Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats.
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.


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.
Han
Songping
S
Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, New Jersey, USA.
Hagan
Deborah L
DL
Taylor
Joseph R
JR
Xin
Li
L
Meng
Wei
W
Biller
Scott A
SA
Wetterau
John R
JR
Washburn
William N
WN
Whaley
Jean M
JM
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001559:Benzhydryl Compounds; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D003001:Cloning, Molecular; D005947:Glucose / Q000378:metabolism; D005960:Glucosides / Q000627:therapeutic use*; D006801:Humans; D051381:Rats; D011924:Rats, Zucker; D012016:Reference Values; D051247:Sodium-Glucose Transport Proteins / Q000037:antagonists & inhibitors*; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors / Q000235:genetics; D051297:Sodium-Glucose Transporter 2 / Q000235:genetics; D000077203:Sodium-Glucose Transporter 2 Inhibitors
D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; C495674:SLC5A1 protein, human; C089180:SLC5A2 protein, human; C495676:Slc5a1 protein, rat; C490300:Slc5a2 protein, rat; D051247:Sodium-Glucose Transport Proteins; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C529054:dapagliflozin; D005947:Glucose