SGLT1 在胰腺 α 细胞中调节小鼠的胰高血糖素分泌，这可能解释了 SGLT2 抑制剂对血浆胰高血糖素水平的不同影响。
SGLT1 in pancreatic α cells regulates glucagon secretion in mice, possibly explaining the distinct effects of SGLT2 inhibitors on plasma glucagon levels.
机构信息
Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan; Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan.
出版信息
Mol Metab. 2019 Jan;19:1-12. doi: 10.1016/j.molmet.2018.10.009. Epub 2018 Oct 27.
OBJECTIVES
It is controversial whether sodium glucose transporter (SGLT) 2 inhibitors increase glucagon secretion via direct inhibition of SGLT2 in pancreatic α cells. The role of SGLT1 in α cells is also unclear. We aimed to elucidate these points that are important not only for basic research but also for clinical insight.
METHODS
Plasma glucagon levels were assessed in the high-fat, high-sucrose diet (HFHSD) fed C57BL/6J mice treated with dapagliflozin or canagliflozin. RT-PCR, RNA sequence, and immunohistochemistry were conducted to test the expression of SGLT1 and SGLT2 in α cells. We also used αTC1 cells and mouse islets to investigate the molecular mechanism by which SGLT1 modulates glucagon secretion.
RESULTS
Dapagliflozin, but not canagliflozin, increased plasma glucagon levels in HFHSD fed mice. SGLT1 and glucose transporter 1 (GLUT1), but not SGLT2, were expressed in αTC1 cells, mouse islets and human islets. A glucose clamp study revealed that the plasma glucagon increase associated with dapagliflozin could be explained as a response to acute declines in blood glucose. Canagliflozin suppressed glucagon secretion by inhibiting SGLT1 in α cells; consequently, plasma glucagon did not increase with canagliflozin, even though blood glucose declined. SGLT1 effect on glucagon secretion depended on glucose transport, but not glucose metabolism. Islets from HFHSD and db/db mice displayed higher SGLT1 mRNA levels and lower GLUT1 mRNA levels than the islets from control mice. These expression levels were associated with higher glucagon secretion. Furthermore, SGLT1 inhibitor and siRNA against SGLT1 suppressed glucagon secretion in isolated islets.
CONCLUSIONS
These data suggested that a novel mechanism regulated glucagon secretion through SGLT1 in α cells. This finding possibly explained the distinct effects of dapagliflozin and canagliflozin on plasma glucagon levels in mice.
目的
SGLT2 抑制剂是否通过直接抑制胰腺α 细胞中的 SGLT2 来增加胰高血糖素分泌存在争议。SGLT1 在α 细胞中的作用也不清楚。我们旨在阐明这些不仅对基础研究而且对临床见解都很重要的观点。
方法
在高脂肪高蔗糖饮食（HFHSD）喂养的 C57BL/6J 小鼠中评估 dapagliflozin 或 canagliflozin 处理后血浆胰高血糖素水平。进行 RT-PCR、RNA 测序和免疫组织化学染色以检测 α 细胞中 SGLT1 和 SGLT2 的表达。我们还使用 αTC1 细胞和小鼠胰岛来研究 SGLT1 调节胰高血糖素分泌的分子机制。
结果
Dapagliflozin 而非 canagliflozin 增加了 HFHSD 喂养小鼠的血浆胰高血糖素水平。SGLT1 和葡萄糖转运蛋白 1（GLUT1），但不是 SGLT2，在 αTC1 细胞、小鼠胰岛和人胰岛中表达。葡萄糖钳夹研究表明，与 dapagliflozin 相关的血浆胰高血糖素升高可解释为对血糖急剧下降的反应。Canagliflozin 通过抑制 α 细胞中的 SGLT1 抑制胰高血糖素分泌；因此，尽管血糖下降，血浆胰高血糖素并未随 canagliflozin 升高。SGLT1 对胰高血糖素分泌的影响取决于葡萄糖转运，而不是葡萄糖代谢。与对照小鼠相比，HFHSD 和 db/db 小鼠的胰岛显示出更高的 SGLT1 mRNA 水平和更低的 GLUT1 mRNA 水平，从而导致胰高血糖素分泌更高。此外，SGLT1 抑制剂和 SGLT1 siRNA 抑制分离胰岛中的胰高血糖素分泌。
结论
这些数据表明，一种新的机制通过 SGLT1 调节 α 细胞中的胰高血糖素分泌。这一发现可能解释了 dapagliflozin 和 canagliflozin 在小鼠中对血浆胰高血糖素水平的不同影响。
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