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( A ) The c.1033 – 1060del mutation. The splice acceptor site for intron 8 is included (small caps). Nucleotides are numbered according to the SLC5A2 cDNA accession number NM_003041. The wild-type amino acid sequence is represented in black; in light gray, the new ORF. ( B ) Suggested mechanism for the renal hypouricaemia associated with defects of SGLT2. In the presence of normally functioning SGLT2 (left side) all the glucose is reabsorbed in the early segment (S1) of the proximal tubule, while in the late S3 segment GLUT9 is normally reabsorbing urate. If SGLT2 is disrupted (right side), either by genetic defects or pharmacological inhibition, the presence of signi fi cant amounts of glucose in the late segments of the proximal tubule reverses the direction of urate transport, with GLUT9 exchanging luminal glucose for intracellular urate and actively promoting urate secretion.
Source publication
Familial renal glucosuria is a rare co-dominantly inherited benign phenotype characterized by the presence of glucose in the
urine. It is caused by mutations in the SLC5A2 gene that encodes SGLT2, the Na+-glucose cotransporter responsible for the reabsorption of the bulk of glucose in the proximal tubule. We report a case of
FRG displaying both sev...
Contexts in source publication
Context 1
... analysis was performed as previously reported [6]. The novel c.1033-1060del; p.V346AfsX17 frameshift mutation was identified in homo- zygosity ( Figure 1A). ...
Context 2
... Aires et al. in the presence of a high glucose concentration in the late proximal tubular lumen, the direction of urate transport could be reversed, with glucose being exchanged for urate and leading to excessive urinary excretion and secondary hypouricaemia ( Figure 1B). To our knowledge, only one report addressed the urinary urate excretion in FRG [14]. ...
Citations
... In mice, the genetic ablation of SGLT2 (Slc5a2 knockout) increased renal urate excretion and increased the fractional excretion of urate [86]. And finally, patients with rare inherited mutations within the SGLT2 gene (SLC5A2; Familial Renal Glucosuria (FRG)), characterized by persistent glucosuria, with normal renal function and plasma glucose levels [87], also exhibit hyperuricosuria with hypouricemia, correlating again chronic high tubular glucose with increased uric acid excretion [88,89]. These data strongly reject a general nonspecific drug effect from SGLT2is on renal urate handling. ...
A relationship between metabolic disorders and hyperuricemia is well established. The nature of the relationship—risk factor, causal agent, or byproduct—remains unclear. Recent studies of sodium–glucose transporter 2 inhibitors (SGLT2i’s) have established that this pharmacological intervention is beneficial to patients with hyperglycemia and type 2 diabetes mellitus (T2D) and also against the common cardio and renal comorbidities associated with diabetes. Hyperuricemia, or high plasma uric acid levels, is one of the comorbidities mitigated with SGLT2i treatment, raising the potential for using SGLT2i’s as part of the treatment for gout and hyperuricemia. However, the mechanisms underlying the lower plasma urate levels and increased uricosuria produced with SGLT2i’s remains poorly understood. Here, we review the renal physiology of glucose and uric acid transport, the renal consequences of hyperglycosuria and diabetes, the benefits and physiology of SGLT2i use, and discuss several potential mechanisms that may be responsible for the favorable uricosuric effect observed in those treated with SGLT2i’s.
... These suggest that diabetes may affect UA metabolism. Moreover, hyperuricosuria and hypouricaemia were found in familial renal glucosuria (i.e., mutation in the gene encoding the sodium-glucose co-transporter 2 (SGLT2) protein) [8]. Increasing evidence has also shown that SUA levels are decreased in individuals with T2D following Y. Qin, S. Zhang, S. Cui have contributed equally to this work. ...
Aims/Introduction
The relationship between urinary excretion rate of glucose (UEGL) and uric acid (UA) metabolism in adults with type 2 diabetes (T2D) remains unclear to date. This study aimed to investigate the relationships of UEGL with serum UA (SUA), urinary excretion rate of uric acid (UEUA), and renal clearance of uric acid (CLUA) in adults with T2D. We hypothesised that high UEGL increases UA excretion, which in turn leads to lower SUA.
Materials and methods
This was a cross-sectional study of 635 inpatients with T2D recruited between 2018 and 2019. The relationships of UEGL with UEUA, CLUA, and hyperuricaemia were assessed using analysis of covariance and multivariate regression analysis.
Results
Patients in the higher quartile of UEGL tended to have lower SUA levels than those in the lower quartile. In contrast, patients in the higher quartile of UEGL tended to have higher CLUA ( p for trend < 0.0001), and a similar trend was observed for UEUA. In adjusted multivariable linear regression model, UEGL was negatively correlated with SUA ( β = − 0.023, 95% CI − 0.034 to − 0.013, p < 0.0001). However, positive correlations of UEGL with UEUA (β = 0.046, 95% CI 0.018–0.074, p = 0.001) and CLUA ( β = 0.063, 95% CI 0.042–0.085, p < 0.0001) were found. Furthermore, consistent significant inverse associations were observed between quartiles of UEGL and hyperuricaemia in the adjusted multivariate logistic regression model.
Conclusions
A high UEGL level was positively correlated with UEUA and CLUA. Moreover, it was inversely associated with SUA level, and a consistently increased UEGL level reduced the risk of hyperuricaemia in patients with T2D.
... The current assumption of hypouricemic effect following treatment with sodiumglucose co-transporter 2 [SGLT2] inhibitors is that glycosuria boosts excretion of UA in the urine. Actually, SUA reduction may be brought by a uricosuric effect secondary to glycosuria since hypouricemia and hyperuricosuria have been observed in subjects with familial renal glycosuria [102] hyperglycemic glycosuric type 1 diabetic patients, and euglycemic glycosuric type 1 diabetic patients following SGLT2 inhibition [103]. In vitro studies and clinical evidence have suggested that increased glucose concentration by gliflozins might carry out an increased efflux of UA into the lumen through GLUT9 in the proximal tubule [104]. ...
This article aims to critically review the evidence on the available therapeutic strategies for the treatment of hyperuricemia. For this reason, several papers were reviewed. Xanthine oxidase inhibitors are the safest and most effective uric acid lowering drugs for the management of chronic hyperuricemia, while the efficacy of uricosuric agents is strongly modulated by pharmacogenetics. Emergent drugs (lesinurad, peglotidase) were found to be more effective for the acute management of refractory hyperuricemia, but their use is supported by a relatively small number of clinical trials so that further well-designed clinical research is needed to deepen their efficacy and safety profile.
... Given that hypouricaemia and hyperuricosuria were observed in individuals with familial renal glycosuria, 19 in hyperglycaemic type 1 diabetes mellitus patients with glucosuria, as well as in euglycaemic type 1 diabetes mellitus patients with glucosuria following SGLT2 inhibition, 20 SUA reduction may be brought on by a uricosuric effect secondary to glycosuria. No direct interaction was observed between SGLT2 inhibitors and major uric acid transporters in an in vitro study. ...
To describe the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid (SUA) in patients with type 2 diabetes mellitus (T2DM), PubMed, CENTRAL, EMBASE, and ClinicalTrials.gov were searched for randomized controlled trials of SGLT2 inhibitors in patients with T2DM up to 20 May 2017. Sixty-two studies totaling 34,941 patients were included. Either SGLT2 inhibitor (empagliflozin, canagliflozin, dapagliflozin, tofogliflozin, luseogliflozin or ipragliflozin) significantly decreased SUA levels compared with control (total WMD -37.73 µmol/L, 95% CI [-40.51, -34.95]). Treatment with empagliflozin resulted in a superior reduction in SUA (WMD -45.83 µmol/L, 95% CI [-53.03, -38.63]). The effect persisted for long-term treatment duration. Dapagliflozin decreased SUA in a dose-dependent manner (from 5 mg to 50 mg, p = 0.014). In subgroup analyses, greater reductions could be observed in early diabetes course and the SUA-lowering effect was abolished in patients with chronic kidney disease (estimated glomerular filtration rate less than 60 mL per min per 1.73 m(2) ). The drug class effect of SUA reduction suggesting SGLT2 inhibitors might be beneficial for diabetic patients with hyperuricemia.
... Individual S-2 was previously reported as homozygous for the p.V346fsX17 frameshift mutation [13] . S-7 is also homozygous for the p.C511S mutation. ...
Familial Renal Glucosuria (FRG) is characterized by the presence of persistent isolated glucosuria in the absence of hyperglycemia. Mutations in SLC5A2, the gene coding for the sodium-glucose co-transporter 2 (SGLT2), are responsible for FRG. Phenotype/genotype correlations in FRG have mostly relied on the quantification of Urinary Glucose Excretion (UGE), which is dependent on both the filtered glucose load and the renal glucose reabsorptive capacity. In the current work, the renal threshold for glucose excretion (RTG) was determined in an FRG cohort, with the purpose of characterizing the impact of SGLT2 mutations on renal glucose transport.
From January to December of 2013, eight FRG individuals with identified SLC5A2 mutations were enrolled. Patients were given a Mixed-Meal Tolerance Test during which blood glucose and UGE were measured over a 4 h period and the data was used to calculate RTG, according to a recently validated protocol.
In patients with homozygous mutations, RTG values were very low, with a mean (SD) of 0.95 (1.17) mmol/l, compared to commonly reported values of approximately 10-11.1 mmol/l in healthy subjects. In subjects with heterozygous mutations, mean (SD) RTG values were 4.91 (1.23) mmol/l, which are approximately one-half of the values in subjects without mutations.
In FRG, mutations in SLC5A2 lead to reductions in RTG and increases in UGE. Because determination of RTG is not influenced by the filtered glucose load, the calculated RTG values provide a more refined measure of the impact of mutations on renal glucose transport than can be obtained from UGE alone. © 2015 S. Karger AG, Basel.
Familial Renal Glucosuria (FRG) is a co‐dominantly inherited trait characterized by orthoglycaemic glucosuria. From 2003 to 2015 we have reported several cohorts validating SLC5A2 (16p11.2), encoding SGLT2 (Na+/glucose cotransporter family member 2), as the gene responsible for FRG. The aim of this work was to validate the variants identified in our extended FRG cohort of published, as well more recent unreported cases, according to the ACMG‐AMP 2015 criteria. Forty‐six variants were evaluated, including 16 novel alleles first described in this study. All are rare, ultra‐rare or absent from population databases and most are missense changes. According to the ACMG‐AMP standards, only 74% of the variants were classified as P/LP. The lack of descriptions of unrelated patients with similar variants or failing to test additional affected family members, averted a conclusion for pathogenicity in the alleles that scored VUS, highlighting the importance of both family testing and variant reporting. Finally, the cryo‐EM structure of the hSGLT2–MAP17 complex in the empagliflozin‐bound state improved the ACMG‐AMP pathogenicity score by identifying critical/functional protein domains.
Purpose Familial renal glucosuria (FRG, OMIM #233100) is a rare but relatively benign genetic condition characterized by persistent isolated glucosuria with a normal blood glucose level. We report three additional SLC5A2 mutations and examine their phenotypic and genetic characteristics in a Korean FRG cohort. We also reviewed the literature and summarized the genotypes of all Korean patients with FRG. Methods A genetic analysis was conducted by directly sequencing all 14 exons of the SLC5A2 gene and their flanking regions in six unrelated Korean children with FRG and their family members. Novel non-synonymous single-nucleotide polymorphisms were identified and compared with known mutations that are repeatedly detected in the Korean population. Results We found two novel mutations [c.274G>A (G92S) and c.1168C>T (L390F)] and one known [c.1382G>A (S461N)] mutation in each family and one recurrent mutation [c.1346G>A (G449D) (rs768392222)] in two pedigrees. The recurrent G449D was predicted to be “possibly damaging,” with a score of 0.883 in Polyphen-2, while G92S, L390F, and S461N were predicted to be “probably damaging,” with scores of 1.000, 0.999, and 0.996, respectively. Conclusions Two novel, one previously reported, and one recurrent mutation were identified in six Korean FRG pedigrees as causative mutations of renal glucosuria. Sequence variations in the SLC5A2 gene were frequently detected in children with persistent isolated glucosuria. A long-term follow-up of this FRG cohort is needed to understand how these specific SGLT2 mutations impair kidney function and energy homeostasis.
