Effect of canagliflozin on renal threshold for glucose, glycemia, and body weight in normal and diabetic animal models - PubMed (original) (raw)

doi: 10.1371/journal.pone.0030555. Epub 2012 Feb 15.

Kenji Arakawa, Kiichiro Ueta, Yasuaki Matsushita, Chiaki Kuriyama, Tonya Martin, Fuyong Du, Yi Liu, June Xu, Bruce Conway, Jamie Conway, David Polidori, Kirk Ways, Keith Demarest

Affiliations

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

Yin Liang et al. PLoS One. 2012.

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

Competing Interests: The authors have read the journal's policy and have the following conflicts: Drs. Liang, Martin, Du, Conway, Polidori, and Demarest are employees of Johnson & Johnson Pharmaceutical Research & Development, LLC. Drs. Arakawa, Ueta, Matsushita, and Kuriyama are employees of Mitsubishi Tanabe Pharma Corporation, Japan. Canagliflozin (JNJ-28431754/TA-7284) is being developed by Johnson & Johnson Pharmaceutical Research & Development, LLC. in collaboration with Mitsubishi Tanabe Pharma Corporation. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1

Figure 1. Inhibitory effects of canagliflozin on human SGLT1 and human SGLT2.

The inhibitory effect of canagliflozin on 14C-AMG uptake in CHOK-hSGLT1 and CHOK-hSGLT2 has been measured in 5 experiments. A typical inhibitory effect on CHOK-hSGLT1 (Panel A) and CHOK-hSGLT2 (Panel B) from a single experiment is presented here.

Figure 2

Figure 2. BG and UGE in untreated and CANA-treated ZDF rats during two GGI studies.

In the first study (GGI only), a GGI was given to untreated ZDF rats (n = 8) to raise BG from 212±24 mg/dl to ∼475 mg/dl over 90 minutes. In the second study (Insulin+GGI), ZDF rats (n = 6/group) were treated with either vehicle or canagliflozin (1 mg/kg), then given insulin to lower BG to 25±1 mg/dl, and finally given the GGI to slowly raise BG. BG and UGE were measured every 5 minutes. Results shown are mean ± S.E. GGI, graded glucose infusion; BG, blood glucose; UGE, urinary glucose excretion; ZDF, Zucker diabetic fatty rats; GG1, graded glucose infusion.

Similar articles

Cited by

References

    1. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27:1047–1053. - PubMed
    1. Hoerger TJ, Segel JE, Gregg EW, Saaddine JB. Is glycemic control improving in U.S. adults? Diabetes Care. 2008;31:81–86. - PubMed
    1. Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med. 2007;261:32–43. - PubMed
    1. Wright EM, Turk E. The sodium/glucose cotransport family SLC5. Pflügers Arch - Eur J Physiol. 2004;447:510–518. - PubMed
    1. Kloeckener-Gruissem B, Vandekerckhove K, Nürnberg G, Neidhardt J, Zeitz C, et al. Mutation of solute carrier SLC16A12 associates with a syndrome combining juvenile cataract with microcornea and renal glucosuria. Am J Hum Genet. 2008;82:772–779. - PMC - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources