Renal threshold for glucose: physiological basis and relationship with water metabolism. A narrative review
DOI:
https://doi.org/10.12775/PPS.2026.31.69828Keywords
renal glucose threshold, SGLT2, osmolality, cellular dehydration, ADH, osmotic diuresis, diabetes mellitus, water metabolism, glucose reabsorption, aquaporins, нирковий поріг глюкози, осмолярність, клітинна дегідратація, АДГ, осмотичний діурез, цукровий діабет, водний обмін, аквапориниAbstract
Background. The renal glucose threshold (RGT) is traditionally regarded as a passive consequence of sodium-glucose cotransporter type 2 (SGLT2) saturation in the proximal tubules of the nephron. However, this explanation addresses only the molecular mechanism, leaving unanswered the fundamental physiological question: why did evolution set this threshold precisely at 8–10 mmol/L? We propose that the answer lies not in the limitations of transport systems, but in the active protection of osmotic homeostasis and cellular hydration.
Objective. To propose a new conceptual model of the RGT based on the priority of protecting cellular hydration over preserving glucose as an energy substrate, and to demonstrate the pathophysiological relationship between glycaemic regulation and water-electrolyte metabolism in diabetes mellitus.
Methods. A narrative review of current literature on renal physiology, osmoregulation, molecular biology of glucose transporters, and clinical diabetology was conducted. The search was performed in the PubMed, Scopus, and Web of Science databases.
Results. The RGT (8–10 mmol/L) mathematically corresponds to the upper limit of normal plasma osmolality (295 mOsm/kg). Glucosuria is a physiologically programmed protective mechanism that prevents critical hyperosmolality and protects cells from osmotic stress. In type 2 diabetes mellitus (T2DM), the adaptive increase in maximum tubular glucose reabsorption (Tm_G) and RGT is a pathological phenomenon contributing to chronic hyperglycaemia and cellular dehydration. SGLT2 inhibitors restore the physiological threshold and the protective mechanism of glucosuria. Studies of the osmoregulatory function of the kidneys during the development of experimental diabetes mellitus confirm impairment of urinary osmotic concentration already at the early stages of the disease (Olenovych et al., 2020; Olenovych & Zukow, 2022; Olenovych et al., 2025).
Conclusions. The RGT is an evolutionarily formed mechanism for the protection of cellular hydration. Understanding this principle opens new perspectives for interpreting the pathophysiology of diabetes mellitus and the mechanisms of action of modern glucose-lowering drugs
References
Alsahli, M., & Gerich, J. E. (2020). Renal glucose metabolism in normal physiological conditions and in diabetes. Diabetes Research and Clinical Practice, 133, 1–9. https://doi.org/10.1016/j.diabres.2017.07.033
Bankir, L., Bichet, D. G., & Morgenthaler, N. G. (2017). Vasopressin: physiology, assessment and osmosensation. Journal of Internal Medicine, 282(4), 284–297. https://doi.org/10.1111/joim.12645
Biber, J., Hernando, N., & Forster, I. (2013). Phosphate transporters and their function. Annual Review of Physiology, 75, 535–550. https://doi.org/10.1146/annurev-physiol-030212-183748
Boychuk, T. M., Olenovych, O. A., & Gozhenko, A. I. (2016). Peculiarities of ionoregulatory renal function disorder in case of diabetes mellitus. Pharmacologyonline, 3, 1–5.
Boychuk, T. M., Olenovych, O. A., & Gozhenko, A. I. (2017). Role of dyslipidemia in the development and progression of diabetic nephropathy. Pharmacologyonline, 2, 169–174.
Boychuk, T. M., Olenovych, O. A., Hrytsyuk, M. I., & Gozhenko, A. I. (2017). Peculiarities of functional state of kidneys disorders in the early period of experimental diabetes mellitus. International Journal of Endocrinology (Ukraine), 13(6), 463–467. https://doi.org/10.22141/2224-0721.13.6.2017.112894
Boychuk, T. M., Olenovych, O. A., & Gozhenko, A. I. (2018). Peculiarities of excretory renal function in the early period of alloxan-induced experimental diabetes. Visnyk Morskoi Medytsyny, 3(80), 102–109. https://doi.org/10.5281/zenodo.1450849
Brenner, B. M., Hostetter, T. H., & Humes, H. D. (1978). Glomerular permselectivity: barrier function based on discrimination of molecular size and charge. American Journal of Physiology, 234(6), F455–F460. https://doi.org/10.1152/ajprenal.1978.234.6.F455
Burg, M. B., Kwon, E. D., & Kültz, D. (1997). Regulation of gene expression by hypertonicity. Annual Review of Physiology, 59, 437–455. https://doi.org/10.1146/annurev.physiol.59.1.437
Calado, J., Loeffler, J., Sakallioglu, O., Gok, F., Lhotta, K., Barata, J., & Rueff, J. (2006). Familial renal glucosuria: SLC5A2 mutation analysis and evidence of salt-wasting. Kidney International, 69(5), 852–855. https://doi.org/10.1038/sj.ki.5000194
Calado, J., Sznajer, Y., Metzger, D., Rita, A., Hogan, M. C., Kattamis, A., Scharf, M., Tasic, V., Greil, J., Brinkert, F., Kemper, M. J., & Santer, R. (2008). Twenty-one additional cases of familial renal glucosuria: absence of genetic heterogeneity, high prevalence of private mutations and further evidence of volume depletion. Nephrology Dialysis Transplantation, 23(12), 3874–3879. https://doi.org/10.1093/ndt/gfn386
Chasis, H., Jolliffe, N., & Smith, H. W. (1933). The action of phlorizin on the excretion of glucose, xylose, sucrose, creatinine and urea by man. Journal of Clinical Investigation, 12(6), 1083–1090. https://doi.org/10.1172/JCI100555
Cherney, D. Z., Perkins, B. A., Soleymanlou, N., Maione, M., Lai, V., Lee, A., Fagan, N. M., Woerle, H. J., Johansen, O. E., Broedl, U. C., & von Eynatten, M. (2014). Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation, 129(5), 587–597. https://doi.org/10.1161/CIRCULATIONAHA.113.005081
Cheuvront, S. N., & Kenefick, R. W. (2014). Dehydration: physiology, assessment, and performance effects. Comprehensive Physiology, 4(1), 257–285. https://doi.org/10.1002/cphy.c130017
Christensen, E. I., Verroust, P. J., & Nielsen, R. (2012). Receptor-mediated endocytosis in renal proximal tubule. Pflügers Archiv – European Journal of Physiology, 458(6), 1039–1048. https://doi.org/10.1007/s00424-009-0685-8
Davison, J. M., & Hytten, F. E. (1974). Glomerular filtration during and after pregnancy. Journal of Obstetrics and Gynaecology of the British Commonwealth, 81(8), 588–595. https://doi.org/10.1111/j.1471-0528.1974.tb00522.x
DeFronzo, R. A. (2009). Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes, 58(4), 773–795. https://doi.org/10.2337/db09-9028
DeFronzo, R. A., Hompesch, M., Kasichayanula, S., Liu, X., Hong, Y., Pfister, M., Morrow, L. A., Leslie, B. R., Boulton, D. W., Ching, A., LaCreta, F. P., & Griffen, S. C. (2013). Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care, 36(10), 3169–3176. https://doi.org/10.2337/dc13-0387
Deng, D., Xu, C., Sun, P., Wu, J., Yan, C., Hu, M., & Yan, N. (2014). Crystal structure of the human glucose transporter GLUT1. Nature, 510(7503), 121–125. https://doi.org/10.1038/nature13306
Dotsyuk, L. H., Kushnir, I. H., & Olenovych, O. A. (2012). Glomerulotubular balance in experimental nephritis in young and old rats. Bukovinian Medical Herald, 16(1), 126–128.
Ferrannini, E., Muscelli, E., Frascerra, S., Baldi, S., Mari, A., Heise, T., Broedl, U. C., & Woerle, H. J. (2014). Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. Journal of Clinical Investigation, 124(2), 499–508. https://doi.org/10.1172/JCI72227
Finkelstein, A. (1987). Water movement through lipid bilayers, pores, and plasma membranes: theory and reality. Wiley-Interscience.
Gerich, J. E. (2010). Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabetic Medicine, 27(2), 136–142. https://doi.org/10.1111/j.1464-5491.2009.02894.x
Goldenberg, R. M., Berard, L. D., Cheng, A. Y. Y., Gilbert, J. D., Verma, S., Woo, V. C., & Yale, J. F. (2016). SGLT2 inhibitor-associated diabetic ketoacidosis: clinical review and recommendations for prevention and diagnosis. Clinical Therapeutics, 38(12), 2654–2664. https://doi.org/10.1016/j.clinthera.2016.11.002
Gozhenko, A. I., Kuznetsova, H. S., Olenovych, O. A., Kuznetsov, S. H., Kuznetsova, K. S., & Byts, T. N. (2017). The number of circulating endotheliocytes in the blood plasma of the patients with diabetes mellitus increases. Pharmacologyonline, 3, 23–26.
Gronda, E., Palazzuoli, A., Iacoviello, M., Correale, M., & Napoli, C. (2023). Renal oxygen demand and nephron function: is glucose a friend or foe? International Journal of Molecular Sciences, 24(12), 9957. https://doi.org/10.3390/ijms24129957
Handelsman, Y., Henry, R. R., Bloomgarden, Z. T., Dagogo-Jack, S., DeFronzo, R. A., Einhorn, D., Ferrannini, E., Fonseca, V. A., Garber, A. J., Grunberger, G., LeRoith, D., Umpierrez, G. E., & Weir, M. R. (2016). American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of SGLT-2 inhibitors and diabetic ketoacidosis. Endocrine Practice, 22(6), 753–762. https://doi.org/10.4158/EP161292.PS
Häussinger, D., Roth, E., Lang, F., & Gerok, W. (1994). Cellular hydration state: an important determinant of protein catabolism in health and disease. The Lancet, 341(8856), 1330–1332. https://doi.org/10.1016/0140-6736(93)90828-5
Heerspink, H. J. L., Perkins, B. A., Fitchett, D. H., Husain, M., & Cherney, D. Z. I. (2016). Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation, 134(10), 752–772. https://doi.org/10.1161/CIRCULATIONAHA.116.021887
Heerspink, H. J. L., Stefánsson, B. V., Correa-Rotter, R., Chertow, G. M., Greene, T., Hou, F. F., Mann, J. F. E., McMurray, J. J. V., Lindberg, M., Rossing, P., Sjöström, C. D., Toto, R. D., Langkilde, A. M., & Wheeler, D. C. (2020). Dapagliflozin in patients with chronic kidney disease. New England Journal of Medicine, 383(15), 1436–1446. https://doi.org/10.1056/NEJMoa2024816
Hillier, T. A., Abbott, R. D., & Barrett, E. J. (1999). Hyponatremia: evaluating the correction factor for hyperglycemia. American Journal of Medicine, 106(4), 399–403. https://doi.org/10.1016/S0002-9343(99)00055-8
Hotait, Z. S., Cascio, J. N. L., Bhatt, D. K., & Bhatt, D. L. (2022). The sugar daddy: the role of the renal proximal tubule in glucose homeostasis. American Journal of Physiology – Cell Physiology, 323(3), C791–C803. https://doi.org/10.1152/ajpcell.00225.2022
Hummel, C. S., Lu, C., Loo, D. D. F., Bhatt, D. L., Bhatt, D. K., & Wright, E. M. (2011). Glucose transport by human renal Na⁺/D-glucose cotransporters SGLT1 and SGLT2. American Journal of Physiology – Cell Physiology, 300(1), C14–C21. https://doi.org/10.1152/ajpcell.00444.2010
International Diabetes Federation. (2023). IDF Diabetes Atlas (11th ed.). IDF. https://www.diabetesatlas.org
Kanai, Y., Lee, W. S., You, G., Brown, D., & Hediger, M. A. (1994). The human kidney low affinity Na⁺/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. Journal of Clinical Investigation, 93(1), 397–404. https://doi.org/10.1172/JCI116972
Kitabchi, A. E., Umpierrez, G. E., Miles, J. M., & Fisher, J. N. (2009). Hyperglycemic crises in adult patients with diabetes. Diabetes Care, 32(7), 1335–1343. https://doi.org/10.2337/dc09-9032
Knepper, M. A., Kwon, T. H., & Nielsen, S. (2015). Molecular physiology of water balance. New England Journal of Medicine, 372(14), 1349–1358. https://doi.org/10.1056/NEJMra1404726
Koeppen, B. M., & Stanton, B. A. (2013). Renal physiology (5th ed.). Elsevier.
Kriz, W., & Kaissling, B. (2008). Structural organization of the mammalian kidney. In R. J. Alpern & S. C. Hebert (Eds.), Seldin and Giebisch's The Kidney: Physiology and Pathophysiology (4th ed., pp. 479–563). Academic Press.
Kuznetsova, H. S., Kuznetsova, K. S., Olenovych, O. A., Gozhenko, O. A., Kuznetsov, S. H., & Gozhenko, A. I. (2018). The desquamation of the endothelium due to normalization of glycemia decreases in patients with diabetes mellitus. Pharmacologyonline, 2, 74–81.
Levey, A. S., Stevens, L. A., Schmid, C. H., Zhang, Y. L., Castro, A. F., Feldman, H. I., Kusek, J. W., Eggers, P., Van Lente, F., Greene, T., & Coresh, J. (2009). A new equation to estimate glomerular filtration rate. Annals of Internal Medicine, 150(9), 604–612. https://doi.org/10.7326/0003-4819-150-9-200905050-00006
Marton, A., Kaneko, T., Kovalik, J. P., Yasuda, M., Nishiyama, A., Kitada, K., & Titze, J. (2024). Organ protection by SGLT2 inhibitors: role of metabolic energy and water conservation. Nature Reviews Nephrology, 17(1), 65–77. https://doi.org/10.1038/s41581-020-00350-x
Masuda, T., & Nagata, D. (2024). Mechanism and evidence of SGLT2 inhibitors for the treatment of heart failure. Journal of Clinical Medicine, 13(2), 447. https://doi.org/10.3390/jcm13020447
Maunsbach, A. B., & Christensen, E. I. (1992). Functional ultrastructure of the proximal tubule. In E. E. Windhager (Ed.), Handbook of Physiology: Renal Physiology (pp. 41–107). Oxford University Press.
McMurray, J. J. V., Solomon, S. D., Inzucchi, S. E., Køber, L., Kosiborod, M. N., Martinez, F. A., Ponikowski, P., Sabatine, M. S., Anand, I. S., Bělohlávek, J., Böhm, M., Chiang, C. E., Chopra, V. K., de Boer, R. A., Desai, A. S., Diez, M., Drozdz, J., Dukát, A., Ge, J., … Wiviott, S. D. (2019). Dapagliflozin in patients with heart failure and reduced ejection fraction. New England Journal of Medicine, 381(21), 1995–2008. https://doi.org/10.1056/NEJMoa1911303
Mogensen, C. E. (1976). Renal function changes in diabetes. Diabetes, 25(2 Suppl), 872–879. https://doi.org/10.2337/diab.25.2.S872
Mudaliar, S., Polidori, D., Zambrowicz, B., & Henry, R. R. (2015). Sodium-glucose cotransporter inhibitors: effects on renal and intestinal glucose transport: from bench to bedside. Diabetes Care, 38(12), 2344–2353. https://doi.org/10.2337/dc15-0642
Neal, B., Perkovic, V., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Erondu, N., Shaw, W., Law, G., Desai, M., & Matthews, D. R. (2017). Canagliflozin and cardiovascular and renal events in type 2 diabetes. New England Journal of Medicine, 377(7), 644–657. https://doi.org/10.1056/NEJMoa1611925
Nielsen, S., Frøkiær, J., Marples, D., Kwon, T. H., Agre, P., & Knepper, M. A. (2002). Aquaporins in the kidney: from molecules to medicine. Physiological Reviews, 82(1), 205–244. https://doi.org/10.1152/physrev.00024.2001
Olenovych, O. A. (2019). Pathophysiology of proteinuria in the early period of alloxan-induced experimental diabetes. Journal of Nephrology and Transplantation, 3(2).
Olenovych, O. A. (2020). Renin-angiotensin system in the regulation of excretory renal function in experimental diabetes mellitus. International Journal of Endocrinology (Ukraine), 16(8), 76–82. https://doi.org/10.22141/2224-0721.16.8.2020.222880
Olenovych, O. A. (2020a). Features of the ionoregulatory function of rat kidneys in the dynamics of experimental diabetes mellitus development against the background of pharmacological blockade of the renin-angiotensin-aldosterone system. Klinichna ta Eksperymentalna Patolohiia, 19(4), 42–52. https://doi.org/10.24061/1727-4338.XIX.4.74.2020.7
Olenovych, O. A. (2020b). Features of the acid-excretory function of rat kidneys in the dynamics of experimental diabetes mellitus development against the background of pharmacological blockade of the renin-angiotensin-aldosterone system. Visnyk Vinnytskoho Natsionalnoho Medychnoho Universytetu, 24(3), 381–388. https://doi.org/10.31393/reports-vnmedical-2020-24(3)-02
Olenovych, O. A. (2020c). Pathophysiology of proteinuria in the dynamics of development of alloxan-induced experimental diabetes mellitus. Visnyk Medychnykh i Biolohichnykh Doslidzhen, 4, 53–58. https://doi.org/10.11603/bmbr.2706-6290.2020.4.11806
Olenovych, O. A. (2020d). Changes in the acid-excretory function of rat kidneys in the dynamics of experimental diabetes mellitus development. Eksperymentalna i Klinichna Medytsyna, 4, 22–29. https://doi.org/10.35339/ekm.2020.89.04.03
Olenovych, O. A. (2020e). Mechanisms of formation of tubulointerstitial renal damage at the initial stages of experimental diabetes mellitus development. Medytsyna Sohodni i Zavtra, 4, 13–19. https://doi.org/10.35339/msz.2020.89.04.02
Olenovych, O. A. (2021). Effect of chronic hyperglycaemia on the development of tubulointerstitial syndrome in experimental diabetes mellitus. Visnyk Medychnykh i Biolohichnykh Doslidzhen, 1, 80–86. https://doi.org/10.11603/bmbr.2706-6290.2021.1.12091
Olenovych, O. A. (2021a). Pathogenetic aspects of the development of tubulointerstitial syndrome in alloxan-induced experimental diabetes mellitus. Visnyk Vinnytskoho Natsionalnoho Medychnoho Universytetu, 25(1), 17–21. https://doi.org/10.31393/reports-vnmedical-2021-25(1)-03
Olenovych, O. A. (2023). Peculiarities of ionoregulatory renal function of rats in the dynamics of experimental diabetes mellitus development. International Journal of Endocrinology (Ukraine), 19(2), 118–124. https://doi.org/10.22141/2224-0721.19.2.2023.1256
Olenovych, O. A., & Zukow, W. (2022). Osmotic concentration of urine in the dynamics of the development of alloxan-induced experimental diabetes. Journal of Education, Health and Sport, 12(10), 389–400. https://doi.org/10.12775/JEHS.2022.12.10.045
Olenovych, O. A., Boychuk, T. M., & Gozhenko, A. I. (2020). Renal mechanisms of carbohydrate status regulation in the dynamics of experimental diabetes mellitus development. Aktualni Problemy Transportnoi Medytsyny, 4, 144–151. https://doi.org/10.5281/zenodo.4396183
Olenovych, O. A., Boychuk, T. M., Davydenko, I. S., & Davydenko, O. M. (2024). Histomorphological peculiarities of the pancreatic parenchyma in rats with alloxan-induced diabetes of different duration. Neonatology, Surgery and Perinatal Medicine (Ukraine), 14(2), 100–107. https://doi.org/10.24061/2413-4260.XIV.2.52.2024.15
Olenovych, O. A., Gozhenko, A. I., & Nikitenko, O. P. (2020). Features of the osmoregulatory function of the kidneys in the dynamics of experimental diabetes mellitus development. Visnyk Morskoi Medytsyny, 4, 101–111. https://doi.org/10.5281/zenodo.4430780
Olenovych, O. A., Gozhenko, A. I., & Cheban, E. (2025). Features of tubular transport of osmotically active substances and osmoregulatory processes in the dynamics of alloxan-induced experimental diabetes mellitus development. Visnyk Morskoi Medytsyny, 2(107), 207–214. https://doi.org/10.5281/zenodo.15881586
Olenovych, O., Gozhenko, A., & Tkach, Ye. (2024a). Peculiarities of transtubular transport of calcium and phosphates in the dynamics of the development of alloxan-induced experimental diabetes mellitus. Romanian Journal of Diabetes Nutrition and Metabolic Diseases, 31(4), 411–419. https://doi.org/10.46389/rjd-2024-1736
Packer, M., Anker, S. D., Butler, J., Filippatos, G., Pocock, S. J., Carson, P., Januzzi, J., Verma, S., Tsutsui, H., Brueckmann, M., Jamal, W., Kimura, K., Schnee, J., Zeller, C., Cotton, D., Bocchi, E., Böhm, M., Choi, D. J., Chopra, V., … Zannad, F. (2020). Cardiovascular and renal outcomes with empagliflozin in heart failure. New England Journal of Medicine, 383(15), 1413–1424. https://doi.org/10.1056/NEJMoa2022190
Palmer, B. F., & Clegg, D. J. (2015). Electrolyte and acid-base disturbances in patients with diabetes mellitus. New England Journal of Medicine, 373(6), 548–559. https://doi.org/10.1056/NEJMra1503102
Perkovic, V., Jardine, M. J., Neal, B., Bompoint, S., Heerspink, H. J. L., Charytan, D. M., Edwards, R., Agarwal, R., Bakris, G., Bull, S., Cannon, C. P., Capuano, G., Chu, P. L., de Zeeuw, D., Greene, T., Levin, A., Pollock, C., Wheeler, D. C., Yavin, Y., … Mahaffey, K. W. (2019). Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. New England Journal of Medicine, 380(24), 2295–2306. https://doi.org/10.1056/NEJMoa1811744
Pickup, J. C. (2012). Monitoring glucose. BMJ, 344, e1702. https://doi.org/10.1136/bmj.e1702
Quamme, G. A. (1997). Renal magnesium handling: new insights in understanding old problems. Kidney International, 52(5), 1180–1195. https://doi.org/10.1038/ki.1997.443
Rahmoune, H., Thompson, P. W., Ward, J. M., Smith, C. D., Hong, G., & Brown, J. (2005). Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes, 54(12), 3427–3434. https://doi.org/10.2337/diabetes.54.12.3427
Rose, B. D., & Post, T. W. (2001). Clinical physiology of acid-base and electrolyte disorders (5th ed.). McGraw-Hill.
Sands, J. M., & Layton, H. E. (2021). Advances in understanding the urine-concentrating mechanism. Annual Review of Physiology, 71, 481–501. https://doi.org/10.1146/annurev.physiol.010908.163240
Santer, R., & Calado, J. (2010). Familial renal glucosuria and SGLT2: from a Mendelian trait to a therapeutic target. Clinical Journal of the American Society of Nephrology, 5(1), 133–141. https://doi.org/10.2215/CJN.04010609
Santer, R., Kinner, M., Lassen, C. L., Schneppenheim, R., Eggert, P., Bald, M., Brodehl, J., Daschner, M., Ehrich, J. H. H., Kemper, M., Li Volti, S., Neuhaus, T., Skovby, F., Swift, P. G. F., Schaub, J., & Klaerke, D. (2003). Molecular analysis of the SGLT2 gene in patients with renal glucosuria. Journal of the American Society of Nephrology, 14(11), 2873–2882. https://doi.org/10.1097/01.ASN.0000092790.89332.D2
Scheen, A. J. (2015). Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs, 75(1), 33–59. https://doi.org/10.1007/s40265-014-0337-y
Schrier, R. W. (2010). Body fluid volume regulation in health and disease: a unifying hypothesis. Annals of Internal Medicine, 113(2), 155–159. https://doi.org/10.7326/0003-4819-113-2-155
Seifter, J. L. (2014). Integration of acid-base and electrolyte disorders. New England Journal of Medicine, 371(19), 1821–1831. https://doi.org/10.1056/NEJMra1215672
Shannon, J. A., Farber, S., & Troast, L. (1941). The measurement of glucose Tm in the normal dog. American Journal of Physiology, 133, 752–761. https://doi.org/10.1152/ajplegacy.1941.133.4.752
Silverman, M. (1981). Glucose and water transport in the proximal nephron. Annual Review of Physiology, 43, 131–142. https://doi.org/10.1146/annurev.ph.43.030181.001023
Smith, H. W. (1951). The kidney: Structure and function in health and disease. Oxford University Press.
Spellman, M. J., Assaf, T., Nangia, S., Bhatt, D. K., & Bhatt, D. L. (2024). Handling the sugar rush: the role of the renal proximal tubule. American Journal of Physiology – Renal Physiology, 326(4), F521–F535. https://doi.org/10.1152/ajprenal.00265.2024
Stachteas, P., Nasoufidou, A., Patoulias, D., Samaras, A., Karagiannidis, E., Tsapas, A., & Fragakis, N. (2024). SGLT2 inhibitors in heart failure: mechanisms of action and clinical implications. Journal of Clinical Medicine, 13(4), 1013. https://doi.org/10.3390/jcm13041013
Stoner, G. D. (2005). Hyperosmolar hyperglycemic state. American Family Physician, 71(9), 1723–1730.
The EMPA-KIDNEY Collaborative Group. (2023). Empagliflozin in patients with chronic kidney disease. New England Journal of Medicine, 388(2), 117–127. https://doi.org/10.1056/NEJMoa2204233
Thorens, B., & Mueckler, M. (2010). Glucose transporters in the 21st Century. American Journal of Physiology – Endocrinology and Metabolism, 298(2), E141–E145. https://doi.org/10.1152/ajpendo.00712.2009
Tikkanen, I., Narko, K., Zeller, C., Green, A., Salsali, A., Broedl, U. C., & Woerle, H. J. (2015). Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care, 38(3), 420–428. https://doi.org/10.2337/dc14-1096
Tuttle, K. R., Bakris, G. L., Bilous, R. W., Chiang, J. L., de Boer, I. H., Goldstein-Fuchs, J., Hirsch, I. B., Kalantar-Zadeh, K., Narva, A. S., Navaneethan, S. D., Neumiller, J. J., Patel, U. D., Ratner, R. E., Whaley-Connell, A. T., & Molitch, M. E. (2014). Diabetic kidney disease: a report from an ADA Consensus Conference. Diabetes Care, 37(10), 2864–2883. https://doi.org/10.2337/dc14-1296
Upadhyay, A. (2024). SGLT2 inhibitors and kidney protection: mechanisms beyond tubuloglomerular feedback. Kidney360, 5(1), 143–153. https://doi.org/10.34067/KID.0000000000000416
Vallon, V., & Thomson, S. C. (2020). The tubular hypothesis of nephron filtration and diabetic kidney disease. Nature Reviews Nephrology, 16(6), 317–336. https://doi.org/10.1038/s41581-020-0256-y
Wanner, C., Inzucchi, S. E., Lachin, J. M., Fitchett, D., von Eynatten, M., Mattheus, M., Johansen, O. E., Woerle, H. J., Broedl, U. C., & Zinman, B. (2016). Empagliflozin and progression of kidney disease in type 2 diabetes. New England Journal of Medicine, 375(4), 323–334. https://doi.org/10.1056/NEJMoa1515920
Wiviott, S. D., Raz, I., Bonaca, M. P., Mosenzon, O., Kato, E. T., Cahn, A., Silverman, M. G., Zelniker, T. A., Kuder, J. F., Murphy, S. A., Bhatt, D. L., Leiter, L. A., McGuire, D. K., Wilding, J. P. H., Ruff, C. T., Gause-Nilsson, I. A. M., Fredriksson, M., Johansson, P. A., Langkilde, A. M., & Sabatine, M. S. (2019). Dapagliflozin and cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine, 380(4), 347–357. https://doi.org/10.1056/NEJMoa1812389
Wright, E. M., Loo, D. D. F., & Hirayama, B. A. (2011). Biology of human sodium glucose transporters. Physiological Reviews, 91(2), 733–794. https://doi.org/10.1152/physrev.00055.2009
Zinman, B., Wanner, C., Lachin, J. M., Fitchett, D., Bluhmki, E., Hantel, S., Mattheus, M., Devins, T., Johansen, O. E., Woerle, H. J., Broedl, U. C., & Inzucchi, S. E. (2015). Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. New England Journal of Medicine, 373(22), 2117–2128. https://doi.org/10.1056/NEJMoa1504720
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Anatoliy Gozhenko, Walery Zukow, Olha Olenovych, Olena Gozhenko
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
The periodical offers access to content in the Open Access system under the Creative Commons Attribution-NonCommercial-ShareAlike 4.0
Stats
Number of views and downloads: 47
Number of citations: 0
