Autosomal recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter (SGLT2)

Heuvel, L.P.W.J. van den; Assink, Karin; Willemsen, M.A.A.P.; Monnens, L.A.H.

doi:10.1007/s00439-002-0820-5

Cited by 194 publications

(35 citation statements)

References 18 publications

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“…However, these individuals have little or no glucosuria. In contrast, those who have SGLT2 gene mutations have persistent renal glucosuria, with glucose excretion of up to 160 g/day in severe cases (180, 381, 543, 563, 667). Recently we directly localized the expression of SGLT2 protein to the apical brush border of the early proximal tubule and demonstrated by free-flow micropuncture that SGLT2 KO mice lack glucose reabsorption in the early proximal tubule and that fractional renal reabsorption of glucose is reduced compared with wild-type mice (36 ± 8 vs. 99.7 ± 0.1%) and varied inversely with the amount of filtered glucose in the KO mice (between 60% and 10%) (656).…”

Section: Tubular Function In Diabetesmentioning

confidence: 99%

Pathophysiology of the Diabetic Kidney

Vallon

Komers

2011

Comprehensive Physiology

219

178

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Diabetes mellitus contributes greatly to morbidity, mortality, and overall health care costs. In major part, these outcomes derive from the high incidence of progressive kidney dysfunction in patients with diabetes making diabetic nephropathy a leading cause of end-stage renal disease. A better understanding of the molecular mechanism involved and of the early dysfunctions observed in the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. Here we review the pathophysiological changes that occur in the kidney in response to hyperglycemia, including the cellular responses to high glucose and the responses in vascular, glomerular, podocyte, and tubular function. The molecular basis, characteristics, and consequences of the unique growth phenotypes observed in the diabetic kidney, including glomerular structures and tubular segments, are outlined. We delineate mechanisms of early diabetic glomerular hyperfiltration including primary vascular events as well as the primary role of tubular growth, hyperreabsorption, and tubuloglomerular communication as part of a “tubulocentric” concept of early diabetic kidney function. The latter also explains the “salt paradox” of the diabetic kidney, that is, a unique and inverse relationship between glomerular filtration rate and dietary salt intake. The mechanisms and consequences of the intrarenal activation of the renin-angiotensin system and of diabetes-induced tubular glycogen accumulation are discussed. Moreover, we aim to link the changes that occur early in the diabetic kidney including the growth phenotype, oxidative stress, hypoxia, and formation of advanced glycation end products to mechanisms involved in progressive kidney disease.

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Section: Tubular Function In Diabetesmentioning

confidence: 99%

Pathophysiology of the Diabetic Kidney

Vallon

Komers

2011

Comprehensive Physiology

219

178

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“…A total of 44 different mutations have been described for the SCL5A2 gene, including missense and nonsense mutations, small deletions (in-frame and frame shift), and splicing mutations, scattered throughout the gene [8]. Although no other complications are known to be consistently associated with mutations of this gene, it is a rare genetic disorder and not well studied [9–12]. New free-flow micropuncture studies in mice lacking SGLT2 confirmed a lack of glucose reabsorption in the early proximal tubule and showed that fractional renal reabsorption of glucose is reduced compared with wild-type mice (36 ± 8 vs. 99.7 ± 0.1%) and varied inversely with the amount of filtered glucose in the knockout mice (between 60 and 10%) [13].…”

Section: Sglt2 and Glucose Reabsorption In The Proximal Renal Tubulementioning

confidence: 99%

Sodium–glucose transport: role in diabetes mellitus and potential clinical implications

Vallon

Sharma

2010

Current Opinion in Nephrology and Hypertension

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Purpose of review Current options for glycemic control is less than optimal in terms of efficacy and to reduce complications in the diabetic population. Selective inhibition of SGLT2 in the proximal tubule increases urinary glucose excretion thereby reducing plasma glucose levels, which may present a novel therapeutic approach. Recent findings SGLT2 inhibitors enhance glucose excretion and improve glycemic control in patients with type 2 diabetes in the absence of clinically relevant hypoglycemia or sustained changes in volume status or glomerular filtration rate. This is associated with lowering of body weight and may reduce systolic blood pressure. The increased glucosuria appears to increase the risk of genital infections but may not increase the risk of urinary tract infections. Summary The ability of SGLT2 inhibitors to reduce plasma glucose without inducing increased insulin secretion, clinically relevant hypoglycemia, or weight gain constitutes a major advance. The ability of increased glucose excretion provides a powerful means to treat caloric excess conditions. Important questions remain to be resolved and more clinical research is needed on the long-term effects of SGLT2 inhibition. Potential extrarenal effects need to be explored in order to determine the safety of these compounds. It also remains to be determined whether these drugs lower the toxicity of glucose directly on renal cells, independent of hyperglycemia, which may slow or prevent the progressive nature of diabetic nephropathy.

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“…Fumarate hydratase (FH) deficiency leads to defects in glutamate oxidation in kidney and other tissues [43], [44], which is also consistent with the decreased indirect renal reabsorption of glutamate predicted by the model. Renal glucosuria, recapitulated in the model, results from deficiency in a sodium-glucose transporter (SLC5A2) [45]. Dicarboxylicamino aciduria [46] exhibits impaired renal glutamate and aspartate reabsorption and hypoglycemia resulting from a deficient glutamate transporter (SLC1A1), all symptoms predicted by the model.…”

Section: Resultsmentioning

confidence: 90%

Drug Off-Target Effects Predicted Using Structural Analysis in the Context of a Metabolic Network Model

et al. 2010

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Recent advances in structural bioinformatics have enabled the prediction of protein-drug off-targets based on their ligand binding sites. Concurrent developments in systems biology allow for prediction of the functional effects of system perturbations using large-scale network models. Integration of these two capabilities provides a framework for evaluating metabolic drug response phenotypes in silico. This combined approach was applied to investigate the hypertensive side effect of the cholesteryl ester transfer protein inhibitor torcetrapib in the context of human renal function. A metabolic kidney model was generated in which to simulate drug treatment. Causal drug off-targets were predicted that have previously been observed to impact renal function in gene-deficient patients and may play a role in the adverse side effects observed in clinical trials. Genetic risk factors for drug treatment were also predicted that correspond to both characterized and unknown renal metabolic disorders as well as cryptic genetic deficiencies that are not expected to exhibit a renal disorder phenotype except under drug treatment. This study represents a novel integration of structural and systems biology and a first step towards computational systems medicine. The methodology introduced herein has important implications for drug development and personalized medicine.

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Autosomal recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter (SGLT2)

Cited by 194 publications

References 18 publications

Pathophysiology of the Diabetic Kidney

Pathophysiology of the Diabetic Kidney

Sodium–glucose transport: role in diabetes mellitus and potential clinical implications

Drug Off-Target Effects Predicted Using Structural Analysis in the Context of a Metabolic Network Model

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