Reduction of Renal Transport Maximum for Glucose by Inhibition of Na+-Glucose Cotransporter Suppresses Blood Glucose Elevation in Dogs

Ueta, Kiichiro; Yoneda, Hikaru; Oku, Akira; Nishiyama, Shinsuke; Saito, Akira; Akita, Keiichi

doi:10.1248/bpb.29.114

Cited by 14 publications

(7 citation statements)

References 9 publications

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“…Sergliflozin-A reduced TmG in a dose-dependent manner, and consequently it increased the urinary excretion of glucose. T-1095A has been evaluated in dogs from a similar standpoint, but it is a nonselective SGLT inhibitor, like phlorizin (Ueta et al, 2006). The present results with our selective SGLT2 inhibitor were similar to those obtained with this nonselective SGLT inhibitor, thus providing pharmacological validation for the notion that SGLT2 is the major player in renal glucose reabsorption.…”

Section: Discussionsupporting

confidence: 80%

Sergliflozin, a Novel Selective Inhibitor of Low-Affinity Sodium Glucose Cotransporter (SGLT2), Validates the Critical Role of SGLT2 in Renal Glucose Reabsorption and Modulates Plasma Glucose Level

Katsuno

Fujimori²,

Takemura³

et al. 2006

J Pharmacol Exp Ther

247

183

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The low-affinity sodium glucose cotransporter (SGLT2), which is expressed specifically in the kidney, plays a major role in renal glucose reabsorption in the proximal tubule. We have discovered sergliflozin, a prodrug of a novel selective SGLT2 inhibitor, based on benzylphenol glucoside. In structure, it belongs to a new category of SGLT2 inhibitors and its skeleton differs from that of phlorizin, a nonselective SGLT inhibitor. We investigated its pharmacological properties and potencies in vitro and in vivo. By examining a Chinese hamster ovary-K1 cell line stably expressing either human SGLT2 or human highaffinity sodium glucose cotransporter (SGLT1), we found sergliflozin-A (active form) to be a highly selective and potent inhibitor of human SGLT2. At pharmacological doses, sergliflozin, sergliflozin-A, and its aglycon had no effects on facilitative glucose transporter 1 activity, which was inhibited by phloretin (the aglycon of phlorizin). The transport maximum for glucose in the kidney was reduced by sergliflozin-A in normal rats. As a result of this effect, orally administered sergliflozin increased urinary glucose excretion in mice, rats, and dogs in a dosedependent manner. In an oral glucose tolerance test in diabetic rats, sergliflozin exhibited glucose-lowering effects independently of insulin secretion. Any glucose excretion induced by sergliflozin did not affect normoglycemia or electrolyte balance. These data indicate that selective inhibition of SGLT2 increases urinary glucose excretion by inhibiting renal glucose reabsorption. As a representative of a new category of antidiabetic drugs, sergliflozin may provide a new and unique approach to the treatment of diabetes mellitus.

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Section: Discussionsupporting

confidence: 80%

Sergliflozin, a Novel Selective Inhibitor of Low-Affinity Sodium Glucose Cotransporter (SGLT2), Validates the Critical Role of SGLT2 in Renal Glucose Reabsorption and Modulates Plasma Glucose Level

Katsuno

Fujimori²,

Takemura³

et al. 2006

J Pharmacol Exp Ther

247

183

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“…In addition, phlorizin normalizes insulin sensitivity (Rossetti et al, 1987;Harmon et al, 2001). However, phlorizin is not suitable for clinical usage because of its low oral bioavailability (Crespy et al, 2001) and toxicity (Hardman et al, 2010) so new inhibitors, such as 3-(benzo [b]furan-5-yl)-2Ј,6Ј-dihydroxy-4Ј-methylpropiophenone 2Ј-O-(6-O-methoxycarbonyl-␤-D-glucopyranoside) (T-1095) (Oku et al, 1999;Arakawa et al, 2001;Ueta et al, 2006), sergliflozin (Katsuno et al, 2007;Pajor et al, 2008), and dapagliflozin (Han et al, 2008;Jabbour and Goldstein, 2008), have been developed as oral agents. Considering that the two isoforms of SGLT with different properties contribute to renal glucose reabsorption and that SGLT1 is expressed not only in the kidney but also in the intestine (Hediger and Rhoads, 1994), selectivity to both the transporters would be an important factor for the efficacy and the target specificity.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Modeling of the Effect of an Sodium-Glucose Cotransporter Inhibitor, Phlorizin, on Renal Glucose Transport in Rats

Yamaguchi¹,

Kato²,

Suzuki³

et al. 2011

Drug Metab Dispos

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ABSTRACT:A pharmacokinetic and pharmacodynamic (PK-PD) model for the inhibitory effect of sodium-glucose cotransporter (SGLT) inhibitors on renal glucose reabsorption was developed to predict in vivo efficacy. First, using the relationship between renal glucose clearance and plasma glucose level in rats and both the glucose affinity and transport capacity obtained from in vitro vesicle experiments, a pharmacodynamic model analysis was performed based on a nonlinear parallel tube model to express the renal glucose transport mediated by SGLT1 and SGLT2. This model suitably expressed the relationship between plasma glucose level and renal glucose excretion. A PK-PD model was developed next to analyze the inhibitory effect of phlorizin on renal glucose reabsorption. The PK-PD model analysis was performed using averaged concentrations of both the drug and glucose in plasma and the corresponding renal glucose clearance. The model suitably expressed the concentration-dependent inhibitory effect of phlorizin on renal glucose reabsorption. The in vivo inhibition constants of phlorizin for SGLT in rats were estimated to be 67 nM for SGLT1 and 252 nM for SGLT2, which are similar to the in vitro data reported previously. This suggests that the in vivo efficacy of SGLT inhibitors could be predicted from an in vitro study based on the present PK-PD model. The present model is based on physiological and biochemical parameters and, therefore, would be helpful in understanding individual differences in the efficacy of an SGLT inhibitor.

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“…The deduced truncated form of SGLT2 in SAMP10-DSglt2 is speculated to be inactive. The elevation of blood glucose during OGTT was suppressed by more than an 80% reduction of the transport maximum for glucose in the kidney using a SGLT2 inhibitor [27], suggesting that glucose absorption is lowered to less than 20% in SAMP10-DSglt2 mice. In euglycemia, renal glucose reabsorption is mainly mediated by SGLT2 (97%), although, under malfunction of SGLT2, the contribution of SGLT1 increases from 3% to 40-50% [28].…”

Section: Discussionmentioning

confidence: 97%

Novel frame-shift mutation in Slc5a2 encoding SGLT2 in a strain of senescence-accelerated mouse SAMP10

Unno

Yamamoto

Toda

et al. 2014

Biochemical and Biophysical Research Communications

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Reduction of Renal Transport Maximum for Glucose by Inhibition of Na+-Glucose Cotransporter Suppresses Blood Glucose Elevation in Dogs

Cited by 14 publications

References 9 publications

Sergliflozin, a Novel Selective Inhibitor of Low-Affinity Sodium Glucose Cotransporter (SGLT2), Validates the Critical Role of SGLT2 in Renal Glucose Reabsorption and Modulates Plasma Glucose Level

Sergliflozin, a Novel Selective Inhibitor of Low-Affinity Sodium Glucose Cotransporter (SGLT2), Validates the Critical Role of SGLT2 in Renal Glucose Reabsorption and Modulates Plasma Glucose Level

Pharmacokinetic and Pharmacodynamic Modeling of the Effect of an Sodium-Glucose Cotransporter Inhibitor, Phlorizin, on Renal Glucose Transport in Rats

Novel frame-shift mutation in Slc5a2 encoding SGLT2 in a strain of senescence-accelerated mouse SAMP10

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