Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia.
Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, 585 University Avenue, 8N-845, Toronto, ON, M5G 2N2, Canada.
Diabetologia. 2018 Oct;61(10):2098-2107. doi: 10.1007/s00125-018-4669-0. Epub 2018 Aug 22.
Inhibition of the sodium-glucose cotransporter (SGLT) 2 in the proximal tubule of the kidney has a broad range of effects on renal function and plasma volume homeostasis, as well as on adiposity and energy metabolism across the entire body. SGLT2 inhibitors are chiefly used in type 2 diabetes for glucose control, achieving reductions in HbA of 7-10 mmol/mol (0.6-0.9%) when compared with placebo. This glucose-lowering activity is proportional to the ambient glucose concentration and glomerular filtration of this glucose, so may be greater in those with poor glycaemic control and/or hyperfiltration at baseline. Equally, the glucose-lowering effects of SGLT2 inhibitors are attenuated in individuals without diabetes and those with a reduced eGFR. However, unlike the glucose-lowering effects of SGLT2 inhibitors, the spill-over of sodium and glucose beyond the proximal nephron following SGLT2 inhibition triggers dynamic and reversible realignment of energy metabolism, renal filtration and plasma volume without relying on losses into the urine. In addition, these processes are observed in the absence of significant glucosuria or ongoing natriuresis. In the long term, the resetting of energy/salt/water physiology following SGLT2 inhibition has an impact, not only on adiposity, renal function and blood pressure control, but also on the health and survival of patients with type 2 diabetes. A better understanding of the precise biology underlying the acute actions of SGLT2 inhibitors in the kidney and how they are communicated to the rest of the body will likely lead to improved therapeutics that augment similar pathways in individuals with, or even without, diabetes to achieve additional benefits.
抑制肾脏近端小管中的钠-葡萄糖协同转运蛋白 2（SGLT2）对肾功能和血浆容量稳态以及全身脂肪量和能量代谢具有广泛的影响。SGLT2 抑制剂主要用于 2 型糖尿病的血糖控制，与安慰剂相比，可使 HbA 降低 7-10mmol/mol（0.6-0.9%）。这种降糖活性与环境葡萄糖浓度以及该葡萄糖的肾小球滤过率成正比，因此在血糖控制较差和/或基线时高滤过的患者中可能更大。同样，在没有糖尿病的个体和 eGFR 降低的个体中，SGLT2 抑制剂的降糖作用会减弱。然而，与 SGLT2 抑制剂的降糖作用不同，SGLT2 抑制后超出近端肾单位的钠和葡萄糖的溢出会触发能量代谢、肾脏过滤和血浆体积的动态和可逆重新调整，而无需依赖尿液中的损失。此外，在没有明显糖尿或持续排钠的情况下也会观察到这些过程。从长远来看，SGLT2 抑制后能量/盐/水生理学的重置不仅对肥胖、肾功能和血压控制有影响，而且对 2 型糖尿病患者的健康和生存也有影响。更好地了解 SGLT2 抑制剂在肾脏中的急性作用的精确生物学及其如何传递到身体的其他部位，可能会导致更好的治疗方法，这些方法可以在有糖尿病甚至没有糖尿病的个体中增强类似途径，以实现额外的益处。
