{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:11:16Z","timestamp":1791231076093,"version":"4.1.0"},"reference-count":36,"publisher":"American Diabetes Association","issue":"6","license":[{"start":{"date-parts":[[2017,5,22]],"date-time":"2017-05-22T00:00:00Z","timestamp":1495411200000},"content-version":"vor","delay-in-days":62,"URL":"http:\/\/www.diabetesjournals.org\/content\/license"}],"funder":[{"name":"Italian Ministry of Education, University, and Research","award":["2010329EKE"],"award-info":[{"award-number":["2010329EKE"]}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,6,1]]},"abstract":"<jats:sec>\n                    <jats:title>OBJECTIVE<\/jats:title>\n                    <jats:p>Pharmacologically induced glycosuria elicits adaptive responses in glucose homeostasis and hormone release, including decrements in plasma glucose and insulin levels, increments in glucagon release, enhanced lipolysis, and stimulation of ketogenesis, resulting in an increase in ketonemia. We aimed at assessing the renal response to these changes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                    <jats:p>We measured fasting and postmeal urinary excretion of glucose, \u03b2-hydroxybutyrate (\u03b2-HB), lactate, and sodium in 66 previously reported patients with type 2 diabetes and preserved renal function (estimated glomerular filtration rate \u226560 mL \u00b7 min\u22121 \u00b7 1.73 m\u22122) and in control subjects without diabetes at baseline and following empagliflozin treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>With chronic (4 weeks) sodium\u2013glucose cotransporter 2 inhibition, baseline fractional glucose excretion (&amp;lt;2%) rose to 38 \u00b1 12% and 46 \u00b1 11% (fasting vs. postmeal, respectively; P &amp;lt; 0.0001) over a range of BMIs (range 23\u201341 kg\/m2) and creatinine clearance (65\u2013168 mL \u00b7 min\u22121 \u00b7 m\u22122). Excretion of \u03b2-HB (median [interquartile range]: 0.08 [0.10] to 0.31 [0.43] \u00b5mol \u00b7 min\u22121), lactate (0.06 [0.06] to 0.28 [0.25] \u00b5mol \u00b7 min\u22121), and sodium (0.27 [0.22] to 0.36 [0.16] mEq \u00b7 min\u22121) all increased (P \u2264 0.001 for all) and were each positively related to glycosuria (P \u2264 0.001). These parameters changed in the same direction in subjects without diabetes, but changes were smaller than in the patients with diabetes. Although plasma N-terminal pro\u2013B-type natriuretic peptide levels were unaltered, plasma erythropoietin concentrations increased by 31 (64)% (P = 0.0078).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>We conclude that the sodium\u2013glucose cotransporter 2 inhibitor\u2013induced increase in \u03b2-HB is not because of reduced renal clearance but because of overproduction. The increased lactate excretion contributes to lower plasma lactate levels, whereas the increased natriuresis may help in normalizing the exchangeable sodium pool. Taken together, glucose loss through joint inhibition of glucose and sodium reabsorption in the proximal tubule induces multiple changes in renal metabolism.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/dc16-2724","type":"journal-article","created":{"date-parts":[[2017,3,21]],"date-time":"2017-03-21T20:27:55Z","timestamp":1490128075000},"page":"771-776","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":168,"title":["Renal Handling of Ketones in Response to Sodium\u2013Glucose Cotransporter 2 Inhibition in Patients With Type 2 Diabetes"],"prefix":"10.2337","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1384-1584","authenticated-orcid":false,"given":"Ele","family":"Ferrannini","sequence":"first","affiliation":[{"name":"CNR Institute of Clinical Physiology, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Baldi","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Frascerra","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenno","family":"Astiarraga","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Barsotti","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aldo","family":"Clerico","sequence":"additional","affiliation":[{"name":"CNR Institute of Clinical Physiology, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elza","family":"Muscelli","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2017,3,21]]},"reference":[{"key":"2022031301431413900_B1","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/nrendo.2011.243","article-title":"SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects","volume":"8","author":"Ferrannini","year":"2012","journal-title":"Nat Rev Endocrinol"},{"key":"2022031301431413900_B2","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1172\/JCI72227","article-title":"Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients","volume":"124","author":"Ferrannini","year":"2014","journal-title":"J Clin Invest"},{"key":"2022031301431413900_B3","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.2337\/db15-1356","article-title":"Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes","volume":"65","author":"Ferrannini","year":"2016","journal-title":"Diabetes"},{"key":"2022031301431413900_B4","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.2337\/dc15-0843","article-title":"Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition","volume":"38","author":"Peters","year":"2015","journal-title":"Diabetes Care"},{"key":"2022031301431413900_B5","doi-asserted-by":"crossref","first-page":"2849","DOI":"10.1210\/jc.2015-1884","article-title":"SGLT2 inhibitors may predispose to ketoacidosis","volume":"100","author":"Taylor","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031301431413900_B6","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.2337\/dc15-1380","article-title":"Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors","volume":"38","author":"Rosenstock","year":"2015","journal-title":"Diabetes Care"},{"key":"2022031301431413900_B7","unstructured":"U.S. Food and Drug Administration. 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