We present a case of a well-thriving infant, who was evaluated for recurrent fever over the past 4 months. History and prior investigations revealed recurrent urinary tract infections (UTIs). A comprehensive workup for recurrent UTIs showed no structural abnormalities of the kidneys or urinary tract. Even after resolved UTIs, the child had persistent glucosuria despite normal blood glucose levels, suggesting a possible tubular disorder. Further evaluation was negative for generalised tubular dysfunction. Whole-exome sequencing (WES) identified novel compound heterozygous variants in the SLC5A2 gene, which encodes the sodium-glucose cotransporter 2, confirming a diagnosis of familial renal glucosuria (FRG). FRG is a rare, benign tubular disorder with no specific treatment; management primarily focuses on preventing and treating associated UTIs. Comprehensive genetic counselling is essential. This case underscores the importance of recognising isolated glucosuria as a potential indicator of an underlying genetic tubular disorder.

The kidneys play a critical role in maintaining glucose homeostasis. Under normal renal tubular function, most of the glucose filtered from the glomeruli is reabsorbed in the proximal tubules, leaving only trace amounts in the urine. Glycosuria can occur as a symptom of generalized proximal tubular dysfunction or when the reabsorption threshold is exceeded or the glucose threshold is reduced, as seen in familial renal glycosuria (FRG). FRG is characterized by persistent glycosuria despite normal blood glucose levels and tubular function and is primarily associated with mutations in the sodium/glucose cotransporter 5A2 gene, which encodes the sodium-glucose cotransporter (SGLT) 2. Inhibiting SGLTs has been proposed as a novel treatment strategy for diabetes, and since FRG is often considered an asymptomatic and benign condition, it has inspired preclinical and clinical studies using SGLT2 inhibitors in type 2 diabetes. However, patients with FRG may exhibit clinical features such as lower body weight or height, altered systemic blood pressure, diaper dermatitis, aminoaciduria, decreased serum uric acid levels, and hypercalciuria. Further research is needed to fully understand the pathophysiology, molecular genetics, and clinical manifestations of renal glucosuria.

Previous reports provided recommendations for familial renal glucosuria diagnosis without complex view on differential diagnosis of glucosuria. The aim of this review was to provide an overview of the causes of glucosuria and to create an evidence-based diagnostic approach for children with glucosuria. We searched the current literature with a focus to identify the possible etiology of glucosuria, gaining insight into the pathophysiology of glucosuria. Urinary glucose is completely reabsorbed in the proximal tubule of kidneys. It only appears in the urine if the plasma glucose concentration exceeds the renal threshold for glucose or in the case of insufficient renal glucose reabsorption. The proteins that provide glucose reabsorption are SGLT2 and SGLT1 - sodium-dependent co-transporters that transport glucose from the lumen into epithelial cells - and GLUT2 - a passive transporter providing facilitative glucose transport from epithelial cells to plasma. Renal glucose reabsorption is affected in case of acquired or inherited complex dysfunction of proximal tubule called Fanconi Syndrome or due to pathogenic variants of genes encoding glucose transporters. Prior to diagnosing any of these, diabetes mellitus must be excluded together with other conditions leading to hyperglycemia. In conclusion, glucosuria is always an abnormal finding. The review provides a simple evidence-based diagnostic approach to navigate the differential diagnosis of glucosuria.

This study aims at find hit compounds as SGLT2 inhibitors through the methods of virtual screening, biological experiment, Structural similarity search and molecular docking. Computer-aided drug design techniques were used to build modelling of quantitative construct validity relationships. Three-dimensional pharmacophore model and the principle of drug properties were used to screen the compounds. The effects of lead compounds on glucose uptake were observed in 293 T cells. Further, structural similarity searches were conducted on 13 hit compounds, then molecular docking the compounds with proteins was performed. Based on virtual screening, 20 highly rated compounds as potential lead candidates for diabetes treatment were selected. Combining the results in glucose uptake assays, 13 hit compounds were identified with strong inhibitory properties against SGLT2, especially, compound 2 had the lowest glucose uptake and the best inhibition of SGLT2. The compounds were classified into 5 classes and each class has the same core skeleton. Molecular docking cleared and definite that the hit compounds had stable and efficient hydrogen-bonding interactions with SGLT2, and their binding to SGLT2 was specific. 13 hit compounds were identified with strong inhibitory properties against SGLT2, and they are likely to become new SGLT2 inhibitors to treat diabetes.

A significant knowledge gap exists in SLC5A2's role in familial renal glycosuria and sodium-glucose cotransporter-2 inhibitors' efficacy. Two percent of individuals in the All-of-Us cohort harbor rare genetic variants in SLC5A2, potentially increasing the risk of familial renal glycosuria. Our trial suggests differential responses to sodium-glucose cotransporter-2 inhibitors in individuals with rare SLC5A2 alleles compared with wild types. Renal glucosuria is a rare inheritable trait caused by loss-of-function variants in the gene that encodes sodium-glucose cotransporter-2 (SGLT2) (i.e., SLC5A2). The genetics of renal glucosuria is poorly understood, and even less is known on how loss-of-function variants in SLC5A2 may affect response to SGLT2 inhibitors, a new class of medication gaining popularity to treat diabetes by artificially inducing glucosuria. We used two biobanks that link genomic with electronic health record data to study the genetics of renal glucosuria. This included 245,394 participants enrolled in the All of Us Research Program and 11,011 enrolled in Marshfield Clinic's Personalized Research Project (PMRP). Association studies in All of Us and PMRP identified ten variants that reached an experiment-wise Bonferroni threshold in either cohort, of which nine were novel. PMRP was further used as a recruitment source for a prospective SGLT2 pharmacogenetic trial. During a glucose tolerance test, the trial measured urine glucose concentrations in 15 SLC5A2 variant–positive individuals and 15 matched wild types with and without an SGLT2 inhibitor. This trial demonstrated that carriers of SLC5A2 risk variants may be more sensitive to SGLT2 inhibitors compared with wild types (P = 0.075). On the basis of population data, 2% of an ethnically diverse population carried rare variants in SLC5A2 and are at risk of renal glucosuria. As a result, 2% of individuals being treated with SGLT2 inhibitors may respond differently to this new class of medication compared with the general population, suggesting that a larger investigation into SLC5A2 variants and SGLT2 inhibitors is needed.