{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T06:40:40Z","timestamp":1790404840527,"version":"4.1.0"},"reference-count":33,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2019,12,16]],"date-time":"2019-12-16T00:00:00Z","timestamp":1576454400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2020,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>\n                      To investigate the effect of dapagliflozin, a sodium\u2010glucose co\u2010transporter\u20102 (SGLT2) inhibitor, on renal gluconeogenesis\n                      <jats:italic>in vitro<\/jats:italic>\n                      ,\n                      <jats:italic>ex vivo<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>We treated HK\u20102 cells (human renal proximal tubule cells) and mouse primary renal proximal tubule cells with dapagliflozin, and evaluated the process of renal gluconeogenesis. We also examined the effect of dapagliflozin on renal gluconeogenesis in normoglycaemic and hyperglycaemic mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Dapagliflozin enhanced renal gluconeogenesis\n                      <jats:italic>in vitro, ex vivo<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      . It increased phosphoenolpyruvate carboxykinase (PEPCK), glucose\u20106\u2010phosphatase (G6Pase), peroxisome proliferative activated receptor\u2010gamma co\u2010activator 1\u03b1 (PGC\u20101\u03b1) and phosphorylated cyclic\u2010AMP response element binding protein (CREB) expression and decreased phosphorylated Forkhead Box O1 (FOXO1) expression in HK\u20102 cells, mouse primary renal proximal tubule cells, and the mouse renal cortex. Glutamine enhanced the gluconeogenic effect of dapagliflozin in HK\u20102 cells. Also, dapagliflozin increased\n                      <jats:sup>14<\/jats:sup>\n                      C\u2010glutamine utilization in HK\u20102 cells. Glucagon did not affect dapagliflozin\u2010induced enhancement in renal gluconeogenesis in HK\u20102 cells. SGLT2 gene knockdown with siRNA resulted in an increase of gluconeogenic gene expression and associated transcription factors in HK\u20102 cells. Dapagliflozin reduced fasting plasma glucose levels and improved oral glucose tolerance and insulin tolerance in high\u2010fat diet\u2010fed hyperglycaemic mice, although renal gluconeogenesis was enhanced.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Dapagliflozin increased levels of gluconeogenic enzyme in the renal cortex and consequently increased renal gluconeogenesis, which is mediated by SGLT2 inhibition.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.13905","type":"journal-article","created":{"date-parts":[[2019,11,6]],"date-time":"2019-11-06T08:28:26Z","timestamp":1573028906000},"page":"373-382","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Effect of dapagliflozin, a sodium\u2010glucose co\u2010transporter\u20102 inhibitor, on gluconeogenesis in proximal renal tubules"],"prefix":"10.1111","volume":"22","author":[{"given":"Jin Hee","family":"Kim","sequence":"first","affiliation":[{"name":"Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine  Seoul Republic of Korea"},{"name":"Department of Internal Medicine Yonsei University College of Medicine  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hae Young","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine Yonsei University College of Medicine  Seoul 120\u2010752 South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Jin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Yonsei University College of Medicine  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyangkyu","family":"Lee","sequence":"additional","affiliation":[{"name":"Biobehavioral Research Centre, Mo\u2010Im Kim Nursing Research Institute, College of Nursing, Yonsei University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"MiJin","family":"Yun","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine Yonsei University College of Medicine  Seoul 120\u2010752 South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0364-4675","authenticated-orcid":false,"given":"Eun Seok","family":"Kang","sequence":"additional","affiliation":[{"name":"Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine  Seoul Republic of Korea"},{"name":"Department of Internal Medicine Yonsei University College of Medicine  Seoul Republic of Korea"},{"name":"Institute of Endocrine Research, Yonsei University College of Medicine  Seoul South 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