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Jurczak, M.J.* ; Lee, H.Y.* ; Birkenfeld, A.L.* ; Jornayvaz, F.R.* ; Frederick, D.W.* ; Pongratz, R.L.* ; Zhao, X.* ; Moeckel, G.W.* ; Samuel, V.T.* ; Whaley, J.M.* ; Shulman, G.I.* ; Kibbey, R.G.*

SGLT2 deletion improves glucose homeostasis and preserves pancreatic beta-cell function.

Diabetes 60, 890-898 (2011)
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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
OBJECTIVE: Inhibition of the Na(+)-glucose cotransporter type 2 (SGLT2) is currently being pursued as an insulin-independent treatment for diabetes; however, the behavioral and metabolic consequences of SGLT2 deletion are unknown. Here, we used a SGLT2 knockout mouse to investigate the effect of increased renal glucose excretion on glucose homeostasis, insulin sensitivity, and pancreatic β-cell function. RESEARCH DESIGN AND METHODS: SGLT2 knockout mice were fed regular chow or a high-fat diet (HFD) for 4 weeks, or backcrossed onto the db/db background. The analysis used metabolic cages, glucose tolerance tests, euglycemic and hyperglycemic clamps, as well as isolated islet and perifusion studies. RESULTS: SGLT2 deletion resulted in a threefold increase in urine output and a 500-fold increase in glucosuria, as well as compensatory increases in feeding, drinking, and activity. SGLT2 knockout mice were protected from HFD-induced hyperglycemia and glucose intolerance and had reduced plasma insulin concentrations compared with controls. On the db/db background, SGLT2 deletion prevented fasting hyperglycemia, and plasma insulin levels were also dramatically improved. Strikingly, prevention of hyperglycemia by SGLT2 knockout in db/db mice preserved pancreatic β-cell function in vivo, which was associated with a 60% increase in β-cell mass and reduced incidence of β-cell death. CONCLUSIONS: Prevention of renal glucose reabsorption by SGLT2 deletion reduced HFD- and obesity-associated hyperglycemia, improved glucose intolerance, and increased glucose-stimulated insulin secretion in vivo. Taken together, these data support SGLT2 inhibition as a viable insulin-independent treatment of type 2 diabetes.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
ISSN (print) / ISBN 0012-1797
e-ISSN 1939-327X
Zeitschrift Diabetes
Quellenangaben Band: 60, Heft: 3, Seiten: 890-898 Artikelnummer: , Supplement: ,
Verlag American Diabetes Association
Verlagsort Alexandria, VA.
Begutachtungsstatus Peer reviewed
Institut(e) Institute for Pancreatic Beta Cell Research (IPI)