目的 基于半乳糖凝集素 3（Galectin-3）表达及磷脂酰肌醇 3-激酶（PI3K）/蛋白激酶 B（Akt）/叉头框蛋白 O1（FoxO1）信号通路探讨中药复方汉唐平改善 db/db 2 型糖尿病（T2DM）小鼠胰岛 β 细胞功能的作用机制。 方法 将 40 只 db/db 小鼠随机分为模型组、二甲双胍组（30 mg·kg-1 ）、汉唐平组（50.6 g·kg-1 ）、GB1107 组 （Galectin-3 抑制剂，30 mg·kg-1 ），每组 10 只；另外选取 10 只 C57BL/6J 小鼠作为对照组。各组均按照 10 mL·kg-1 给药体积进行灌胃，每日 1 次，连续 12 周。药物干预第 12 周末，测定小鼠空腹血糖（FBG）；进行口服葡萄糖 耐量（OGTT）实验，计算 OGTT 实验血糖曲线下面积（AUCOGTT）；ELISA 法检测血清空腹胰岛素（FINS）含量；HE 染色法观察胰腺组织病理形态变化；免疫荧光法检测胰腺组织胰岛素（INS）表达情况；免疫组化法检测胰腺 组织巨噬细胞标记物分化簇 68（CD68）、Galectin-3 表达情况；RT-qPCR 法检测胰腺组织肌腱膜纤维肉瘤癌基 因同源物 A （MafA）、胰十二指肠同源盒 1（Pdx-1）、Nanog 同源框蛋白（Nanog）、神经元素 3（Ngn3）mRNA 表达 水平；Western Blot 法检测小鼠胰腺组织中 MafA、Pdx-1、Nanog、Ngn3 及 PI3K/Akt/FoxO1 信号通路相关蛋白 表达水平。结果 与对照组比较，模型组小鼠的 FBG、AUCOGTT水平显著升高（P＜0.001），FINS 水平显著降低 （P＜0.001）；胰腺组织结构受损严重，腺泡细胞广泛脱颗粒，胰岛明显萎缩，且总数减少，边界模糊，形状不 规则，胰岛细胞数量明显减少，排列疏松，胞质内出现大量空泡，胰岛及周围组织大量单核细胞浸润；胰岛素 分泌水平显著降低（P＜0.001）；胰岛巨噬细胞标记物 CD68 及炎症因子 Galectin-3 表达水平均显著升高（P＜ 0.001）；胰岛 β 细胞功能性标志物 MafA、Pdx-1 mRNA 及蛋白表达水平显著降低（P＜0.001），去分化标记物 Nanog、Ngn3 mRNA 及蛋白表达水平显著升高（P＜0.001）；胰腺组织 PI3K 蛋白表达水平及 Akt、FoxO1 蛋白磷 酸化水平均显著降低（P＜0.001）。与模型组比较，各给药组小鼠的 FBG 水平显著降低（P＜0.001）；胰腺组织 受损程度明显减轻，胰岛数量增多，边界较规则，结构较为完整，胰岛细胞亦表现出一定程度的恢复，包括细 胞计数增加，胞质液泡减少，胰岛及周围组织少量单核细胞浸润；胰岛素分泌水平显著升高（P＜0.01，P＜ 0.001）；胰岛 CD68 及 Galectin-3 表达水平均显著降低（P＜0.05，P＜0.01，P＜0.001）；胰腺组织 MafA、Pdx-1 mRNA 及蛋白表达水平显著升高（P＜0.05，P＜0.01，P＜0.001），Nanog、Ngn3 mRNA 及蛋白表达水平显著降 低（P＜0.05，P＜0.01，P＜0.001），PI3K 蛋白表达水平及 FoxO1 蛋白磷酸化水平显著升高（P＜0.05，P＜0.01， P＜0.001）。与模型组比较，汉唐平组、GB1107 组小鼠的 FINS 水平明显升高（P＜0.05，P＜0.01），AUCOGTT 水 平明显降低（P＜0.05）；胰腺组织 Akt 蛋白磷酸化水平显著升高（P＜0.05，P＜0.01）。结论 汉唐平能够改善 db/db T2DM 小鼠的糖代谢紊乱，抑制去分化标志物 Naong、Ngn3 表达，上调功能性标志物 MafA、Pdx-1 表 达，从而有效逆转胰岛 β 细胞的去分化，恢复其正常表型和功能，改善胰岛素分泌功能，其作用机制可能与 抑制 Galectin-3 的过度表达，增强 PI3K/Akt/FoxO1 信号通路的活性有关。

Objective To investigate the mechanism by which the Chinese herbal formula Hantangping improves islet β-cell function in db/db type 2 diabetes mellitus （T2DM） mice，based on Galectin-3 expression and the phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt）/forkhead box protein O1（FoxO1） signaling pathway. Methods Forty db/db mice were randomly divided into a model group，a metformin group （30 mg·kg-1 ），a Hantangping group （50.6 g·kg-1 ）， and a GB1107 group （Galectin-3 inhibitor，30 mg·kg-1 ），with 10 mice per group. An additional 10 C57BL/6J mice were selected as the control group. All groups received gavage administration once daily at a volume of 10 mL· kg-1 for 12 consecutive weeks. At the end of the 12-week intervention，fasting blood glucose （FBG） levels were measured. An oral glucose tolerance test （OGTT） was performed，and the area under the curve for OGTT （AUCOGTT） was calculated. Serum fasting insulin （FINS） levels were detected by ELISA. Histopathological changes in pancreatic tissue were observed using hematoxylin and eosin （HE） staining. Insulin （INS） expression in pancreatic tissue was detected by immunofluorescence. Expression of the macrophage marker cluster of differentiation 68（CD68） and Galectin-3 in pancreatic tissue was detected by immunohistochemistry. mRNA expression levels of musculoaponeurotic fibrosarcoma oncogene homolog A （MafA），pancreatic and duodenal homeobox 1（Pdx-1），Nanog homeobox protein （Nanog），and neurogenin 3（Ngn3） in pancreatic tissue were detected by RT-qPCR. Protein expression levels of MafA， Pdx-1， Nanog，Ngn3，and key proteins of the PI3K/Akt/FoxO1 signaling pathway in mouse pancreatic tissue were detected by Western Blot. Results Compared with the control group，FBG and AUCOGTT levels were significantly increased （P＜ 0.001），while FINS levels were significantly decreased （P＜0.001） in the model group. Pancreatic tissue structure was severely damaged，with widespread degranulation of acinar cells，marked atrophy and a reduced total number of islets， blurred boundaries， irregular shapes， significantly decreased islet cell counts， loose cell arrangement， numerous cytoplasmic vacuoles， and extensive mononuclear cell infiltration within and around the islets. Islets were markedly atrophied，with reduced and disorganized cell numbers，and insulin secretion levels were significantly reduced （P＜ 0.001）. Expression levels of the islet macrophage marker CD68 and the inflammatory factor Galectin-3 were significantly increased （P＜0.001）. mRNA and protein expression levels of islet β-cell functional markers MafA and Pdx-1 were significantly decreased （P＜0.001），while mRNA and protein expression levels of dedifferentiation markers Nanog and Ngn3 were significantly increased （P＜0.001）. PI3K protein expression levels and phosphorylation levels of Akt and FoxO1 proteins in pancreatic tissue were significantly decreased （P＜0.001）. Compared with the model group，FBG levels were significantly decreased in all treatment groups （P＜0.001）. Pancreatic tissue damage was markedly alleviated，with increased islet number，more regular boundaries，relatively intact structure，and a degree of recovery in islet cells， including increased cell counts， reduced cytoplasmic vacuolation， and reduced mononuclear cell infiltration within and around the islets. Islet cell numbers increased， and insulin secretion levels were significantly elevated （P＜0.01，P＜0.001）. Expression levels of CD68 and Galectin-3 in islets were significantly reduced （P＜ 0.05， P＜0.01， P＜0.001）. mRNA and protein expression levels of MafA and Pdx-1 in pancreatic tissue were significantly increased （P＜0.05， P＜0.01， P＜0.001）， while mRNA and protein expression levels of Nanog and Ngn3 were significantly decreased （P＜0.05，P＜0.01，P＜0.001）. PI3K protein expression levels and FoxO1 protein phosphorylation levels were significantly increased （P＜0.05，P＜0.01，P＜0.001）. Compared with the model group， FINS levels were significantly increased （P＜0.05， P＜0.01） and AUCOGTT levels were significantly decreased （P＜ 0.05） in the Hantangping and GB1107 groups. Akt protein phosphorylation levels in pancreatic tissue were significantly increased in these two groups （P＜0.05， P＜0.01）. Conclusion Hantangping can ameliorate glucose metabolism disorders in db/db T2DM mice，inhibit the expression of dedifferentiation markers Nanog and Ngn3，and upregulate the expression of functional markers MafA and Pdx-1，thereby effectively reversing islet β-cell dedifferentiation，restoring their normal phenotype and function，and improving insulin secretion. Its mechanism may be related to inhibiting the overexpression of Galectin-3 and enhancing the activity of the PI3K/Akt/FoxO1 signaling pathway.

R285.5

国家自然科学基金青年基金项目（82104791）；广东省基础与应用基础研究基金面上项目（21202104030001057）。