胞的葡萄糖转运体 （如 SGLT2）的表达明显上调，而胃泌素处理可以恢复 SGLT2 的异常表达，并减 少细胞对葡萄糖的摄取。进一步实验发现，胃泌素的这一效应依赖于其受体 CCKBR。 胃泌素可缓解 Cckbrfl/fl糖尿病小鼠的高血糖症状，而在 CckbrCKO 小鼠中，胃泌素的 功能受限。机制上，胃泌素/CCKBR 信号通过调节 Erk/NF-κB 信号通路，显著降低 了高糖诱导的 SGLT2 的表达，进而抑制葡萄糖的过度重吸收。 结论：胃泌素通过作用于肾脏 CCKBR 抑制 SGLT2 介导的葡萄糖重吸收，显著缓解 糖尿病小鼠的高血糖，改善糖尿病。这一发现揭示了胃泌素及肾脏 CCKBR 在糖尿 病发生发展中的关键作用，强调了胃泌素-肾脏 CCKBR 在 T2DM 治疗中的重要价 值。

Background：Type 2 diabetes mellitus (T2DM) is a prevalent chronic metabolic disorder closely associated with a range of both macrovascular and microvascular complications. Currently, approximately 537 million adults aged 20 to 79 years have diabetes worldwide, representing 11.3% of the global population in this age group. It is projected that the number of individuals with diabetes will increase to 643 million (11.3%) by 2030, and to 783 million (12.2%) by 2045. Therefore, it is imperative to implement effective prevention strategies and optimal management approaches to reduce the significant health burden imposed by T2DM.Gastrin is synthesized and secreted by G-cells in the gastric antrum and is known for its role in regulating gastric acid secretion through binding to the cholecystokinin B receptor (CCKBR). Recent studies suggest that the gastrin/CCKBR signaling pathway may also play a protective role in diabetes. The sodium-glucose cotransporter (SGLT) and the Na+/H+exchanger (NHE) regulate glucose reabsorption in the kidney by maintaining the Na+electrochemical gradient. It has been shown that gastrin inhibits NHE activity via CCKBR, potentially influencing renal water-salt homeostasis and glucose metabolism. The objective of this study is to investigate the potential therapeutic mechanism of renal CCKBR in diabetes mellitus, specifically focusing on its role in SGLT2-mediated glucose reabsorption. Methods: Renal tubule-specific Cckbr knockout mice (CckbrCKO) and littermate control mice (Cckbrfl/fl) were used to assess the effects of renal CCKBR on systemic glucose metabolism by measuring blood glucose levels, glucose tolerance, and blood biochemistry in mice with diabetes induced by a normal diet, a high-fat diet (HFD), and a combination of HFD and low-dose streptozotocin (STZ). The effects of CCKBR on SGLT2 expression were evaluated using Western blot, RT-qPCR, and immunofluorescence staining. In vitro, HK2 cells were used to measure glucose levels in both cells and culture medium supernatant following gastrin treatment, after interference with the gastrin/CCKBR signaling pathway using CCKBR siRNA. The regulation of cellular glucose uptake by gastrin/CCKBR and the effects of gastrin/CCKBR on SGLT2 expression were further investigated by Western blot and RT-qPCR. Results: CCKBR expression was significantly downregulated in the kidneys of diabetic mice. CckbrCKO mice exhibited increased obesity and heightened susceptibility to diabetes in response to a high-fat diet compared to Cckbrfl/fl mice. In vitro, the expression of glucose transporters, including SGLT2, was significantly upregulated under high-glucose culture conditions, and this upregulation was significantly attenuated by gastrin treatment, leading to a corresponding decrease in cellular glucose uptake. Furthermore, gastrin effectively inhibited SGLT2-mediated glucose reabsorption via the CCKBR receptor, alleviating hyperglycemia symptoms in Cckbrfl/fl diabetic mice. However, in CckbrCKO mice, this effect was significantly impaired. Mechanistically, gastrin/CCKBR reduced SGLT2 expression and inhibited excessive glucose reabsorption in Human proximaltubular epithelial cell line （HK2 cells）under high-glucose conditions by modulating the Erk/NF-κB signaling pathway. Conclusion: The present study demonstrated that the gastrin/CCKBR signaling pathway in the kidney significantly alleviated hyperglycemic symptoms in diabetic mice by inhibiting SGLT2-mediated glucose reabsorption. These findings highlight the critical role of gastrin/CCKBR in regulating the pathological processes of diabetes, providing a new scientific basis for its potential use as a therapeutic target, and emphasizing the importance of gastrin - renal CCKBR in diabetes intervention.