No direct effect of SGLT2 activity on glucagon secretion
No direct effect of SGLT2 activity on glucagon secretion
复制标题
DOI：
10.1007/s00125-019-4849-6
复制
发表时间：
2019-06-01
期刊：
影响因子：
8.2
通讯作者：
Holst, Jens J.
中科院分区：
文献类型：
--
作者：
Kuhre, Rune E.;Ghiasi, Seyed M.;Holst, Jens J.
目的/假设钠-葡萄糖协同转运蛋白（SGLT）2抑制剂是一类新的降糖药物，但它们会增加胰高血糖素的分泌，这可能会抵消其降糖作用。先前使用分离的人胰岛或胰高血糖素分泌细胞系α-TC 1静态孵育的研究表明，这是由于α细胞SGLT 1/2活性的直接抑制所致。本研究的目的是测试是否SGLT 2对胰高血糖素分泌的影响表明，在体外可以重现在一个更生理setting.Methods我们探讨了SGLT 2活性对胰高血糖素分泌的影响，使用离体灌注大鼠胰腺，胰高血糖素分泌的生理模型。此外，我们研究了大鼠胰岛以及小鼠和人类胰岛以及小鼠和人类α，β和δ细胞中的Slc 5a 2（编码SGLT 2的基因）表达，以测试潜在的种间变异。结果从低血糖（3.5 mmol/l）到高血糖（10 mmol/l）转换，胰高血糖素的分泌在几分钟内减少了3 - 5倍（4.0 +/- 0.5 pmol/15 min vs 1.3 +/- 0.3 pmol/15 min，p < 0.05）。无论在低或高葡萄糖浓度下，输出均不受达格列净或根皮苷抑制SGLT 1/2或添加SGLT 1/2底物α-甲基吡喃葡萄糖苷的影响（p = 0.29-0.99）。胰岛素和生长抑素分泌（潜在的旁分泌调节剂）也不受影响。Slc 5a 2表达和SGLT 2蛋白在大鼠，小鼠和人类胰岛和小鼠和人类α，β和δ细胞中的边缘或低于检测限。结论/解释我们的综合数据显示，在SGLT 2抑制剂治疗过程中血浆胰高血糖素增加不太可能直接抑制α细胞中的SGLT 2，而是可能发生在其降血糖作用的下游。
Aims/hypothesis Sodium-glucose cotransporter (SGLT) 2 inhibitors constitute a new class of glucose-lowering drugs, but they increase glucagon secretion, which may counteract their glucose-lowering effect. Previous studies using static incubation of isolated human islets or the glucagon-secreting cell line alpha-TC1 suggested that this results from direct inhibition of alpha cell SGLT1/2-activity. The aim of this study was to test whether the effects of SGLT2 on glucagon secretion demonstrated in vitro could be reproduced in a more physiological setting.Methods We explored the effect of SGLT2 activity on glucagon secretion using isolated perfused rat pancreas, a physiological model for glucagon secretion. Furthermore, we investigated Slc5a2 (the gene encoding SGLT2) expression in rat islets as well as in mouse and human islets and in mouse and human alpha, beta and delta cells to test for potential inter-species variations. SGLT2 protein content was also investigated in mouse, rat and human islets.Results Glucagon output decreased three- to fivefold within minutes of shifting from low (3.5 mmol/l) to high (10 mmol/l) glucose (4.0 +/- 0.5 pmol/15min vs 1.3 +/- 0.3 pmol/15min, p < 0.05). The output was unaffected by inhibition of SGLT1/2 with dapagliflozin or phloridzin or by addition of the SGLT1/2 substrate alpha-methylglucopyranoside, whether at low or high glucose concentrations (p = 0.29-0.99). Insulin and somatostatin secretion (potential paracrine regulators) was also unaffected. Slc5a2 expression and SGLT2 protein were marginal or below detection limit in rat, mouse and human islets and in mouse and human alpha, beta and delta cells.Conclusions/interpretation Our combined data show that increased plasma glucagon during SGLT2 inhibitor treatment is unlikely to result from direct inhibition of SGLT2 in alpha cells, but instead may occur downstream of their blood glucose-lowering effects.