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Blocking tubular SGLT2 and spilling glucose into the urine, which triggers a metabolic counter-regulation similar to fasting, provides unique benefits, not only as an anti-hyperglycemic strategy. These include a low hypoglycemia risk and a shift from carbohydrate to lipid utilization and mild ketogenesis, thereby reducing body weight and providing an additional energy source. SGLT2 inhibitors counteract hyperreabsorption in the early proximal tubule, which acutely lowers glomerular pressure and filtration and thereby reduces the physical stress on the filtration barrier, the filtration of tubule-toxic compounds, and the oxygen demand for tubular reabsorption. This improves cortical oxygenation, which, together with lesser tubular gluco-toxicity and improved mitochondrial function and autophagy, can reduce pro-inflammatory, pro-senescence, and pro-fibrotic signaling and preserve tubular function and GFR in the long-term. By shifting transport downstream, SGLT2 inhibitors more equally distribute the transport burden along the nephron and may mimic systemic hypoxia to stimulate erythropoiesis, which improves oxygen delivery to the kidney and other organs. SGLT1 inhibition improves glucose homeostasis by delaying intestinal glucose absorption and by increasing the release of gastrointestinal incretins. Combined SGLT1 and SGLT2 inhibition has additive effects on renal glucose excretion and blood glucose control. SGLT1 in the macula densa senses luminal glucose, which affects glomerular hemodynamics and has implications for blood pressure control. More studies are needed to better define the therapeutic potential of SGLT1 inhibition to protect the kidney, alone or in combination with SGLT2 inhibition.<\/jats:p>","DOI":"10.3390\/kidneydial2020032","type":"journal-article","created":{"date-parts":[[2022,6,19]],"date-time":"2022-06-19T10:14:52Z","timestamp":1655633692000},"page":"349-368","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["The Pathophysiological Basis of Diabetic Kidney Protection by Inhibition of SGLT2 and SGLT1"],"prefix":"10.3390","volume":"2","author":[{"given":"Yuji","family":"Oe","sequence":"first","affiliation":[{"name":"Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, La Jolla, CA 92161, USA"},{"name":"VA San Diego Healthcare System, San Diego, CA 92161, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"Vallon","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, La Jolla, CA 92161, USA"},{"name":"VA San Diego Healthcare System, San Diego, CA 92161, USA"},{"name":"Department of Pharmacology, University of California San Diego, La Jolla, CA 92161, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.diabres.2017.03.024","article-title":"IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040","volume":"128","author":"Ogurtsova","year":"2017","journal-title":"Diabetes Res. 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