{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T23:13:47Z","timestamp":1791328427567,"version":"4.3.1"},"reference-count":19,"publisher":"American Diabetes Association","issue":"5","license":[{"start":{"date-parts":[[2016,11,1]],"date-time":"2016-11-01T00:00:00Z","timestamp":1477958400000},"content-version":"vor","delay-in-days":266,"URL":"http:\/\/www.diabetesjournals.org\/site\/license"}],"funder":[{"DOI":"10.13039\/100008349","name":"Boehringer Ingelheim","doi-asserted-by":"publisher","award":["U10-2392-01"],"award-info":[{"award-number":["U10-2392-01"]}],"id":[{"id":"10.13039\/100008349","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,5,1]]},"abstract":"<jats:p>Pharmacologically induced glycosuria elicits adaptive responses in glucose homeostasis and hormone release. In type 2 diabetes (T2D), along with decrements in plasma glucose and insulin levels and increments in glucagon release, sodium\u2013glucose cotransporter 2 (SGLT2) inhibitors induce stimulation of endogenous glucose production (EGP) and a suppression of tissue glucose disposal (TGD). We measured fasting and postmeal glucose fluxes in 25 subjects without diabetes using a double glucose tracer technique; in these subjects and in 66 previously reported patients with T2D, we also estimated lipolysis (from [2H5]glycerol turnover rate and circulating free fatty acids, glycerol, and triglycerides), lipid oxidation (LOx; by indirect calorimetry), and ketogenesis (from circulating \u03b2-hydroxybutyrate concentrations). In both groups, empagliflozin administration raised EGP, lowered TGD, and stimulated lipolysis, LOx, and ketogenesis. The pattern of glycosuria-induced changes was similar in subjects without diabetes and in those with T2D but quantitatively smaller in the former. With chronic (4 weeks) versus acute (first dose) drug administration, glucose flux responses were attenuated, whereas lipid responses were enhanced; in patients with T2D, fasting \u03b2-hydroxybutyrate levels rose from 246 \u00b1 288 to 561 \u00b1 596 \u00b5mol\/L (P &amp;lt; 0.01). We conclude that by shunting substantial amounts of carbohydrate into urine, SGLT2-mediated glycosuria results in a progressive shift in fuel utilization toward fatty substrates. The associated hormonal milieu (lower insulin-to-glucagon ratio) favors glucose release and ketogenesis.<\/jats:p>","DOI":"10.2337\/db15-1356","type":"journal-article","created":{"date-parts":[[2016,2,9]],"date-time":"2016-02-09T22:13:51Z","timestamp":1455056031000},"page":"1190-1195","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":654,"title":["Shift to Fatty Substrate Utilization in Response to Sodium\u2013Glucose Cotransporter 2 Inhibition in Subjects Without Diabetes and Patients With Type 2 Diabetes"],"prefix":"10.2337","volume":"65","author":[{"given":"Ele","family":"Ferrannini","sequence":"first","affiliation":[{"name":"CNR Institute of Clinical Physiology, Pisa, Italy"},{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 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":"Tim","family":"Heise","sequence":"additional","affiliation":[{"name":"Profil, Neuss, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Bizzotto","sequence":"additional","affiliation":[{"name":"CNR Institute of Neurosciences, Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Mari","sequence":"additional","affiliation":[{"name":"CNR Institute of Neurosciences, Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas R.","family":"Pieber","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria"}],"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":[[2016,2,9]]},"reference":[{"key":"2022031211334150600_B1","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1172\/JCI112981","article-title":"Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats","volume":"79","author":"Rossetti","year":"1987","journal-title":"J Clin Invest"},{"key":"2022031211334150600_B2","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":"2022031211334150600_B3","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":"2022031211334150600_B4","doi-asserted-by":"crossref","first-page":"E225","DOI":"10.1152\/ajpendo.90960.2008","article-title":"Decreased whole body lipolysis as a mechanism of the lipid-lowering effect of pioglitazone in type 2 diabetic patients","volume":"297","author":"Gastaldelli","year":"2009","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2022031211334150600_B5","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/ajcn\/33.1.27","article-title":"Total body water volumes for adult males and females estimated from simple anthropometric measurements","volume":"33","author":"Watson","year":"1980","journal-title":"Am J Clin Nutr"},{"key":"2022031211334150600_B6","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/S0169-2607(02)00097-4","article-title":"A circulatory model for calculating non-steady-state glucose fluxes. 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