SGLT2 is not expressed in pancreatic α- and β-cells, and its inhibition does not directly affect glucagon and insulin secretion in rodents and humans.
SGLT2 is not expressed in pancreatic α- and β-cells, and its inhibition does not directly affect glucagon and insulin secretion in rodents and humans.
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DOI：
10.1016/j.molmet.2020.101071
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发表时间：
2020-12
影响因子：
8.1
通讯作者：
Gilon P
中科院分区：
文献类型：
--
作者：
Chae H;Augustin R;Gatineau E;Mayoux E;Bensellam M;Antoine N;Khattab F;Lai BK;Brusa D;Stierstorfer B;Klein H;Singh B;Ruiz L;Pieper M;Mark M;Herrera PL;Gribble FM;Reimann F;Wojtusciszyn A;Broca C;Rita N;Piemonti L;Gilon P
钠-葡萄糖共转运蛋白2 （SGLT2）抑制剂（SGLT2i）或格列净是一种通过促进血糖来降低血糖的降糖药物，但它们也刺激内源性葡萄糖和酮体的产生。这些代谢反应的可能原因是血液中胰高血糖素水平的升高和血液中胰岛素水平的降低，但其中的机制一直争论不休。本研究通过多种方法验证SGLT2i是否通过直接作用于三种物种的胰岛细胞来影响胰高血糖素和胰岛素的分泌。我们测试了两种选择性SGLT1/2i（达格列净、恩格列净）和一种选择性SGLT1/2i（索他列净）对小鼠体内各种生物学参数（血糖、血糖、胰高血糖素血症、胰岛素血症）的影响。在大鼠、小鼠和人facs纯化的α-和β-细胞中，并通过分析两个人胰岛细胞转录组数据集，评估SGLT2和其他葡萄糖转运蛋白的mRNA表达。胰腺组织中SGLT2的免疫检测采用一种有效的抗体。采用离体大鼠、小鼠和人胰岛及原位灌注小鼠胰腺，观察达格列净、恩格列净和索他列净对胰高血糖素和胰岛素分泌的影响。最后，我们测试了SGLT2i对胰高血糖素基因表达的长期影响。小鼠的SGLT2抑制增加了空腹状态下的血浆胰高血糖素/胰岛素比率，这一效应与血糖下降有关。基因表达分析和免疫检测显示，鼠和人胰岛细胞中无SGLT2 mRNA或蛋白表达，但人α-细胞中有适度的SGLT1 mRNA表达。然而，对大鼠、小鼠和人（29个供体）胰岛和原位灌注小鼠胰腺的功能实验未发现达格列净、恩格列净或索他列净对胰高血糖素和胰岛素分泌有任何直接影响。SGLT2i不影响胰高血糖素基因在大鼠和人胰岛中的表达。数据表明，sgltti诱导的体内血浆胰高血糖素/胰岛素比值的增加不是由格列净对胰岛细胞的直接作用引起的。格列净（SGLT2和SGLT1/2抑制剂）增加血浆胰高血糖素/胰岛素比值。SGLT2在啮齿动物和人胰腺α-和β-细胞中不表达。然而，SGLT1在人α-细胞中表达。SGLT2和SGLT1/2抑制剂不直接影响胰高血糖素和胰岛素的分泌。
Sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i), or gliflozins, are anti-diabetic drugs that lower glycemia by promoting glucosuria, but they also stimulate endogenous glucose and ketone body production. The likely causes of these metabolic responses are increased blood glucagon levels, and decreased blood insulin levels, but the mechanisms involved are hotly debated. This study verified whether or not SGLT2i affect glucagon and insulin secretion by a direct action on islet cells in three species, using multiple approaches. We tested the in vivo effects of two selective SGLT2i (dapagliflozin, empagliflozin) and a SGLT1/2i (sotagliflozin) on various biological parameters (glucosuria, glycemia, glucagonemia, insulinemia) in mice. mRNA expression of SGLT2 and other glucose transporters was assessed in rat, mouse, and human FACS-purified α- and β-cells, and by analysis of two human islet cell transcriptomic datasets. Immunodetection of SGLT2 in pancreatic tissues was performed with a validated antibody. The effects of dapagliflozin, empagliflozin, and sotagliflozin on glucagon and insulin secretion were assessed using isolated rat, mouse and human islets and the in situ perfused mouse pancreas. Finally, we tested the long-term effect of SGLT2i on glucagon gene expression. SGLT2 inhibition in mice increased the plasma glucagon/insulin ratio in the fasted state, an effect correlated with a decline in glycemia. Gene expression analyses and immunodetections showed no SGLT2 mRNA or protein expression in rodent and human islet cells, but moderate SGLT1 mRNA expression in human α-cells. However, functional experiments on rat, mouse, and human (29 donors) islets and the in situ perfused mouse pancreas did not identify any direct effect of dapagliflozin, empagliflozin or sotagliflozin on glucagon and insulin secretion. SGLT2i did not affect glucagon gene expression in rat and human islets. The data indicate that the SGLT2i-induced increase of the plasma glucagon/insulin ratio in vivo does not result from a direct action of the gliflozins on islet cells. Gliflozins (SGLT2 and SGLT1/2 inhibitors) increase plasma glucagon/insulin ratio. SGLT2 is not expressed in rodent and human pancreatic α- and β-cells. SGLT1 is however expressed in human α-cells. SGLT2 and SGLT1/2 inhibitors do not directly affect glucagon and insulin secretion.
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影响因子：
64.5
作者：
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影响因子：
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