Abstract

Selective inhibitors of sodium glucose cotransporter-2 (SGLT2) are widely used for the treatment of type 2 diabetes and act primarily to lower blood glucose by preventing glucose reabsorption in the kidney. However, it is controversial whether these agents also act on the pancreatic islet, specifically the α cell, to increase glucagon secretion. To determine the effects of SGLT2 on human islets, we analyzed SGLT2 expression and hormone secretion by human islets treated with the SGLT2 inhibitor dapagliflozin (DAPA) in vitro and in vivo. Compared to the human kidney, SLC5A2 transcript expression was 1600-fold lower in human islets and SGLT2 protein was not detected. In vitro, DAPA treatment had no effect on glucagon or insulin secretion by human islets at either high or low glucose concentrations. In mice bearing transplanted human islets, 1 and 4 weeks of DAPA treatment did not alter fasting blood glucose, human insulin, and total glucagon levels. Upon glucose stimulation, DAPA treatment led to lower blood glucose levels and proportionally lower human insulin levels, irrespective of treatment duration. In contrast, after glucose stimulation, total glucagon was increased after 1 week of DAPA treatment but normalized after 4 weeks of treatment. Furthermore, the human islet grafts showed no effects of DAPA treatment on hormone content, endocrine cell proliferation or apoptosis, or amyloid deposition. These data indicate that DAPA does not directly affect the human pancreatic islet, but rather suggest an indirect effect where lower blood glucose leads to reduced insulin secretion and a transient increase in glucagon secretion.

中文翻译：

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Dapagliflozin 不直接影响人类 α 或 β 细胞。

摘要

钠葡萄糖协同转运蛋白 2 (SGLT2) 的选择性抑制剂广泛用于治疗 2 型糖尿病，主要通过防止肾脏对葡萄糖的重吸收来降低血糖。然而，这些药物是否也作用于胰岛，特别是 α 细胞，以增加胰高血糖素的分泌是有争议的。为了确定 SGLT2 对人类胰岛的影响，我们在体外和体内分析了用 SGLT2 抑制剂达格列净 (DAPA) 处理的人类胰岛的 SGLT2 表达和激素分泌。与人类肾脏相比，SLC5A2人类胰岛中的转录本表达低 1600 倍，并且未检测到 SGLT2 蛋白。在体外，DAPA 治疗对高或低葡萄糖浓度下人胰岛分泌胰高血糖素或胰岛素没有影响。在携带移植人胰岛的小鼠中，DAPA 治疗 1 周和 4 周没有改变空腹血糖、人胰岛素和总胰高血糖素水平。葡萄糖刺激后，DAPA 治疗可降低血糖水平并成比例地降低人胰岛素水平，而与治疗持续时间无关。相反，葡萄糖刺激后，总胰高血糖素在 DAPA 治疗 1 周后增加，但在治疗 4 周后恢复正常。此外，人类胰岛移植物未显示 DAPA 处理对激素含量、内分泌细胞增殖或凋亡或淀粉样蛋白沉积的影响。