背景：肥胖及肥胖相关 2 型糖尿病（type 2 diabetes mellitus，T2DM）严重影响了肥胖患者的生活质量，我国成年人肥胖问题日益凸显，已有超过半数的成年人存在超重或肥胖。减重代谢手术治疗肥胖及肥胖相关 T2DM 具有良好的效果，胃袖状切除术（sleeve gastrectomy，SG）是目前开展比例最高的术式，具有操作相对简单、治疗效果显著的特点。胃袖状切除术治疗 T2DM 的机制目前仍在探索中，其中手术对于胰岛及 β 细胞的影响是研究的一大热点，而糖尿病大鼠手术模型的转录组学研究报道较少。本研究的目的在于通过动物模型，结合动物生理、组织学及单细胞转录组学测序的方法，进一步证实 SG 手术的降糖作用并探究可能机制。方法：本研究采用瘦素受体突变的 ZDF （Zucker diabetic fatty）大鼠作为肥胖糖尿病大鼠模型。将 ZDF 大鼠随机分为胃袖状切除术手术组（SG， n=8）及假手术饮食配对组（Sham，n=8）。于 13 周龄行手术处理。术后记录两组大鼠的体重变化及随机血糖。采用腹腔注射葡萄糖耐量试验（intraperitoneal glucose tolerance test， IPGTT）及口服葡萄糖糖耐量试验（oral glucose tolerance test，OGTT）对术前术后大鼠糖耐量进行评估。于术后第 3 周进行大鼠胰腺取材，行胰腺组织染色及胰岛提取分离。采用胰腺灌注分离提取胰岛，将胰岛解离为单细胞后行单细胞转录组测序。结果：本研究的 SG 手术设计实现了术后大鼠存活率 100%。术前、术后 2 周及术后4 周行 IPGTT，结果显示 SG 组术后 4 周 IPGTT 结果较术前显著改善（P＜0.05），术后 SG 组 IPGTT 结果较 Sham 组相比显著改善（P＜0.05），而 Sham 组术前与术后 IPGTT 结果相比无显著差异。术后 3 周 OGTT 显示 SG 组大鼠结果较术前及 Sham组相比有显著改善（P＜0.05），且血糖曲线模式改善。 SG 组大鼠术后葡萄糖敏感性提高。术后 3 周胰腺 HE 染色结果显示 SG 组大鼠胰岛与 Sham 组相比数量较多、大小较大。单细胞转录组测序结果显示术后 SG 组大鼠与 Sham 组相比胰岛细胞的基因表达（如 Btbd1、 Cele2a、 Itln1、 Pnlip）及信号通路表达（如钙信号通路、 MAPK通路）存在差异。结论：本研究建立了重复性较好的糖尿病大鼠胃袖状切除手术模型，证实了胃袖状切除手术对 ZDF 大鼠降糖作用及对胰岛的可能保护作用，通过单细胞转录组测序证实了胃袖状切除手术对胰岛 β 细胞基因表达及信号通路的影响，证实了 SG 手术治疗糖尿病的有效性并为进一步的机制探究提供了潜在研究靶点。

Objectives: Obesity and obesity-related type 2 diabetes mellitus (T2DM) affect the quality of life of obese patients. The issue of obesity has become increasingly prominent among Chinese adults. Bariatric surgery is effective in treating obesity and T2DM. Sleeve gastrectomy (SG) is the most common surgical type, which is relatively simple with remarkable therapeutic effect. The mechanism of SG in treating T2DM has been widely explored. The effect of SG on pancreatic islets and β cells is a research hotspot. Research combining diabetic rat model with transcriptomics is still limited. The aim of this study is to further confirm the hypoglycemic effect of SG and explore the potential mechanism through single cell RNA sequencing. Methods: In this study, ZDF (Zucker diabetic fatty) rats were used as obese diabetic rat model. ZDF rats were randomly divided into SG group (SG, n=8) and Sham-operated, pairfed group (Sham, n=8). The operation was performed at 13 weeks of age. Body weight and random blood glucose were recorded after surgery. Intraperitoneal glucose tolerance test (IPGTT) and oral glucose tolerance test (OGTT) were used to evaluate glucose metabolism before and after surgery. Pancreas samples were collected at the 3rd week after surgery, and histological staining was performed. Pancreatic islets were isolated by pancreatic perfusion and single cell RNA sequencing was further performed. Results: The SG surgical design in this study achieved a survival rate of 100%. The results of postoperative IPGTT and OGTT in the SG group were significantly improved compared with both preoperative baseline and the results of that in the Sham group (P<0.05). Glucose sensitivity of the SG group was increased postoperatively. Histological staining of the pancreas at 3 weeks after surgery showed that the number and size of pancreatic islets in the SG group were greater than those in the Sham group. Pancreatic islets were successfully isolated with collagenase perfusion and density gradient isolation. Single cell RNA sequencing revealed differences in β cell gene expression (e.g., Btbd1, Cele2a, Itln1, Pnlip) and signaling pathways (e.g., calcium signaling pathway, MAPK pathway) of pancreatic islet between SG group and Sham group. Conclusions: In this study, a reproducible SG model of diabetic rats was established. This study confirmed the hypoglycemic effect of SG on ZDF rats and its potential protective effect on pancreatic islets. Single cell RNA sequencing revealed potential influences of SG on pancreatic islet β cell gene expression and signaling pathways. This study confirmed the effectiveness of SG surgery in the treatment of diabetes and provided a potential research target for future investigation of underlying mechanism.