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Published online March 20, 2008
Diabetes 57:1723-1729, 2008
DOI: 10.2337/db07-1472
© 2008 by the American Diabetes Association
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Dapagliflozin, a Selective SGLT2 Inhibitor, Improves Glucose Homeostasis in Normal and Diabetic Rats

Songping Han1, Deborah L. Hagan1, Joseph R. Taylor1, Li Xin1, Wei Meng2, Scott A. Biller2,3, John R. Wetterau1,4, William N. Washburn2, and Jean M. Whaley1

1 Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, New Jersey
2 Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development, Princeton, New Jersey
3 Novartis Institute for Biomedical Research, Cambridge, Massachusetts
4 Cerenis Therapeutics, Ann Arbor, Michigan

Corresponding author: Jean M. Whaley, Bristol-Myers Squibb Research and Development, 311 Pennington Rocky Hill Rd., Mail Code 21-2.01, Pennington, NJ 08534. E-mail: jean.whaley{at}bms.com

Abbreviations: EC50, half-maximal response; FPG, fasting plasma glucose; SGLT, sodium-glucose cotransporter

OBJECTIVE—The inhibition of gut and renal sodium-glucose cotransporters (SGLTs) has been proposed as a novel therapeutic approach to the treatment of diabetes. We have identified dapagliflozin as a potent and selective inhibitor of the renal sodium-glucose cotransporter SGLT2 in vitro and characterized its in vitro and in vivo pharmacology.

RESEARCH DESIGN AND METHODS—Cell-based assays measuring glucose analog uptake were used to assess dapagliflozin's ability to inhibit sodium-dependent and facilitative glucose transport activity. Acute and multi-dose studies in normal and diabetic rats were performed to assess the ability of dapagliflozin to improve fed and fasting plasma glucose levels. A hyperinsulinemic-euglycemic clamp study was performed to assess the ability of dapagliflozin to improve glucose utilization after multi-dose treatment.

RESULTS—Dapagliflozin potently and selectively inhibited human SGLT2 versus human SGLT1, the major cotransporter of glucose in the gut, and did not significantly inhibit facilitative glucose transport in human adipocytes. In vivo, dapagliflozin acutely induced renal glucose excretion in normal and diabetic rats, improved glucose tolerance in normal rats, and reduced hyperglycemia in Zucker diabetic fatty (ZDF) rats after single oral doses ranging from 0.1 to 1.0 mg/kg. Once-daily dapagliflozin treatment over 2 weeks significantly lowered fasting and fed glucose levels at doses ranging from 0.1 to 1.0 mg/kg and resulted in a significant increase in glucose utilization rate accompanied by a significant reduction in glucose production.

CONCLUSIONS—These data suggest that dapagliflozin has the potential to be an efficacious treatment for type 2 diabetes.


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