日本志贺大学Hiroshi Maegawa、Shinji Kume等研究人员合作发现，SGLT2抑制通过促进酮体诱导的mTORC1抑制介导对糖尿病肾病的保护。2020年7月28日，《细胞—代谢》杂志在线发表了这项成果。
Title: SGLT2 Inhibition Mediates Protection from Diabetic Kidney Disease by Promoting Ketone Body-Induced mTORC1 Inhibition
Author: Issei Tomita, Shinji Kume, Sho Sugahara, Norihisa Osawa, Kosuke Yamahara, Mako Yasuda-Yamahara, Naoko Takeda, Masami Chin-Kanasaki, Tatsuroh Kaneko, Eric Mayoux, Michael Mark, Motoko Yanagita, Hisakazu Ogita, Shin-ichi Araki, Hiroshi Maegawa
Abstract: SGLT2 inhibitors offer strong renoprotection in subjects with diabetic kidney disease(DKD). But the mechanism for such protection is not clear. Here, we report that indamaged proximal tubules of high-fat diet-fed ApoE-knockout mice, a model of non-proteinuricDKD, ATP production shifted from lipolysis to ketolysis dependent due to hyperactivationof the mechanistic target of rapamycin complex 1 (mTORC1). We further found that empagliflozinraised endogenous ketone body (KB) levels, and thus its use or treatment with 1,3-butanediol,a KB precursor, prevented decreases in renal ATP levels and organ damage in the mice.The renoprotective effect of empagliflozin was abolished by gene deletion of Hmgcs2,a rate-limiting enzyme of ketogenesis. Furthermore, KBs attenuated mTORC1-associatedpodocyte damage and proteinuria in diabetic db/db mice. Our findings show that SGLT2 inhibition-associated renoprotection is mediatedby an elevation of KBs that in turn corrects mTORC1 hyperactivation that occurs innon-proteinuric and proteinuric DKD.