Gallo Linda A, Wright Ernest M, Vallon Volker
Glycation and Diabetes Complications Research Group, Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia
Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Diab Vasc Dis Res. 2015 Mar;12(2):78-89. doi: 10.1177/1479164114561992. Epub 2015 Jan 23.
Traditional treatments for type 1 and type 2 diabetes are often associated with side effects, including weight gain and hypoglycaemia that may offset the benefits of blood glucose lowering. The kidneys filter and reabsorb large amounts of glucose, and urine is almost free of glucose in normoglycaemia. The sodium-dependent glucose transporter (SGLT)-2 in the early proximal tubule reabsorbs the majority of filtered glucose. Remaining glucose is reabsorbed by SGLT1 in the late proximal tubule. Diabetes enhances renal glucose reabsorption by increasing the tubular glucose load and the expression of SGLT2 (as shown in mice), which maintains hyperglycaemia. Inhibitors of SGLT2 enhance urinary glucose excretion and thereby lower blood glucose levels in type 1 and type 2 diabetes. The load-dependent increase in SGLT1-mediated glucose reabsorption explains why SGLT2 inhibitors in normoglycaemic conditions enhance urinary glucose excretion to only ~50% of the filtered glucose. The role of SGLT1 in both renal and intestinal glucose reabsorption provides a rationale for the development of dual SGLT1/2 inhibitors. SGLT2 inhibitors lower blood glucose levels independent of insulin and induce pleiotropic actions that may be relevant in the context of lowering cardiovascular risk. Ongoing long-term clinical studies will determine whether SGLT2 inhibitors have a safety profile and exert cardiovascular benefits that are superior to traditional agents.
1型和2型糖尿病的传统治疗方法往往伴有副作用，包括体重增加和低血糖，这些副作用可能会抵消血糖降低带来的益处。肾脏过滤并重吸收大量葡萄糖，在血糖正常时尿液中几乎不含葡萄糖。早期近端小管中的钠依赖性葡萄糖转运蛋白（SGLT）-2重吸收大部分滤过的葡萄糖。剩余的葡萄糖由晚期近端小管中的SGLT1重吸收。糖尿病通过增加肾小管葡萄糖负荷和SGLT2的表达（如在小鼠中所示）来增强肾脏对葡萄糖的重吸收，从而维持高血糖状态。SGLT2抑制剂可增加尿糖排泄，从而降低1型和2型糖尿病患者的血糖水平。SGLT1介导的葡萄糖重吸收随负荷增加，这解释了为什么在血糖正常的情况下，SGLT2抑制剂只能将尿糖排泄量提高到滤过葡萄糖的约50%。SGLT1在肾脏和肠道葡萄糖重吸收中的作用为开发双SGLT1/2抑制剂提供了理论依据。SGLT2抑制剂可独立于胰岛素降低血糖水平，并诱导多效性作用，这可能与降低心血管风险有关。正在进行的长期临床研究将确定SGLT2抑制剂是否具有优于传统药物的安全性和心血管益处。
