Abstract
BackgroundCanagliflozin is a sodium glucose co-transporter (SGLT) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus (T2DM).Methods 14C-alpha-methylglucoside uptake in Chinese hamster ovary-K cells expressing human, rat, or mouse SGLT2 or SGLT1; 3H-2-deoxy-d-glucose uptake in L6 myoblasts; and 2-electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed. Graded glucose infusions were performed to determine rate of urinary glucose excretion (UGE) at different blood glucose (BG) concentrations and the renal threshold for glucose excretion (RTG) in vehicle or canagliflozin-treated Zucker diabetic fatty (ZDF) rats. This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity.ResultsTreatment with canagliflozin 1 mg/kg lowered RTG from 415±12 mg/dl to 94±10 mg/dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RTG. Canagliflozin dose-dependently decreased BG concentrations in db/db mice treated acutely. In ZDF rats treated for 4 weeks, canagliflozin decreased glycated hemoglobin (HbA1c) and improved measures of insulin secretion. In obese animal models, canagliflozin increased UGE and decreased BG, body weight gain, epididymal fat, liver weight, and the respiratory exchange ratio.ConclusionsCanagliflozin lowered RTG and increased UGE, improved glycemic control and beta-cell function in rodent models of T2DM, and reduced body weight gain in rodent models of obesity.
Highlights
Due in part to the increasing prevalence of obesity and the aging of the global population, type 2 diabetes (T2DM) is becoming an increasingly prevalent disorder [1]
The majority of renal glucose resorption is mediated by sodium glucose cotransporter 2 (SGLT2), a high-capacity, low-affinity glucose transporter localized in the luminal membrane of early proximal renal tubular cells [3,4]
The filtered glucose not resorbed by SGLT2 is subsequently resorbed in more distal portions of the proximal tubule by SGLT1, a high-affinity, low-capacity glucose transporter and is transported from the proximal tubular cell into the renal interstitium by the facilitative glucose transporter 1 (GLUT1) [3,4]
Summary
Due in part to the increasing prevalence of obesity and the aging of the global population, type 2 diabetes (T2DM) is becoming an increasingly prevalent disorder [1]. As plasma glucose concentrations increase above normal, UGE remains negligible until the filtered glucose load begins to saturate the capacity of the renal glucose transporters. The majority of renal glucose resorption is mediated by sodium glucose cotransporter 2 (SGLT2), a high-capacity, low-affinity glucose transporter localized in the luminal membrane of early proximal renal tubular cells [3,4]. Once transported by SGLT2 into the tubular cell, glucose is transported down its concentration gradient and into the renal interstitium by the facilitative glucose transporter 2 (GLUT2) [3,4]. The filtered glucose not resorbed by SGLT2 is subsequently resorbed in more distal portions of the proximal tubule by SGLT1, a high-affinity, low-capacity glucose transporter and is transported from the proximal tubular cell into the renal interstitium by the facilitative GLUT1 [3,4]. Canagliflozin is a sodium glucose co-transporter (SGLT) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus (T2DM)
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