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Renal GLUT2 is Essential in Regulating Systemic Glucose Homeostasis by Glycosuria

Diabetes increases renal GLUT2 levels and consequently, worsens hyperglycemia by enhancing glucose reabsorption. We recently demonstrated that renal GLUT2 is a primary effector of the central melanocortin system in regulating glucose homeostasis. Therefore, we hypothesized that renal GLUT2 is essent...

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Autores principales: de Souza Cordeiro, Leticia M, Devisetty, Nagavardhini, McDougal, David, Peters, Dorien J M, Chhabra, Kavaljit H
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090411/
http://dx.doi.org/10.1210/jendso/bvab048.661
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author de Souza Cordeiro, Leticia M
Devisetty, Nagavardhini
McDougal, David
Peters, Dorien J M
Chhabra, Kavaljit H
author_facet de Souza Cordeiro, Leticia M
Devisetty, Nagavardhini
McDougal, David
Peters, Dorien J M
Chhabra, Kavaljit H
author_sort de Souza Cordeiro, Leticia M
collection PubMed
description Diabetes increases renal GLUT2 levels and consequently, worsens hyperglycemia by enhancing glucose reabsorption. We recently demonstrated that renal GLUT2 is a primary effector of the central melanocortin system in regulating glucose homeostasis. Therefore, we hypothesized that renal GLUT2 is essential for maintaining systemic glucose homeostasis by regulating glycosuria. To test the hypothesis, we generated kidney-specific inducible Glut2 knockout (KO) mice [Glut2(LoxP/LoxP) x KspCad(CreERT2) (inducible by tamoxifen)]. These mice exhibited 90% reduction in Glut2 expression selectively in the kidneys, without affecting the expressions of other renal glucose transporters, such as Glut1, Sglt1, and Sglt2. To evaluate the physiological contribution of renal GLUT2 in systemic glucose homeostasis, we performed oral glucose tolerance tests (OGTT) in kidney-specific Glut2 KO mice and their control littermates (Ctrl). We observed that the kidney-specific GLUT2 deficient mice exhibited improved glucose tolerance compared to their Ctrls (AUC for OGTT, 41,950 ±2,014 vs. 52,165 ±1,686 mg/dL.min). To measure glycosuria in the kidney-specific Glut2 KO mice, we placed the mice in metabolic cages and collected 24h urine after acclimating the mice in the new cages. Indeed, the GLUT2 deficient mice had ~1,800-fold increase in urine glucose levels (53.5 ±11 vs. 0.03 ±0.005 mg/24h) and exhibited an increased urine volume (2.5 ±0.3 vs. 0.9 ±0.3 mL/24h) and water intake (7.6 ±0.7 vs. 4.9 ±0.7 mL/24h) compared to their Ctrl littermates. The improvement in glucose tolerance in the kidney-specific Glut2 KO mice was independent of the insulin signaling because we did not observe any changes in insulin tolerance tests (ITT) (AUC for ITT, 10,982 ±414 vs. 11,275 ±583 mg/dL.min) and serum insulin levels (1.07 ±0.14 vs. 1.05 ±0.13 ng/mL) between the groups. Importantly, the kidney-specific GLUT2 deficient mice had normal serum creatinine (0.42 ±0.02 vs. 0.41 ±0.03 mg/dL), free fatty acid (0.43 ±0.14 vs. 0.53±0.14 nmol/µL), β-hydroxybutyrate (0.29 ±0.01 vs. 0.27 ±0.02 mM) and glucagon (14 ±4 vs. 10 ±1 pg/mL) levels. Moreover, the kidney-specific Glut2 KO mice had normal glomerular area (4,190 ±119 vs. 4,219 ±186 µm(2)) as measured by kidney histology and normal glomerular filtration rate (153 ±9 vs. 173 ±10 [µL/min/b.w.]/100) compared with their Ctrl littermates, indicating the absence of any known renal injury. Altogether, we have developed a new mouse model in which we can knockout Glut2 selectively in the kidneys in adult mice. We show that loss-of-function of kidney-specific GLUT2 improves glucose tolerance due to elevated glycosuria without producing any known side effects. In conclusion, blocking kidney-specific GLUT2 has the potential to treat diabetes.
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spelling pubmed-80904112021-05-06 Renal GLUT2 is Essential in Regulating Systemic Glucose Homeostasis by Glycosuria de Souza Cordeiro, Leticia M Devisetty, Nagavardhini McDougal, David Peters, Dorien J M Chhabra, Kavaljit H J Endocr Soc Diabetes Mellitus and Glucose Metabolism Diabetes increases renal GLUT2 levels and consequently, worsens hyperglycemia by enhancing glucose reabsorption. We recently demonstrated that renal GLUT2 is a primary effector of the central melanocortin system in regulating glucose homeostasis. Therefore, we hypothesized that renal GLUT2 is essential for maintaining systemic glucose homeostasis by regulating glycosuria. To test the hypothesis, we generated kidney-specific inducible Glut2 knockout (KO) mice [Glut2(LoxP/LoxP) x KspCad(CreERT2) (inducible by tamoxifen)]. These mice exhibited 90% reduction in Glut2 expression selectively in the kidneys, without affecting the expressions of other renal glucose transporters, such as Glut1, Sglt1, and Sglt2. To evaluate the physiological contribution of renal GLUT2 in systemic glucose homeostasis, we performed oral glucose tolerance tests (OGTT) in kidney-specific Glut2 KO mice and their control littermates (Ctrl). We observed that the kidney-specific GLUT2 deficient mice exhibited improved glucose tolerance compared to their Ctrls (AUC for OGTT, 41,950 ±2,014 vs. 52,165 ±1,686 mg/dL.min). To measure glycosuria in the kidney-specific Glut2 KO mice, we placed the mice in metabolic cages and collected 24h urine after acclimating the mice in the new cages. Indeed, the GLUT2 deficient mice had ~1,800-fold increase in urine glucose levels (53.5 ±11 vs. 0.03 ±0.005 mg/24h) and exhibited an increased urine volume (2.5 ±0.3 vs. 0.9 ±0.3 mL/24h) and water intake (7.6 ±0.7 vs. 4.9 ±0.7 mL/24h) compared to their Ctrl littermates. The improvement in glucose tolerance in the kidney-specific Glut2 KO mice was independent of the insulin signaling because we did not observe any changes in insulin tolerance tests (ITT) (AUC for ITT, 10,982 ±414 vs. 11,275 ±583 mg/dL.min) and serum insulin levels (1.07 ±0.14 vs. 1.05 ±0.13 ng/mL) between the groups. Importantly, the kidney-specific GLUT2 deficient mice had normal serum creatinine (0.42 ±0.02 vs. 0.41 ±0.03 mg/dL), free fatty acid (0.43 ±0.14 vs. 0.53±0.14 nmol/µL), β-hydroxybutyrate (0.29 ±0.01 vs. 0.27 ±0.02 mM) and glucagon (14 ±4 vs. 10 ±1 pg/mL) levels. Moreover, the kidney-specific Glut2 KO mice had normal glomerular area (4,190 ±119 vs. 4,219 ±186 µm(2)) as measured by kidney histology and normal glomerular filtration rate (153 ±9 vs. 173 ±10 [µL/min/b.w.]/100) compared with their Ctrl littermates, indicating the absence of any known renal injury. Altogether, we have developed a new mouse model in which we can knockout Glut2 selectively in the kidneys in adult mice. We show that loss-of-function of kidney-specific GLUT2 improves glucose tolerance due to elevated glycosuria without producing any known side effects. In conclusion, blocking kidney-specific GLUT2 has the potential to treat diabetes. Oxford University Press 2021-05-03 /pmc/articles/PMC8090411/ http://dx.doi.org/10.1210/jendso/bvab048.661 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Diabetes Mellitus and Glucose Metabolism
de Souza Cordeiro, Leticia M
Devisetty, Nagavardhini
McDougal, David
Peters, Dorien J M
Chhabra, Kavaljit H
Renal GLUT2 is Essential in Regulating Systemic Glucose Homeostasis by Glycosuria
title Renal GLUT2 is Essential in Regulating Systemic Glucose Homeostasis by Glycosuria
title_full Renal GLUT2 is Essential in Regulating Systemic Glucose Homeostasis by Glycosuria
title_fullStr Renal GLUT2 is Essential in Regulating Systemic Glucose Homeostasis by Glycosuria
title_full_unstemmed Renal GLUT2 is Essential in Regulating Systemic Glucose Homeostasis by Glycosuria
title_short Renal GLUT2 is Essential in Regulating Systemic Glucose Homeostasis by Glycosuria
title_sort renal glut2 is essential in regulating systemic glucose homeostasis by glycosuria
topic Diabetes Mellitus and Glucose Metabolism
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090411/
http://dx.doi.org/10.1210/jendso/bvab048.661
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