Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Biopharm Drug Dispos
2014 Oct 01;357:391-404. doi: 10.1002/bdd.1909.
Show Gene links
Show Anatomy links
SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria.
Chino Y
,
Samukawa Y
,
Sakai S
,
Nakai Y
,
Yamaguchi J
,
Nakanishi T
,
Tamai I
.
???displayArticle.abstract???
Sodium glucose cotransporter 2 (SGLT2) inhibitors have been reported to lower the serum uric acid (SUA) level. To elucidate the mechanism responsible for this reduction, SUA and the urinary excretion rate of uric acid (UE(UA)) were analysed after the oral administration of luseogliflozin, a SGLT2 inhibitor, to healthy subjects. After dosing, SUA decreased, and a negative correlation was observed between the SUA level and the UE(UA), suggesting that SUA decreased as a result of the increase in the UE(UA). The increase in UE(UA) was correlated with an increase in urinary D-glucose excretion, but not with the plasma luseogliflozin concentration. Additionally, in vitro transport experiments showed that luseogliflozin had no direct effect on the transporters involved in renal UA reabsorption. To explain that the increase in UE(UA) is likely due to glycosuria, the study focused on the facilitative glucose transporter 9 isoform 2 (GLUT9ΔN, SLC2A9b), which is expressed at the apical membrane of the kidney tubular cells and transports both UA and D-glucose. It was observed that the efflux of [(14) C]UA in Xenopus oocytes expressing the GLUT9 isoform 2 was trans-stimulated by 10 mm D-glucose, a high concentration of glucose that existed under SGLT2 inhibition. On the other hand, the uptake of [(14) C]UA by oocytes was cis-inhibited by 100 mm D-glucose, a concentration assumed to exist in collecting ducts. In conclusion, it was demonstrated that the UE(UA) could potentially be increased by luseogliflozin-induced glycosuria, with alterations of UA transport activity because of urinary glucose.
Figure 1. Effect of luseogliflozin on the serum uric acid (SUA) level. Changes in the SUA level from the baseline after a single dose (A, n = 3â14) and after multiple doses (B, n = 8) are shown. Data are mean ± SEM. **p < 0.01 vs placebo (0 mg) (Dunnettâs test)
Figure 2. Effects of luseogliflozin on the urinary excretion rate (UEUA) and the renal clearance (CLUA) of uric acid. Changes in UEUA and CLUA from the baseline after a single dose (A and C, n = 3â14) and after multiple doses (B and D, n = 8) are shown. Data are mean ± SEM. **p < 0.01 vs placebo (0 mg) (Dunnettâs test)
Figure 3. Relationship between the serum uric acid (SUA) level and the urinary excretion rate of uric acid (UEUA) after a single dose. The daily changes in the SUA level (A) and UEUA (B) from the baseline in the 1, 5 and 25 mg dosing groups are shown. Data are mean ± SEM. *p < 0.05, **p < 0.01 vs placebo (Dunnettâs test, Studentâs t-test or Aspin-Welchâs t-test). (C) Correlation between the changes in the SUA level and the UEUA on day 1 from the baseline values in the single dose study
Figure 4. Comparison of the urinary excretion rate of uric acid (UEUA), the plasma concentration of luseogliflozin and the urinary excretion rate of glucose (UEGL) in the single dose study. (AâC) Time course profiles of UEUA, the plasma concentration of luseogliflozin and UEGL. Data are mean ± SEM. (D) Relationship between UEUA and UEGL. (E) Relationship between UEUA and AUC0â24h of plasma luseogliflozin
Figure 5. Effect of luseogliflozin on transporters involved in renal uric acid handling in humans. URAT1 (A) and OAT4 (C) were examined in gene-expressing HEK293 and S2 cells, respectively. GLUT9 isoform 1 (B), OAT10 (D) and SMCT1 (E) were examined in gene-expressing Xenopus oocytes. Data are mean ± SEM
Figure 6. Trans-stimulatory effect of d-glucose on uric acid transport by GLUT9 isoform 2. Effect of the injected amount of cRNA of GLUT9 isoform 2 into Xenopus oocytes on UA efflux (n = 7â8) determined at 5 min and (B) time-course of UA efflux from the oocytes injected with 0.25 ng of cRNA (closed circle) or water (open circle) (n = 4â8). (C) Trans-stimulatory effect of d-glucose (n = 5â10) and (D) cis-inhibitory effect of benzbromarone (Benz) (n = 7â10) on GLUT9 isoform 2-mediated [14C]UA efflux. (E) Trans-stimulatory effect of d-glucose on GLUT9 isoform 2-mediated [14C]UA uptake (n = 14â17). The efflux and uptake of [14C]UA were evaluated using oocytes injected with 0.25 ng and 25 ng of cRNA, respectively. Data are mean ± SEM. *p < 0.05 vs 10 mm l-glucose (C, Dunnettâs test) or vs 10 mm d-glucose (D, Aspin-Welchâs t-test), **p < 0.01 vs 100 mm l-glucose (E, Aspin-Welchâs t-test)
Figure 7. Cis-inhibitory effect of d-glucose on GLUT9 isoform 2-mediated [14C]UA uptake in oocytes injected with 25 ng of cRNA (n = 8â12). Data are mean ± SEM. *p < 0.05 vs control (transport buffer) (Aspin-Welchâs t-test), Significant difference was not observed as a result of multiple comparison (Dunnettâs test) was used
Figure 8. Proposed model for uricosuric effect of SGLT2 inhibitors by glycosuria-induced uric acid secretion via GLUT9 isoform 2 or any other functionally similar transporters at the proximal tubule and inhibition of uric acid uptake via GLUT9 isoform 2 at the collecting duct of renal tubule
Alderman,
Serum uric acid and cardiovascular events in successfully treated hypertensive patients.
1999, Pubmed
Alderman,
Serum uric acid and cardiovascular events in successfully treated hypertensive patients.
1999,
Pubmed
Anzai,
Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans.
2008,
Pubmed
,
Xenbase
Augustin,
Identification and characterization of human glucose transporter-like protein-9 (GLUT9): alternative splicing alters trafficking.
2004,
Pubmed
,
Xenbase
Bahn,
Identification of a new urate and high affinity nicotinate transporter, hOAT10 (SLC22A13).
2008,
Pubmed
,
Xenbase
Bailey,
Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial.
2010,
Pubmed
Bailey,
Renal glucose reabsorption inhibitors to treat diabetes.
2011,
Pubmed
BENEDICT,
The metabolism of uric acid in the normal and gouty human studied with the aid of isotopic uric acid.
1949,
Pubmed
Bonsnes,
ON THE INCREASED URIC ACID CLEARANCE FOLLOWING THE INTRAVENOUS INFUSION OF HYPERTONIC GLUCOSE SOLUTIONS.
1946,
Pubmed
BONSNES,
On the increased uric acid clearance following the intravenous infusion of hypertonic glucose solutions.
1946,
Pubmed
Campion,
Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study.
1987,
Pubmed
Caulfield,
SLC2A9 is a high-capacity urate transporter in humans.
2008,
Pubmed
,
Xenbase
Cefalu,
Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial.
2013,
Pubmed
Choi,
Prevalence of the metabolic syndrome in individuals with hyperuricemia.
2007,
Pubmed
Choi,
Haemoglobin A1c, fasting glucose, serum C-peptide and insulin resistance in relation to serum uric acid levels--the Third National Health and Nutrition Examination Survey.
2008,
Pubmed
Chonchol,
Relationship of uric acid with progression of kidney disease.
2007,
Pubmed
Enomoto,
Molecular identification of a renal urate anion exchanger that regulates blood urate levels.
2002,
Pubmed
,
Xenbase
Facchini,
Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration.
1991,
Pubmed
Ferrannini,
A Phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes.
2013,
Pubmed
González-Sicilia,
Renal metabolism of uric acid in type I insulin-dependent diabetic patients: relation to metabolic compensation.
1997,
Pubmed
Gotfredsen,
Renal hypouricaemia in insulin treated diabetes mellitus.
1982,
Pubmed
Hagos,
Human renal organic anion transporter 4 operates as an asymmetric urate transporter.
2007,
Pubmed
,
Xenbase
Herman,
Diabetes, prediabetes and uricaemia.
1976,
Pubmed
Herman,
Uric acid and diabetes: observations in a population study.
1982,
Pubmed
Hosomi,
Extra-renal elimination of uric acid via intestinal efflux transporter BCRP/ABCG2.
2012,
Pubmed
Iseki,
Significance of hyperuricemia on the early detection of renal failure in a cohort of screened subjects.
2001,
Pubmed
Ishizaka,
Association between serum uric acid, metabolic syndrome, and carotid atherosclerosis in Japanese individuals.
2005,
Pubmed
Iwanaga,
Concentration-dependent mode of interaction of angiotensin II receptor blockers with uric acid transporter.
2007,
Pubmed
,
Xenbase
Iwanaga,
Involvement of uric acid transporter in increased renal clearance of the xanthine oxidase inhibitor oxypurinol induced by a uricosuric agent, benzbromarone.
2005,
Pubmed
,
Xenbase
Kakinuma,
(1S)-1,5-anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol (TS-071) is a potent, selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for type 2 diabetes treatment.
2010,
Pubmed
Kanai,
The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose.
1994,
Pubmed
,
Xenbase
Kimura,
Expression of SLC2A9 isoforms in the kidney and their localization in polarized epithelial cells.
2014,
Pubmed
Knight,
Effects of intraluminal D-glucose and probenecid on urate absorption in the rat proximal tubule.
1979,
Pubmed
Kolz,
Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations.
2009,
Pubmed
Li,
The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts.
2007,
Pubmed
Lin,
The interaction between uric acid level and other risk factors on the development of gout among asymptomatic hyperuricemic men in a prospective study.
2000,
Pubmed
Lu,
Functional cooperation of SMCTs and URAT1 for renal reabsorption transport of urate.
2013,
Pubmed
,
Xenbase
Nair,
Sodium glucose cotransporter 2 inhibitors as a new treatment for diabetes mellitus.
2010,
Pubmed
Nozawa,
Functional characterization of pH-sensitive organic anion transporting polypeptide OATP-B in human.
2004,
Pubmed
Quiñones Galvan,
Effect of insulin on uric acid excretion in humans.
1995,
Pubmed
Sasaki,
Safety, pharmacokinetics, and pharmacodynamics of single and multiple luseogliflozin dosing in healthy Japanese males: a randomized, single-blind, placebo-controlled trial.
2014,
Pubmed
Shankar,
The association between serum uric acid level and long-term incidence of hypertension: Population-based cohort study.
2006,
Pubmed
Skeith,
Effect of phloridzin on uric acid excretion in man.
1970,
Pubmed
So,
Uric acid transport and disease.
2010,
Pubmed
Thangaraju,
c/ebpdelta Null mouse as a model for the double knock-out of slc5a8 and slc5a12 in kidney.
2006,
Pubmed
Vitart,
SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout.
2008,
Pubmed
,
Xenbase
Ward,
Uric acid as an independent risk factor in the treatment of hypertension.
1998,
Pubmed
Wilding,
Efficacy and safety of ipragliflozin in patients with type 2 diabetes inadequately controlled on metformin: a dose-finding study.
2013,
Pubmed
Witkowska,
Human SLC2A9a and SLC2A9b isoforms mediate electrogenic transport of urate with different characteristics in the presence of hexoses.
2012,
Pubmed
,
Xenbase
Yamamoto,
TS-071 is a novel, potent and selective renal sodium-glucose cotransporter 2 (SGLT2) inhibitor with anti-hyperglycaemic activity.
2011,
Pubmed
You,
Molecular characteristics of Na(+)-coupled glucose transporters in adult and embryonic rat kidney.
1995,
Pubmed
,
Xenbase
Yu,
Abnormal expression and dysfunction of novel SGLT2 mutations identified in familial renal glucosuria patients.
2011,
Pubmed
Zoppini,
Elevated serum uric acid concentrations independently predict cardiovascular mortality in type 2 diabetic patients.
2009,
Pubmed
