Effect of canagliflozin on renal threshold for glucose, glycemia, and body weight in normal and diabetic animal models

PLoS One. 2012;7(2):e30555. doi: 10.1371/journal.pone.0030555. Epub 2012 Feb 15.


Background: Canagliflozin is a sodium glucose co-transporter (SGLT) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus (T2DM).

Methods: (14)C-alpha-methylglucoside uptake in Chinese hamster ovary-K cells expressing human, rat, or mouse SGLT2 or SGLT1; (3)H-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 (RT(G)) 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.

Results: Treatment with canagliflozin 1 mg/kg lowered RT(G) 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 RT(G). 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.

Conclusions: Canagliflozin lowered RT(G) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism*
  • Body Weight / drug effects*
  • CHO Cells
  • Canagliflozin
  • Cells, Cultured
  • Cricetinae
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Glucose Tolerance Test
  • Glucosides / therapeutic use*
  • Humans
  • Hyperglycemia / drug therapy*
  • Hyperglycemia / metabolism
  • Hyperglycemia / pathology
  • Kidney / drug effects
  • Kidney / physiopathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Rats
  • Rats, Zucker
  • Sodium-Glucose Transport Proteins / genetics
  • Sodium-Glucose Transport Proteins / metabolism
  • Sodium-Glucose Transporter 1 / genetics
  • Sodium-Glucose Transporter 1 / metabolism
  • Sodium-Glucose Transporter 2 / genetics
  • Sodium-Glucose Transporter 2 / metabolism
  • Sodium-Glucose Transporter 2 Inhibitors
  • Thiophenes / therapeutic use*
  • Weight Gain / drug effects


  • Blood Glucose
  • Glucosides
  • SLC5A4 protein, human
  • Slc5a1 protein, rat
  • Slc5a2 protein, rat
  • Sodium-Glucose Transport Proteins
  • Sodium-Glucose Transporter 1
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors
  • Thiophenes
  • Canagliflozin