Selective SGLT2 inhibition by tofogliflozin reduces renal glucose reabsorption under hyperglycemic but not under hypo- or euglycemic conditions in rats
Selective SGLT2 inhibition by tofogliflozin reduces renal glucose reabsorption under hyperglycemic but not under hypo- or euglycemic conditions in rats
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DOI：
10.1152/ajpendo.00545.2012
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发表时间：
2013-02-01
影响因子：
5.1
通讯作者：
Kawabe, Yoshiki
中科院分区：
文献类型：
--
作者：
Nagata, Takumi;Fukazawa, Masanori;Kawabe, Yoshiki
Nagata T, Fukazawa M, Honda K, Yata T, Kawai M, Yamane M, Murao N, Yamaguchi K, Kato M, Mitsui T, Suzuki Y, Ikeda S, Kawabe Y. tofogliflozin选择性抑制高血糖大鼠肾葡萄糖重吸收，但在低血糖或血糖状态下没有作用。[J] .中国生物医学工程学报，2013,31(4):444 - 444。首次发表于2012年12月18日；doi: 10.1152 / ajpendo.00545.2012。为了了解钠-葡萄糖共转运体（SGLT）抑制剂诱导的尿糖排泄（UGE）相关低血糖的风险，有必要了解SGLT2与SGLT1对肾葡萄糖重吸收（RGR）的贡献比与体内血糖水平的关系。为了研究SGLT2和SGLT1在正常大鼠中的作用，我们比较了高特异性SGLT2抑制剂tofogliflozin和SGLT1和SGLT2 （SGLT1/2）抑制剂phlorizin在血浆浓度足以完全抑制大鼠SGLT2 （rSGLT2）同时不同程度抑制rSGLT1时对RGR的抑制作用。葡萄糖滴定法测定高血糖条件下，tofogliflozin和phlorizin对RGR的抑制达到>= 50%。在高胰岛素钳夹的低血糖状态下，苯酞素使RGR降低了20-50%，tofogliflozin使RGR降低了1-5%，这表明在低血糖状态下rSGLT2对RGR的贡献小于高血糖状态。接下来，为了评估SGLT1/2抑制的降糖潜力，我们同时测量了SGLT抑制剂诱导UGE后的血浆葡萄糖（PG）和内源性葡萄糖产量（EGP）。Tofogliflozin （400 ng/ml）诱导UGE约为2 mg.kg（-1）。min(-1)， EGP增加1-2 mg.kg（-1）。min(-1)，导致PG在正常范围内。phenlorizin （1,333 ng/ml）诱导UGE约为6 mg.kg（-1）。min(-1)， EGP升高约4 mg.kg(-1).min(-1)；这比tofogliflozin组高，但最低PG更低。这些结果表明，在低血糖状态下，SGLT1对RGR的贡献大于高血糖状态下，sglt2选择性抑制剂比SGLT1/2抑制剂具有更低的低血糖风险。
Nagata T, Fukazawa M, Honda K, Yata T, Kawai M, Yamane M, Murao N, Yamaguchi K, Kato M, Mitsui T, Suzuki Y, Ikeda S, Kawabe Y. Selective SGLT2 inhibition by tofogliflozin reduces renal glucose reabsorption under hyperglycemic but not under hypo- or euglycemic conditions in rats. Am J Physiol Endocrinol Metab 304: E414-E423, 2013. First published December 18, 2012; doi:10.1152/ajpendo.00545.2012.-To understand the risk of hypoglycemia associated with urinary glucose excretion (UGE) induced by sodium-glucose cotransporter (SGLT) inhibitors, it is necessary to know the relationship between the ratio of contribution of SGLT2 vs. SGLT1 to renal glucose reabsorption (RGR) and the glycemic levels in vivo. To examine the contributions of SGLT2 and SGLT1 in normal rats, we compared the RGR inhibition by tofogliflozin, a highly specific SGLT2 inhibitor, and phlorizin, an SGLT1 and SGLT2 (SGLT1/2) inhibitor, at plasma concentrations sufficient to completely inhibit rat SGLT2 (rSGLT2) while inhibiting rSGLT1 to different degrees. Under hyperglycemic conditions by glucose titration, tofogliflozin and phlorizin achieved >= 50% inhibition of RGR. Under hypoglycemic conditions by hyperinsulinemic clamp, RGR was reduced by 20-50% with phlorizin and by 1-5% with tofogliflozin, suggesting the smaller contribution of rSGLT2 to RGR under hypoglycemic conditions than under hyperglycemic conditions. Next, to evaluate the hypoglycemic potentials of SGLT1/2 inhibition, we measured the plasma glucose (PG) and endogenous glucose production (EGP) simultaneously after UGE induction by SGLT inhibitors. Tofogliflozin (400 ng/ml) induced UGE of about 2 mg.kg(-1).min(-1) and increased EGP by 1-2 mg.kg(-1).min(-1), resulting in PG in the normal range. Phlorizin (1,333 ng/ml) induced UGE of about 6 mg.kg(-1).min(-1) and increased EGP by about 4 mg.kg(-1).min(-1); this was more than with tofogliflozin, but the minimum PG was lower. These results suggest that the contribution of SGLT1 to RGR is greater under lower glycemic conditions than under hyperglycemic conditions and that SGLT2-selective inhibitors pose a lower risk of hypoglycemia than SGLT1/2 inhibitors.