Dapagliflozin improves pancreatic islet function by attenuating microvascular endothelial dysfunction in type 2 diabetes
Dapagliflozin improves pancreatic islet function by attenuating microvascular endothelial dysfunction in type 2 diabetes
复制标题
达格列净通过减轻 2 型糖尿病微血管内皮功能障碍来改善胰岛功能
DOI：
10.1002/dmrr.3607
复制
发表时间：
2022-12-30
影响因子：
8
通讯作者：
Wei，Rui
中科院分区：
文献类型：
--
作者：
Le，Yunyi;Yang，Jin;Wei，Rui
目的钠-葡萄糖协同转运蛋白2抑制剂，包括达格列净，改善2型糖尿病患者的β细胞功能。材料与方法db/db小鼠分别用达格列净或溶媒处理6周，检测胰岛微血管内皮细胞（IMECs）的β细胞功能、胰岛毛细血管和炎性趋化因子水平。将小鼠IMEC细胞系MS-1细胞与棕榈酸酯和/或达格列净孵育24小时。评估血管生成和炎症趋化因子水平，并分析相关信号通路。在存在或不存在与MS-1细胞共培养的情况下，用棕榈酸酯和/或达格列净处理小鼠细胞系MIN 6细胞24 h。结果达格列净显著改善胰岛β细胞功能，增加胰岛毛细血管，降低IMECs indb/db小鼠炎性趋化因子水平。在棕榈酸酯处理的MS-1细胞中，达格列净增强了血管生成，并下调了炎症趋化因子的水平。PI 3 K抑制剂或mTOR抑制剂可消除达格列净介导的效应。重要的是，达格列净减弱了棕榈酸诱导的与MS-1细胞共培养的MIN 6细胞中β细胞功能相关基因表达和胰岛素分泌的下调，但在单培养的MIN 6细胞中没有。达格列净诱导的β细胞功能改善至少部分归因于其以PI 3 K/Akt-mTOR依赖性方式对IMEC的有益作用。
AimsSodium‐glucose co‐transporter 2 inhibitors, including dapagliflozin, improveßcell function in type 2 diabetic individuals. Whether dapagliflozin can protect islet microvascular endothelial cells (IMECs) and thus contribute to the improvement ofßcell function remains unknown.Materials and MethodsThedb/dbmice were treated with dapagliflozin or vehicle for 6 weeks.ßcell function, islet capillaries and the levels of inflammatory chemokines in IMECs were detected. The mouse IMEC cell line MS‐1 cells were incubated with palmitate and/or dapagliflozin for 24 h. Angiogenesis and inflammatory chemokine levels were evaluated, and the involved signalling pathways were analysed. The mouseßcell line MIN6 cells, in the presence or absence of co‐culture with MS‐1 cells, were treated with palmitate and/or dapagliflozin for 24 h. The expression ofßcell specific markers and insulin secretion in MIN6 cells were determined.ResultsDapagliflozin significantly improvedßcell function, increased islet capillaries and decreased the levels of inflammatory chemokines of IMECs indb/dbmice. In the palmitate‐treated MS‐1 cells, angiogenesis was enhanced and the levels of inflammatory chemokines were downregulated by dapagliflozin. Either a PI3K inhibitor or mTOR inhibitor eliminated the dapagliflozin‐mediated effects. Importantly, dapagliflozin attenuated the palmitate‐induced downregulation ofßcell function‐related gene expression and insulin secretion in MIN6 cells co‐cultured with MS‐1 cells but not in those on mono‐culture.ConclusionsDapagliflozin restores islet vascularisation and attenuates the inflammation of IMECs in type 2 diabetic mice. The dapagliflozin‐induced improvement ofßcell function is at least partially accounted for by its beneficial effects on IMECs in a PI3K/Akt‐mTOR‐dependent manner.