Department of Physiology, Geffen School of Medicine at UCLA, Los Angeles, CA, 90095-1751, USA.
Diabetologia. 2018 Oct;61(10):2087-2097. doi: 10.1007/s00125-018-4656-5. Epub 2018 Aug 22.
The concentration of glucose in plasma is held within narrow limits (4-10 mmol/l), primarily to ensure fuel supply to the brain. Kidneys play a role in glucose homeostasis in the body by ensuring that glucose is not lost in the urine. Three membrane proteins are responsible for glucose reabsorption from the glomerular filtrate in the proximal tubule: sodium-glucose cotransporters SGLT1 and SGLT2, in the apical membrane, and GLUT2, a uniporter in the basolateral membrane. 'Knockout' of these transporters in mice and men results in the excretion of filtered glucose in the urine. In humans, intravenous injection of the plant glucoside phlorizin also results in excretion of the full filtered glucose load. This outcome and the finding that, in an animal model, phlorizin reversed the symptoms of diabetes, has stimulated the development and successful introduction of SGLT2 inhibitors, gliflozins, in the treatment of type 2 diabetes mellitus. Here we summarise the current state of our knowledge about the physiology of renal glucose handling and provide background to the development of SGLT2 inhibitors for type 2 diabetes treatment.
血浆中的葡萄糖浓度被控制在狭窄的范围内（4-10mmol/L），主要是为了确保大脑的燃料供应。肾脏通过确保葡萄糖不会在尿液中丢失，在体内的葡萄糖稳态中发挥作用。三种膜蛋白负责从近端肾小管的肾小球滤液中重吸收葡萄糖：位于顶膜的钠-葡萄糖协同转运蛋白 SGLT1 和 SGLT2，以及位于基底外侧膜的单转运蛋白 GLUT2。在小鼠和人类中敲除这些转运蛋白会导致滤过的葡萄糖在尿液中排出。在人类中，静脉注射植物糖苷根皮苷也会导致全部滤过的葡萄糖负荷排出。这一结果以及在动物模型中发现根皮苷逆转了糖尿病症状，刺激了 SGLT2 抑制剂（格列净）的开发和成功引入，用于治疗 2 型糖尿病。在这里，我们总结了我们目前对肾脏葡萄糖处理生理学的了解，并为 SGLT2 抑制剂用于 2 型糖尿病治疗的开发提供了背景。
