1] European Genomic Institute for Diabetes, Lille, France. [2] INSERM UMR 1190, Lille, France. [3] Centre Hospitalier Régional Universitaire, Lille, France.
1] European Genomic Institute for Diabetes, Lille, France. [2] INSERM UMR 1190, Lille, France. [3] Centre Hospitalier Régional Universitaire, Lille, France. [4] Université de Lille, Lille, France.
Nat Med. 2015 May;21(5):512-7. doi: 10.1038/nm.3828. Epub 2015 Apr 20.
Type 2 diabetes (T2D) is characterized by chronic hyperglycemia resulting from a deficiency in insulin signaling, because of insulin resistance and/or defects in insulin secretion; it is also associated with increases in glucagon and endogenous glucose production (EGP). Gliflozins, including dapagliflozin, are a new class of approved oral antidiabetic agents that specifically inhibit sodium-glucose co-transporter 2 (SGLT2) function in the kidney, thus preventing renal glucose reabsorption and increasing glycosuria in diabetic individuals while reducing hyperglycemia. However, gliflozin treatment in subjects with T2D increases both plasma glucagon and EGP by unknown mechanisms. In spite of the rise in EGP, T2D patients treated with gliflozin have lower blood glucose levels than those receiving placebo, possibly because of increased glycosuria; however, the resulting increase in plasma glucagon levels represents a possible concerning side effect, especially in a patient population already affected by hyperglucagonemia. Here we demonstrate that SGLT2 is expressed in glucagon-secreting alpha cells of the pancreatic islets. We further found that expression of SLC5A2 (which encodes SGLT2) was lower and glucagon (GCG) gene expression was higher in islets from T2D individuals and in normal islets exposed to chronic hyperglycemia than in islets from non-diabetics. Moreover, hepatocyte nuclear factor 4-α (HNF4A) is specifically expressed in human alpha cells, in which it controls SLC5A2 expression, and its expression is downregulated by hyperglycemia. In addition, inhibition of either SLC5A2 via siRNA-induced gene silencing or SGLT2 via dapagliflozin treatment in human islets triggered glucagon secretion through KATP channel activation. Finally, we found that dapagliflozin treatment further promotes glucagon secretion and hepatic gluconeogenesis in healthy mice, thereby limiting the decrease of plasma glucose induced by fasting. Collectively, these results identify a heretofore unknown role of SGLT2 and designate dapagliflozin an alpha cell secretagogue.
2 型糖尿病（T2D）的特征是由于胰岛素抵抗和/或胰岛素分泌缺陷导致慢性高血糖，也与胰高血糖素和内源性葡萄糖生成（EGP）的增加有关。格列净类药物，包括达格列净，是一类新的已批准的口服抗糖尿病药物，它们特异性地抑制肾脏中的钠-葡萄糖协同转运蛋白 2（SGLT2）功能，从而防止肾脏重吸收葡萄糖，并在糖尿病患者中增加糖尿，同时降低高血糖。然而，SGLT2 抑制剂在 T2D 患者中的治疗会通过未知机制增加血浆胰高血糖素和 EGP。尽管 EGP 增加，但接受格列净治疗的 T2D 患者的血糖水平低于接受安慰剂的患者，这可能是由于糖尿增加所致；然而，由于血浆胰高血糖素水平升高而产生的潜在不良影响，特别是在已经受到高胰高血糖素血症影响的患者群体中。在这里，我们证明 SGLT2 在胰岛的胰高血糖素分泌α细胞中表达。我们还发现，SLC5A2（编码 SGLT2）的表达在 T2D 个体的胰岛中和在暴露于慢性高血糖的正常胰岛中低于非糖尿病个体的胰岛，并且胰高血糖素（GCG）基因表达更高。此外，肝细胞核因子 4-α（HNF4A）特异性地在人α细胞中表达，在其中它控制 SLC5A2 的表达，并且其表达被高血糖下调。此外，通过 siRNA 诱导的基因沉默抑制 SLC5A2 或通过达格列净治疗抑制 SGLT2 在人胰岛中均通过 KATP 通道激活触发胰高血糖素分泌。最后，我们发现达格列净治疗进一步促进了健康小鼠的胰高血糖素分泌和肝糖异生，从而限制了禁食引起的血浆葡萄糖降低。总的来说，这些结果确定了 SGLT2 的一个以前未知的作用，并指定达格列净为α细胞分泌激动剂。
