Important role of the kidney in human carbohydrate metabolism

Stümvoll, Michael; Meyer, Christian; Mitrakou, Asimina; Gerich, John E.

doi:10.1054/mehy.1997.0655

Cited by 38 publications

(20 citation statements)

References 34 publications

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“…13 In addition, the kidneys and liver are the only organs that express the glucose-6-phosphatase enzyme, thus enabling them to perform gluconeogenesis. 14,15 This enzyme is only expressed in the PT, 16 highlighting the importance of this kidney segment in carbohydrate metabolism.…”

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confidence: 99%

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Functional Role of Glucose Metabolism, Osmotic Stress, and Sodium-Glucose Cotransporter Isoform-Mediated Transport on Na+/H+ Exchanger Isoform 3 Activity in the Renal Proximal Tubule

Pessoa

Campos

Carraro‐Lacroix

et al. 2014

Journal of the American Society of Nephrology

167

114

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Na + -glucose cotransporter 1 (SGLT1)-mediated glucose uptake leads to activation of Na + -H + exchanger 3 (NHE3) in the intestine by a process that is not dependent on glucose metabolism. This coactivation may be important for postprandial nutrient uptake. However, it remains to be determined whether SGLTmediated glucose uptake regulates NHE3-mediated NaHCO 3 reabsorption in the renal proximal tubule. Considering that this nephron segment also expresses SGLT2 and that the kidneys and intestine show significant variations in daily glucose availability, the goal of this study was to determine the effect of SGLTmediated glucose uptake on NHE3 activity in the renal proximal tubule. Stationary in vivo microperfusion experiments showed that luminal perfusion with 5 mM glucose stimulates NHE3-mediated bicarbonate reabsorption. This stimulatory effect was mediated by glycolytic metabolism but not through ATP production. Conversely, luminal perfusion with 40 mM glucose inhibited NHE3 because of cell swelling. Notably, pharmacologic inhibition of SGLT activity by Phlorizin produced a marked inhibition of NHE3, even in the absence of glucose. Furthermore, immunofluorescence experiments showed that NHE3 colocalizes with SGLT2 but not SGLT1 in the rat renal proximal tubule. Collectively, these findings show that glucose exerts a bimodal effect on NHE3. The physiologic metabolism of glucose stimulates NHE3 transport activity, whereas, supraphysiologic glucose concentrations inhibit this exchanger. Additionally, Phlorizin-sensitive SGLT transporters and NHE3 interact functionally in the proximal tubule. 25: 202825: -203925: , 201425: . doi: 10.1681 The kidney proximal tubule (PT) is the site where the reabsorption of approximately 70% of filtered sodium bicarbonate occurs. It is mainly performed by the Na + /H + exchanger isoform 3 (NHE3). 1 The physiologic importance of NHE3 became evident after the development of NHE3 knockout mice, which presented mild metabolic acidosis and volume depletion with reduced BP, underscoring the role of NHE3 in volume homeostasis. 2 It has been shown that NHE3 physically and functionally interacts with dipeptidyl-peptidase IV, an enzyme that degrades and inactivates the incretin hormone glucagon like peptide-1. 3 The inhibition of dipeptidyl-peptidase IV and the action of glucagon like peptide-1 were shown to inhibit NHE3 and promote natriuresis. 3-8 Additionally, various conditions and substances related to glucose metabolism, including diabetes, insulin, ATP, and glucose, modulate NHE3 in different tissues, J Am Soc Nephrol

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confidence: 99%

“…14 The PT has a low expression of hexokinase but the highest concentration and activity of glucose-6-phosphate dehydrogenase, indicating that this segment is able to metabolize glucose. 16,17 However, it is currently believed that the PT uses noncarbohydrate compounds as energy sources.…”

mentioning

confidence: 99%

Functional Role of Glucose Metabolism, Osmotic Stress, and Sodium-Glucose Cotransporter Isoform-Mediated Transport on Na+/H+ Exchanger Isoform 3 Activity in the Renal Proximal Tubule

Pessoa

Campos

Carraro‐Lacroix

et al. 2014

Journal of the American Society of Nephrology

167

114

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“…3,4 Previous studies evaluating renal glucose release and uptake, as well as the participation of gluconeogenic substrates in renal gluconeogenesis, have been thoroughly reviewed by Cano. 5 These studies highlighted the significance and magnitude of renal glucose production and also suggested a greater sensitivity of renal glucose release toward hormone action compared with hepatic glucose release.…”

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confidence: 99%

Deletion of the Insulin Receptor in the Proximal Tubule Promotes Hyperglycemia

Tiwari

Singh

et al. 2013

Journal of the American Society of Nephrology

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Nearly all renal tubular epithelial cells express insulin receptor. The insulin receptor in the distal tubule appears to modulate BP, but the role of the insulin receptor in the proximal tubule is unknown. Here, we selectively knocked out the insulin receptor from the proximal tubules of mice. Western blotting confirmed a two-to three-fold reduction in renal cortical homogenate insulin receptor-b among knockout mice compared with wild-type littermates. Young knockout mice exhibited a mildly diabetic phenotype, evidenced by higher fasting plasma glucose levels than wild-type mice. Assessments by hyperinsulinemic-euglycemic clamp and a glucose tolerance test revealed no differences in insulin sensitivity or overt pancreatic function, respectively. Renal cortical mRNA expression and enzyme activity of glucose-6-phosphatase, which catalyzes the final step of glucose production, were significantly higher in knockout mice. Taken together, these results support a role for insulin receptor in the proximal tubule in the modulation of systemic glucose levels. Downregulation of the insulin receptor in the proximal tubule, which occurs in insulinresistant states, may promote hyperglycemia through enhanced gluconeogenesis.

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“…The kidney has long been the subject of metabolic studies (52)(53)(54)(55)(56). It has the capacity to metabolize a large variety of substrates (e.g.…”

Section: Discussionmentioning

confidence: 99%

Reduction of Proteinuria through Podocyte Alkalinization

Altintas

Moriwaki

Wei

et al. 2014

Journal of Biological Chemistry

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Background: Podocyte injury can be caused by cytosolic cathepsin L activity, leading to foot process effacement and proteinuria. Results: Glutamine blunts the damaging activity of induced cytosolic cathepsin L in podocytes by modulating intracellular pH. Conclusion: Podocyte pH modulation is a novel way to tackle proteinuric kidney disease. Significance: The optimization of amino acid metabolism fluxes and associated pH i of podocytes may form a basis for novel therapeutic approaches.

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Important role of the kidney in human carbohydrate metabolism

Cited by 38 publications

References 34 publications

Functional Role of Glucose Metabolism, Osmotic Stress, and Sodium-Glucose Cotransporter Isoform-Mediated Transport on Na+/H+ Exchanger Isoform 3 Activity in the Renal Proximal Tubule

Functional Role of Glucose Metabolism, Osmotic Stress, and Sodium-Glucose Cotransporter Isoform-Mediated Transport on Na+/H+ Exchanger Isoform 3 Activity in the Renal Proximal Tubule

Deletion of the Insulin Receptor in the Proximal Tubule Promotes Hyperglycemia

Reduction of Proteinuria through Podocyte Alkalinization

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