Dapagliflozin, a Selective SGLT2 Inhibitor, Improves Glucose Homeostasis in Normal and Diabetic Rats

Abstract

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.

SHR3824, a novel selective inhibitor of renal sodium glucose cotransporter 2, exhibits antidiabetic efficacy in rodent models

“…These increases were much more apparent within the first 6 h rather than 6 h to 24 h postdose administration and were accompanied by an obvious decrease in blood glucose levels, demonstrating the ability of acute oral administration of SHR3824 to reduce blood glucose levels by enhancing urinary glucose excretion in diabetic rats and mice. BMS512148 showed pharmacological effects that were similar to SHR3824, consistent with previous reports using other SGLT2 inhibitors in glucose intolerant rodents, including rats fed a high-fat diet and Zucker fatty rats and mice [13,28] .…”

“…Furthermore, the HbA1c levels in GK rats were also dose-dependently reduced after 38 d of treatment, suggesting that the hyperglycemia in these type 2 diabetic animal models can be treated by chronic administration of the SGLT2 inhibitor SHR3824. Although SGLT2 inhibitors have been demonstrated to decrease body weight in clinical studies, the chronic administration of SHR3824 affected neither the body weight nor the food intake in GK rats or db/db mice, as reported previously by several other SGLT2 inhibitor studies [13,29] .…”

“…The correction of hyperglycemia by the inhibition of SGLT2 is thought to improve this metabolic disorder. Two weeks of treatment with dapagliflozin improved glucose utilization and was accompanied by reduced glucose production and enhanced glucose influx into liver tissue, but the treatment showed no effect on glucose uptake in skeletal muscle and adipose tissue [13] . Similar results have been described for other SGLT-2 inhibitors, for example, T-1095 and empagliflozin [14,15] .…”

“…As the first rate-limiting step in skeletal muscle glucose metabolism, glucose uptake is markedly impaired under diabetic conditions [33] . A few studies have demonstrated that long-term treatment with SGLT2 inhibitors could enhance insulin sensitivity in the livers of type 2 diabetic animal models, but did not effect insulin sensitivity in muscle and adipose tissue [13][14][15] . In this study, a significant decrease in serum insulin levels www.chinaphar.com Yan PK et al Acta Pharmacologica Sinica npg was observed after chronic treatment with SHR3824 that was accompanied by decreased fasting blood glucose and HbA1c levels, suggesting that whole-body insulin sensitivity was improved.…”

“…Subsequently, several companies developed SGLT2 inhibitors that lacked the disadvantages of phlorizin, and some of these compounds have progressed to late stage clinical trials or are even available for clinical use [9][10][11][12]. One of the earliest selective SGLT2 inhibitors reported, dapagliflozin (formerly known as BMS512148), was shown to be a selective and orally effective SGLT2 inhibitor able to induce renal glucose excretion and reduce glucose excursions in normal and diabetic rats [13] .…”