Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion
Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion
复制标题
DOI：
10.1038/nm.3828
复制
发表时间：
2015-05-01
期刊：
影响因子：
82.9
通讯作者：
Pattou, Francois
中科院分区：
文献类型：
--
作者：
Bonner, Caroline;Kerr-Conte, Julie;Pattou, Francois
2型糖尿病（T2 D）的特征是由于胰岛素抵抗和/或胰岛素分泌缺陷导致的胰岛素信号传导缺陷导致的慢性高血糖症;它还与胰高血糖素和内源性葡萄糖产生（EGP）增加有关（1）。格列净（包括达格列净）是一类新的获批口服降糖药，可特异性抑制肾脏中的钠-葡萄糖协同转运蛋白2（SGLT 2）功能（2-5），从而防止糖尿病患者的肾脏葡萄糖重吸收并增加糖尿，同时降低高血糖症。然而，T2 D受试者中的神经胶质瘤治疗通过未知机制增加血浆胰高血糖素和EGP（6，7）。尽管EGP升高，但与接受安慰剂治疗的患者相比，接受神经胶质瘤治疗的T2 D患者的血糖水平较低，可能是由于糖尿增加（6，7）;然而，由此导致的血浆胰高血糖素水平升高代表了可能的相关副作用，尤其是在已经受到高胰高血糖素血症影响的患者人群中。在这里，我们证明了SGLT 2在胰岛的胰高血糖素分泌α细胞中表达。我们进一步发现，与来自非糖尿病患者的胰岛相比，来自T2 D个体的胰岛和暴露于慢性高血糖症的正常胰岛中的SLC 5A 2（其编码SGLT 2）的表达较低，而胰高血糖素（GCG）基因表达较高。此外，肝细胞核因子4-α（HNF 4A）在人α细胞中特异性表达，其中它控制SLC 5A 2表达，并且其表达被高血糖下调。此外，在人胰岛中，通过siRNA诱导的基因沉默抑制SLC 5A 2或通过达格列净治疗抑制SGLT 2，通过K-ATP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健康小鼠的胰高血糖素分泌和肝脏新生，从而限制禁食诱导的血糖降低。总之，这些结果确定了SGLT 2迄今未知的作用，并将达格列净指定为α细胞促分泌素。
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)(1). 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(2-5), 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(6,7) 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(6,7); 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-alpha (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 K-ATP 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.