Familial Renal Glucosuria and SGLT2: from a Mendelian Trait to a Therapeutic Target

In-Depth Review

Familial Renal Glucosuria and SGLT2: From a Mendelian Trait to a Therapeutic Target

Rene´Santer* and Joaquim Calado†‡ *Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; †Department of Genetics, Faculty of Medical Sciences, New University of Lisbon, Lisbon, Portugal; and ‡Department of Nephrology, Hospital de Curry Cabral, Lisbon, Portugal

Four members of two glucose transporter families, SGLT1, SGLT2, GLUT1, and GLUT2, are differentially expressed in the kidney, and three of them have been shown to be necessary for normal glucose resorption from the glomerular filtrate. Mutations in SGLT1 are associated with glucose-galactose malabsorption, SGLT2 with familial renal glucosuria (FRG), and GLUT2 with Fanconi-Bickel syndrome. Patients with FRG have decreased renal tubular resorption of glucose from the urine in the absence of hyperglycemia and any other signs of tubular dysfunction. Glucosuria in these patients can range from <1 to >150 g/1.73 m2 per d. The majority of patients do not seem to develop significant clinical problems over time, and further description of specific disease sequelae in these individuals is reviewed. SGLT2, a critical transporter in tubular glucose resorption, is located in the S1 segment of the proximal tubule, and, as such, recent attention has been given to SGLT2 inhibitors and their utility in patients with type 2 diabetes, who might benefit from the glucose-lowering effect of such compounds. A natural analogy is made of SGLT2 inhibition to observations with inactivating mutations of SGLT2 in patients with FRG, the hereditary condition that results in benign glucosuria. This review provides an overview of renal glucose transport physiology, FRG and its clinical course, and the potential of SGLT2 inhibition as a therapeutic target in type 2 diabetes. Clin J Am Soc Nephrol 5: 133–141, 2010. doi: 10.2215/CJN.04010609

lucose is the primary energy source for brain, muscle, transporter MCT12, encoded by the SLC16A12 gene, were and other organs. Membrane lipid bilayers, however, found to be responsible for an autosomal dominant inherited G are virtually impermeable to hydrophilic glucose condition characterized by juvenile cataracts with microcornea molecules and rely on glucose transporters to facilitate their and mild renal glucosuria (OMIM 612018), underlining the role movement across cell membranes and their distribution to and of transporters other than the GLUTs and SGLTs in renal glu- within various tissues (1,2). The kidney contributes to glucose cose handling (3). homeostasis by reabsorbing approximately 180 g from the glo- There are Ͼ220 members in the SLC5 family, also known as merular filtrate each day. Because of the activity of glucose the sodium substrate symporter gene family (SSSF); of these, 12 Ͻ transporters in the renal proximal tubule, 0.5 g/d (range 0.03 have been identified in the human genome (4,5). SGLT mem- to 0.3 g/d) is excreted in the urine of healthy adults (1,2). bers are multifunctional membrane-bound proteins that dis- There are two means of glucose transport, facilitative and play a vast array of functions from sodium-coupled co-trans- secondary active transport, each of which involves different port for sugars, monocarboxylates, amino acids, vitamins, classes of transporters. Facilitative transport, which is driven by osmolytes, and ions to sodium uniporter activity, channels for the concentration gradient across cellular membranes, occurs in urea and water, glucose sensing, and tumor suppression (4,5). essentially all cell types and is mediated by members of the At least two sodium-coupled glucose transporters, SGLT1 GLUT transporter family. Secondary active transport is the first step in transcellular glucose transport in the intestine and kid- and SGLT2, play an important role in the apical membrane of proximal tubular cells in the kidney (Figure 1). These transport- ney and is mediated by members of the SGLT transporter ϩ SLC2 ers first bind Na , before they bind glucose, and the electro- family. GLUTs are encoded by the genes, whereas SGLTs ϩ ϩ ϩ are encoded by the SLC5 genes. It is possible that other trans- chemical Na gradient generated by the Na /K -ATPase is porters may account for additional glucose transport activity in the driving force for the symporter activity. SGLT1 is predom- the kidney. For instance, mutations in the monocarboxylate inantly expressed in enterocytes (6). Its primary function here is to mediate active glucose and galactose transport across the apical membrane at low sugar concentration, but it also medi- Published online ahead of print. Publication date available at www.cjasn.org. ates expression of facilitative transporters at high glucose con- Correspondence: Dr. Joaquim Calado, Department of Genetics, Faculty of Med- centration. Although not involved in resorption of the bulk of ical Sciences, Institute of Hygiene and Tropical Medicine, Universidade Nova de Lisboa, Rua da Junqueira no 96, 1349-008, Lisbon, Portugal. Phone: 351- glucose in the kidney, the kinetic characteristics of SGLT1 are 213610297; Fax: 351-213622018; E-mail: [email protected] favorable for transport of glucose when present at low concen-

are predicted to exist in the human genome, different functions have been reported. For instance, SGLT3, initially assigned to be a co-transporter on the basis of sequence homology, was later characterized as a glucose-gated ion channel expressed in cholinergic neurons and the neuromuscular junction (8) and might play a role in diet-triggered intestinal motility.

Location and Relative Affinities of Renal SGLTs for Glucose SGLT2 and SGLT1 can be distinguished by their affinities for ϩ glucose and Na and their location in the kidney (9–12). SGLT2 is expressed exclusively near the early proximal convoluted tubule (termed S1) (13), whereas SGLT1 is expressed near the medullary proximal tubule (termed S3) (9–11). SGLT2 is a low-affinity, high-capacity glucose transporter, whereas SGLT1 is a high-affinity, low-capacity glucose transporter. SGLT1

transports glucose and galactose (10), has a K0.5 for glucose of ϩ approximately 0.4 mM, and carries two molecules of Na for

every molecule of glucose. SGLT1 has a K0.5 of approximately ϩ 3 mM for Na (14). SGLT2 has a K0.5 for glucose of approxi- ϩ mately 2 mM, carries one molecule of Na for every molecule ϩ ϩ of glucose, and has a K for Na of 100 mM (14). SGLT2, Figure 1. A model for Na /glucose transport in the kidney. 0.5 unlike SGLT1, does not transport galactose. Thus, the bulk of SGLT2 is predominantly expressed in the S1 segment of the glucose is reabsorbed at the S1 segment by the high-capacity proximal tubule and is responsible for the vast majority of glucose reabsorption from urine. SGLT2 transporter, whereas the remaining glucose that enters the S3 segment is reabsorbed by the high-affinity SGLT1 transporter; together they minimize glucose loss in the urine (14). trations. In addition to the intestine and kidney, SGLT1 is expressed in organs such as the brain and the heart. SGLT Protein Structure and Transport Dynamics SGLT2 expression occurs predominantly in the luminal Human SLC5 genes code for proteins with a molecular mass brush border of the proximal tubule of the renal cortex, where of approximately 75 kD. They exhibit considerable functional it is the principal transporter that mediates glucose resorption similarity, despite that transported solutes are variable. The (7) (Table 1). It is also expressed to a much lower degree in topology and secondary structure model of SGLT1, the most other organs, including the liver. SGLT4, SGLT5, SGLT6, and extensively studied member of the SSSF group, has been ex- SMIT1 are expressed in several tissues, including the kidney, perimentally delineated by extensive analyses of its primary and a putative role in glucose transport in the kidney is antic- sequence, sequence comparison, computational prediction ipated but has yet to be shown. SGLTs are multifunctional methods, and both functional and electron microscopic assays proteins, and for the remaining six products of SLC5 genes that performed in heterologous expression systems (2,4,15,16). The

Table 1. Substrates and distribution of human glucose transporters

Size (Amino Transporter (Gene) Substrate Acids) Distribution

SGLT1 (SLC5A1) Glucose Galactose 664 Intestine, trachea, kidney, heart, brain, testis, and prostate SGLT2 (SLC5A2) Glucose 672 Kidney, brain, liver, thyroid, muscle, and heart SGLT4 (SLC5A9) Glucose Mannose 699 Intestine, trachea, kidney, liver, brain, lung, uterus, and pancreas SGLT5 (SLC5A10) Glucose (predicted) 596 Kidney SGLT6/SMIT2 (SLC5A11) Myoinositol 675 Brain, kidney, and intestine Glucose SMIT1 (SLC5A3) Myoinositol 718 Brain, heart, kidney, and lung Glucose

Adapted from reference (2). Clin J Am Soc Nephrol 5: 133–141, 2010 Familial Renal Glucosuria and SGLT2 135 membrane topology of other members of the SGLT family is anticipated to be similar on the basis of their common ancestry, function, and similar primary sequences. SGLT2, which is com- posed of 672 amino acids, bears 59% identity with the 664 amino acids that constitute SGLT1 (17). In general, cytoplasmic domains are better conserved than extracellular domains among SGLTs. The members of the SGLT family share a common core of 13 transmembrane helices (TMH), although some members have one or two additional C-terminal helices. SGLT1 and SGLT2 both have 14 TMHs with both the hydrophobic N- and C- terminal domains lying extracellular (2). The SSSF consensus sequence [GS]-2(2)-[LIY]-x(3)-[LIVMFYWSTAG](7)-x(3)-[LIY]- [STAV]-x(2)-G-G-[LMF]-x-[SAP] lies in TMH5. In addition, the smaller eukaryote SGLTs and SMIT subfamily members share an R-x-T-x(4)-F-L-A-G-x(4)-W-W-x(2)-G-A-S motif near the N- terminal domain, proximal in TMH2. The crystal structure of vSGLT, a sodium-galactose symporter from Vibrio parahaemolyticus and a member of the SSSF, was reported recently (18). The protein assembles as a tightly packed parallel dimer, although previous work has shown that SGLT1 is fully functional as a monomer. The structural core is formed from inverted repeats of five TMHs (2 through 6 and 7 through 11; Figure 2A). Seven TMHs (2 through 4, 7 through 9, and 11) contribute to side-chain interaction for ligand selectiv- ity. Extracellular and intracellular gates delineating the galactose pathway were identified, with residues M73, Y87, and F424 forming the extracellular and Y263, Y262, and W264 forming ϩ Figure 2. Structure of vSGLT. (A) Topology. The structure is the intracellular ones. There is a plausible Na -binding site at colored as a rainbow from the N-terminus (red) to the C- the intersection of TMH2 and TMH9, approximately 10 Å away ϩ terminus (purple). The blue and red trapeziums represent the from the substrate-binding site. External Na binds first, which inverted topology of TMH2 through TMH6 and TMH7 through facilitates TMH2 rearrangements to form the substrate-binding TMH11. The gray hexagon with red outline represents galac- site. Galactose binding induces the formation of the extracellu- tose. Residues involved in sugar recognition, gate residues, and ϩ lar gate and enlarges the intracellular cavity by conformational a proposed Na site are shown in cyan, gray, and yellow changes in TMH3, TMH4, TMH7 and 8, and TMH9 through 11. circles. (B) Alternating accessibility. (Left) Slice through surface ϩ Finally, displacement of Y263 releases Na and then galactose of the outward-facing model viewed from the membrane plane intracellularly (Figure 2B). showing the extracellular cavity (blue mesh). (Right) Slice through surface of the inward-facing structure in the membrane plane showing the intracellular cavity (blue mesh). He- lices showing structural rearrangement are colored orange, Other Functions of SGLTs green, and blue for helices TMH3, TMH7, and TMH11, respec- In addition to their role in sugar transport, SGLTs can func- ϩ tively; helices with little movement are colored white. The tion as uniporters. SGLT1, SGLT3, and SGLT5 transport Na in surface is shown in beige. Galactose is shown as black and red ϩ the absence of sugar (19). SGLT3 functions as a glucose sensor spheres for the C and O atoms, respectively. Y263 and the Na in visceral neuronal cells (8). SGLT1 and other co-transporters ion are colored as gray and blue spheres, respectively. Re- have been shown to function as channels for water and other printed from reference (18), with permission. small hydrophilic solutes when expressed in oocytes (20,21) and are proposed to play an important role in fluid and urea transport across the intestine. SGLT1 has been shown to play a Regulation of SGLT2 Expression and significant role in water transport across the intestinal brush Activity (in Diabetes) border membrane by either co-transporting water along with It was previously shown that patients with type 1 diabetes ϩ Na and glucose or by osmosis (20,22,23). SGLT1 does not had a significant increase in the renal transport maximum for simply mediate secondary active transport at the apical mem- glucose (25), and several rodent models of diabetes have shown brane of enterocytes itself but also regulates other glucose upregulation of the GLUT2 protein in the renal proximal tu- transport mechanisms, such as promoting insertion of GLUT2 bules of diabetic animals with long-term hyperglycemia, sup- into the apical membrane to provide a facilitative component of porting the need for higher glucose efflux and glucose reab- absorption up to three times greater than that of SGLT1 alone to sorption (26,27). It is interesting that no changes in the SGLT1 match dietary intake of carbohydrates (24). protein expression were detected (27). Regarding SGLT2 ex- 136 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 5: 133–141, 2010 pression, however, studies have been hampered by the lack of glucose as the only source of carbohydrate, and individuals suitable antibodies. should have normal carbohydrate storage and use (38). By the Renal proximal cells isolated from the urine of patients with mid-1950s, renal titration studies delineated renal glucosurias type 2 diabetes displayed an elevation of SGLT2 mRNA com- into type A and type B (39). Patients with type A renal glucos- pared with healthy individuals (28), and in a rat model of uria are characterized by a low renal threshold for glucose and diabetes, SGLT2 and hepatocyte nuclear factor 1␣ (HNF1␣) a low maximum tubular glucose reabsorption in contrast to mRNA expression was increased but reversed upon treatment individuals with FRG type B, who have a low threshold but still with insulin or phlorizin, an inhibitor of SGLTs (29). Similar can reach a normal maximum tubular glucose reabsorption, changes have been reported for GLUT2 in diabetic rats at day 6 causing an abnormal splay of their filtration-resorption curve of treatment with either insulin or phlorizin (30). HNF1␣ is a (Figure 3). Later, the complete absence of renal glucose trans- transcriptional activator encoded by the TCF1 gene, found to be port was found in very few individuals and designated as type mutated in maturity-onset diabetes of the young type 3 O glucosuria (40). Glucose quantification in the collected urine (MODY3), an autosomal dominant form of non–insulin-depen- 2 to 4 h after a glucose load of 50 g in three pedigrees gave the dent diabetes (31). Defective renal glucose resorption in several first insight that the mode of inheritance for FRG could be one families with MODY3, including in some euglycemic members, of co-dominance: Individuals supposed to be homozygous for Ϫ Ϫ has been described (32,33). HNF1␣ / homozygous mice, com- the condition had persistent heavy glucosuria and experienced pared with wild-type or heterozygous healthy littermates, dis- “renal glucosuria,” whereas putative heterozygotes had mild played deficient insulin secretion and hyperglycemia (34); how- (or no glucosuria) and had only the “renal glucosuria trait” (41). ever, plasma glucose concentrations were lower than expected Elsas and Rosenberg (42) reported that both type A and type B in light of the severity of the insulin secretory defect, probably renal glucosuria could be observed in the same family and that secondary to the associated glucose resorption defect detected both parents could be completely normal or show an abnor- in these mice (33–35). SGLT2 expression has been shown in mality in renal tubular glucose transport. They postulated that murine systems to be controlled by HNF1␣, and HNF1␣ bind- this could be due to the variable expression of a dominant ing sites have been identified in the mouse SLC5A2 gene pro- mutation or, alternatively, that two different genes could be moter (29,33); therefore, plasma glucose concentration seems to involved: A mutant B gene that leads to decreased affinity of a be an important modulator of SGLT2 activity, and this activity glucose transporter for glucose and a mutant A gene that leads may be in part regulated by HNF1␣ expression. to reduced transport capacity. Characterization of FRG into types A/B/O is presented here Familial Renal Glucosuria mainly for historical reasons. Current molecular findings have Glucosuria can occur in the setting of global dysfunction of enabled appropriate genotype–phenotype correlations in the the proximal tubule, known as the Fanconi-de Toni-Debre´syn- vast majority of cases and, consequently, a simpler and easier drome, or renal Fanconi syndrome. Glucosuria in this instance classification in FRG. accompanies the excessive urinary excretion of amino acids, phosphate, bicarbonate, and other solutes that typically are Molecular Genetics reabsorbed in the proximal tubule. The occurrence of glucos- Since SLC5A2 was cloned and the delineation of the major uria in the absence of both generalized proximal tubular dys- renal resorptive mechanism for glucose made apparent, this function and hyperglycemia is known as renal glucosuria and recognized as an inherited disorder and hence the designation of familial renal glucosuria (FRG).

Diagnostic Criteria and Mode of Inheritance Depending on the diagnostic criteria used, different preva- lences and modes of inheritance were reported for FRG. Initial investigations used a nonquantitative assessment of glucosuria after an oral glucose tolerance test as a diagnostic technique (36). Under these circumstances, evidence emerged for an autosomal dominant inheritance. When later this technique was applied for screening purposes, an incidence of renal glucosuria in the general population of 0.29% was proposed (37). Marble in 1947 (38) defined more stringent diagnostic criteria, Figure 3. Correlation between glomerular glucose load and and the condition was reported to be autosomal recessive and tubular glucose reabsorption (TG) in various renal glucosurias. uncommon. These revised criteria included a normal oral glu- TmG, maximum tubular glucose reabsorption; PG, plasma glucose tolerance test in regard to plasma glucose concentration, cose concentration. The hatched area is the splay—the differ- normal plasma levels of insulin, free fatty acids, glycosylated ence between actual and ideal reabsorption that is exhibited hemoglobin, and relatively stable urinary glucose levels (10 to when the reabsorption curve shows a nonlinear transition as 100 g/d; except during pregnancy, when it may increase) with the TmG is reached. Redrawn from reference (72), with permis- glucose present in all urine samples. Urine should contain sion. Clin J Am Soc Nephrol 5: 133–141, 2010 Familial Renal Glucosuria and SGLT2 137 transporter was implicated as a major candidate gene for FRG donor and acceptor splice consensus sequences GT/AG, and a (7). The first mutation in the SLC5A2 gene, positioned in previously unreported CA repeat was identified in intron 1. 16p11.2, was reported by Santer et al. (43), and more case series The 2019-bp coding sequence accurately predicts the 672-resi- have confirmed that mutations in SLC5A2 are indeed respon- due SGLT2 protein previously reported after cloning of SGLT2 sible for the large majority of cases of FRG (44–46). Additional from a human kidney cDNA library (17). There are no reports support has come from several case reports (47–51). of splice variants or isoforms. Although the pattern of inheritance that best fits FRG is one of co-dominance, surprisingly, increased glucose excretion was Genotype–Phenotype Correlations in FRG not observed in all individuals with similar or identical muta- Establishing definite genotype–phenotype correlations in tions, heterozygosity for mutations in particular, suggesting a FRG is a difficult task because of the variable expressivity and role of nongenetic factors or other genes in renal glucose trans- because other genes may have an impact on overall renal port. Furthermore, in only a few patients with FRG does the glucose resorption. In general, patients with mild glucosuria renal excretion approach the filtered load (e.g., in the original (Ͻ10 g/1.73 m2 per d) will usually be heterozygous for SGLT2 patient with familial renal glucosuria type O and homozygosity mutations, both nonsense and missense, although, as previ- for a premature stop codon [347X]); however, other patients ously stated, this may not happen in all carriers of such muta- with truncating mutations (e.g., p.W440X) were found to ex- tions. Cases of severe glucosuria (Ն10 g/1.73 m2 per d) show crete only approximately half the filtered load. This again sug- the characteristics of autosomal recessive inheritance with ho- gests that other transporters under certain circumstances may mozygosity or compound heterozygosity for SGLT2 mutations reabsorb a significant amount of glucose in these patients. In (44–46). particular, other SGLTs that are known to be expressed in the Forty-four different mutations, scattered throughout the kidney and whose functions have not yet been clarified are SCL5A2 gene, have been reported, with most being private (46) candidates for modifier genes in FRG. At least three patients (Figure 4). Among them are missense and nonsense mutations, have been reported not to have any mutation identified after small deletions (in-frame and frame shift), and splicing muta- sequencing of the entire coding region of SLC5A2 (44,45), which tions. IVS7 ϩ 5G may be considered a mutational hot spot also raises the possibility of genetic heterogeneity. Indeed, a because of the recurrent finding of the IVS7 ϩ 5G3A allele in locus on chromosome 6, in close genetic linkage with the HLA several unrelated families who have FRG and are of different complex, has been positioned and named GLYS1 on the basis of ethnic origin (44,46). segregation analysis in five unrelated affected pedigrees (52); Molecular analysis may also be helpful in understanding the however, this hypothetical gene remains to be cloned. Alterna- findings of earlier titration studies. Haploinsufficiency will re- tively, mutations in the promoter region or heterozygosity for sult in a reduced number of normally functioning carriers in the large deletions that are not detectable by PCR may also account renal tubule, thereby leading to type A glucosuria, whereas for those findings. certain missense mutations might decrease SGLT2 affinity for Analysis of the genomic structure of human SGLT2 revealed glucose and patients will display type B glucosuria (44). Com- a 14-exon gene that spans 8 kb with an intron-exon organiza- pound heterozygosity for SGLT2 mutations, however, is prob- tion that is similar to SGLT1 (44). All of the introns display the ably the reason that many past cases of severe glucosuria could

ϩ Figure 4. Mutation analysis of the human Na /glucose co-transporter gene SLC5A2 that encodes SGLT2. Transmembrane domains 1 through 14 are shown as dark gray boxes. Redrawn from reference (46), with permission. 138 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 5: 133–141, 2010 not be clearly classified into type A or B and that a broad phlorizin, a natural product isolated from the root bark of the spectrum of impaired tubular glucose transport has been found apple tree and known since the 19th century to cause glucos- in those patients. We therefore propose that individuals with uria. When phlorizin was administered to partially pancreate- FRG be characterized according to the amount of glucose ex- ctomized rats, the hyperglycemia was corrected without chang- creted in a 24-h urine collection, normalized for body surface: ing insulin levels, and both insulin sensitivity (62) and insulin Mild renal glucosuria for Ͻ10 g/1.73 m2 per d and severe renal secretion (63) were restored to normal. This provided the first glucosuria for Ն10 g/1.73 m2 per d. evidence that hyperglycemia per se can lead to the development of insulin resistance. Despite demonstrating utility as an anti- Clinical Consequences of FRG hyperglycemic agent in several rodent models of diabetes, Overall, patients with renal glucosuria have not been shown phlorizin was discontinued because it was readily hydrolyzed to be affected by severe clinical consequences, and this entity is and poorly absorbed by the intestine, and it inhibited SGLT1 considered a benign condition, more a phenotype than a dis- equally as well as SGLT2 (64). Furthermore, its active metabo- ease. For example, polyuria and enuresis and later a mild lite, phloretin, inhibits nonspecifically other glucose transport- growth and pubertal maturation delay were the only manifes- ers. tations observed during a follow-up period of 30 yr (53). Sev- Several selective inhibitors of SGLT2 have been developed to eral other manifestations have occasionally been reported in overcome the disadvantages of phlorizin. In a variety of animal severe forms of FRG, such as episodic dehydration and ketosis models, they have been shown to induce glucosuria, lower during pregnancy and starvation (40), the presence of several blood glucose without altering insulin levels, improve insulin autoantibodies without clinical evidence of autoimmune dis- sensitivity, and reduce hepatic glucose output (65–69). Some ease (54), or an increased incidence of urinary tract infections are now under evaluation in clinical trials, and published data (54,55). Activation of the renin-angiotensin-aldosterone system, are available for dapagliflozin, which is 1200-fold more selec- secondary to natriuresis and possible extracellular volume de- tive for SGLT2 than SGLT1. When administered for 14 d to pletion, has also been observed (45,46). drug-naive or metformin-treated patients with type 2 diabetes, Hypercalciuria was identified as an accompanying feature in dapagliflozin induced a dosage-dependent increase in urinary five of seven male children with renal glucosuria in one study glucose excretion, reaching a maximum of 70 g/d, and im- (56), and in one patient who displayed severe renal glucosuria, proved fasting blood glucose and glucose tolerance (70). In a an elevated calcium/creatinine ratio on spot urine was also more prolonged study, a total of 348 drug-naive patients with described (53). The reason for this finding remains unknown. type 2 diabetes were randomly assigned to receive 2.5, 5.0, 10.0, There are several case reports of selective aminoaciduria 20.0, or 50.0 mg of dapagliflozin; 1.5 g of metformin; or placebo associated with renal glucosuria, involving aspartic acid in one; (71). Significant reduction of glycosylated hemoglobin, fasting glutamic acid, citrulline, and alanine in another; and arginine, plasma glucose, and body weight had occurred by the end of carnosine, and taurine in yet another patient (57,58). Six chil- the study. The compound was found to have a mild diuretic dren who had glucosuria, were from three pedigrees, and were effect with a decrease in systolic BP. In the short-duration homozygous for the novel SGLT2 p.K321R mutation were treatment trial with dapagliflozin previously reported, an in- shown to have generalized aminoaciduria not accompanied by crease in urinary sodium was initially observed, returning to any other proximal tubular transport abnormalities (51). It was baseline by day 13 (70). In the pilot study that enrolled 348 postulated that aminoaciduria could be secondary to glucosuria patients with type 2 diabetes, it was shown that dapagliflozin and not a primary effect of the SGLT2 mutation. Indeed, ami- displayed a dosage-dependent mild diuretic effect as assessed noaciduria has been found not only in MODY3 but also in types by daily urine output (71). Unfortunately, urinary sodium was 1 and 2 diabetes, where it correlated positively with the amount not reported, so we can only speculate whether this diuretic of glucosuria (59). The proposed mechanism is that glucosuria effect was a consequence of glucosuric osmosis or, alterna- is causing depolarization and dissipation of the electric gradi- tively, dependent of true natriuresis reflecting the failure of the ϩ ent of sodium-dependent amino acid transporters in the prox- distal nephron to compensate for the Na proximal losses. In imal renal tubule. any circumstance, no changes in serum sodium (namely hyper- natremia) were reported, leading to the impression that the SGLT2 Inhibition: A New Option for the increase in free water clearance is clinically irrelevant. Treatment of Type 2 Diabetes In addition, treated patients experienced sustained weight Type 2 diabetes is characterized by hyperglycemia that re- loss. Hypoglycemic episodes were similar when compared sults both from peripheral resistance to the action of insulin and with the metformin-treated group, but the incidence of genital from progressive failure of pancreatic ␤ cell function (60). infections was higher. Chronic hyperglycemia of diabetes can lead to microvascular Of note, both studies with dapagliflozin reported incomplete and macrovascular complications and also contributes, by inhibition of SGLT2 with lower levels of glucosuria than in the means of glucotoxicity, to ␤ cell dysfunction and insulin resis- most severe forms of FRG. It is possible that the accumulating tance, which aggravates the disease process (61). A novel strat- tubular glucose competes with dapagliflozin for SGLT2 bind- egy to reduce hyperglycemia is to target renal glucose excretion ing, thereby limiting the degree of inhibition. by inhibiting SGLT2. Evidence for such a beneficial effect comes Inhibition of renal glucose absorption may provide several not only from patients with FRG but also from studies of advantages in the treatment of patients with type 2 diabetes. Clin J Am Soc Nephrol 5: 133–141, 2010 Familial Renal Glucosuria and SGLT2 139

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