Dapagliflozin promotes beta cell regeneration by inducing pancreatic endocrine cell phenotype conversion in type 2 diabetic mice.
Dapagliflozin promotes beta cell regeneration by inducing pancreatic endocrine cell phenotype conversion in type 2 diabetic mice.
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Dapagliflozin 通过诱导 2 型糖尿病小鼠的胰腺内分泌细胞表型转换来促进 β 细胞再生。
DOI：
10.1016/j.metabol.2020.154324
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发表时间：
2020-07
期刊：
影响因子：
--
通讯作者：
Hong T
中科院分区：
文献类型：
--
作者：
Wei R;Cui X;Feng J;Gu L;Lang S;Wei T;Yang J;Liu J;Le Y;Wang H;Yang K;Hong T
背景临床试验和动物研究表明，钠-葡萄糖协同转运蛋白2（SGLT 2）抑制剂可改善胰腺β细胞功能。方法采用高脂饮食联合链脲佐菌素（STZ）诱导的糖尿病小鼠模型db/db和胰α细胞谱系示踪（glucagon-β-gal）小鼠，观察达格列净对胰岛形态和细胞表型的影响，探讨胰岛β细胞再生的来源和可能原因。通过每日胃内施用达格列净（lmg/kg）或媒介物治疗小鼠，持续6周。采用酶联免疫吸附法测定血浆胰岛素、胰高血糖素和胰高血糖素样肽-1（GLP-1）。免疫荧光法检测胰岛形态和细胞表型。将原代啮齿类动物胰岛和α TC 1.9（一种小鼠α细胞系）与达格列净（0.25-25 μmol/L）或溶剂在常规或高葡萄糖培养基中孵育24 h，其中存在或不存在GLP-1受体拮抗剂。特异性标志物和激素水平的表达进行了determined.ResultsTreatment与达格列净显着降低血糖在两个糖尿病模型和上调血浆胰岛素和GLP-1水平indb/db小鼠。达格列净治疗增加了两只糖尿病小鼠的胰岛和β细胞数量。达格列净促进了由C肽和BrdU双阳性细胞所指示的β细胞增殖。通过胰高血糖素和胰岛素双阳性细胞评价并通过使用α细胞谱系追踪证实，达格列净促进了α细胞向β细胞的转化。达格列净治疗后，一些胰岛素阳性细胞位于导管室中，甚至与导管细胞标志物共定位，提示导管来源的β细胞新生。在培养的原代啮齿动物胰岛和α TC 1. 9细胞中，在高糖条件下，达格列净上调胰腺内分泌祖细胞和β细胞特异性标志物（包括Pdx 1）的表达。此外，达格列净上调Pcsk 1（编码激素原转化酶1/3，一种将胰高血糖素原加工为GLP-1的重要酶）的表达，并增加α TC 1.9细胞中GLP-1的含量和分泌。重要的是，达格列净诱导的Pdx 1表达上调被GLP-1受体拮抗剂减弱。结论除了降糖作用外，达格列净对2型糖尿病β细胞有额外的保护作用。达格列净增强β细胞自我复制，诱导α细胞向β细胞转化，并促进导管来源的β细胞新生。达格列净对β细胞再生的促进作用可能部分通过α细胞分泌的GLP-1介导。
BackgroundClinical trials and animal studies have shown that sodium-glucose co-transporter type 2 (SGLT2) inhibitors improve pancreatic beta cell function. Our study aimed to investigate the effect of dapagliflozin on islet morphology and cell phenotype, and explore the origin and possible reason of the regenerated beta cells.MethodsTwo diabetic mouse models,db/dbmice and pancreatic alpha cell lineage-tracing (glucagon-β-gal) mice whose diabetes was induced by high fat diet combined with streptozotocin, were used. Mice were treated by daily intragastric administration of dapagliflozin (1 mg/kg) or vehicle for 6 weeks. The plasma insulin, glucagon and glucagon-like peptide-1 (GLP-1) were determined by using ELISA. The evaluation of islet morphology and cell phenotype was performed with immunofluorescence. Primary rodent islets and αTC1.9, a mouse alpha cell line, were incubated with dapagliflozin (0.25–25 μmol/L) or vehicle in the presence or absence of GLP-1 receptor antagonist for 24 h in regular or high glucose medium. The expression of specific markers and hormone levels were determined.ResultsTreatment with dapagliflozin significantly decreased blood glucose in the two diabetic models and upregulated plasma insulin and GLP-1 levels indb/dbmice. The dapagliflozin treatment increased islet and beta cell numbers in the two diabetic mice. The beta cell proliferation as indicated by C-peptide and BrdU double-positive cells was boosted by dapagliflozin. The alpha to beta cell conversion, as evaluated by glucagon and insulin double-positive cells and confirmed by using alpha cell lineage-tracing, was facilitated by dapagliflozin. After the dapagliflozin treatment, some insulin-positive cells were located in the duct compartment or even co-localized with duct cell markers, suggestive of duct-derived beta cell neogenesis. In cultured primary rodent islets and αTC1.9 cells, dapagliflozin upregulated the expression of pancreatic endocrine progenitor and beta cell specific markers (includingPdx1) under high glucose condition. Moreover, dapagliflozin upregulated the expression ofPcsk1(which encodes prohormone convertase 1/3, an important enzyme for processing proglucagon to GLP-1), and increased GLP-1 content and secretion in αTC1.9 cells. Importantly, the dapagliflozin-induced upregulation ofPdx1expression was attenuated by GLP-1 receptor antagonist.ConclusionsExcept for glucose-lowering effect, dapagliflozin has extra protective effects on beta cells in type 2 diabetes. Dapagliflozin enhances beta cell self-replication, induces alpha to beta cell conversion, and promotes duct-derived beta cell neogenesis. The promoting effects of dapagliflozin on beta cell regeneration may be partially mediatedviaGLP-1 secreted from alpha cells.
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影响因子：
4.8
作者：
E. Abraham;C. Leech;Julia C. Lin;H. Zulewski;J. Habener
通讯作者：
E. Abraham;C. Leech;Julia C. Lin;H. Zulewski;J. Habener
影响因子：
4.3
作者：
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通讯作者：
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作者：
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影响因子：
16.2
作者：
Jabbour, Serge A.;Hardy, Elise;Parikh, Shamik
通讯作者：
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影响因子：
7.7
作者：
Saponaro, Chiara;Muhlemann, Markus;Bonner, Caroline
通讯作者：
Bonner, Caroline