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PLoS One. 2015 Jan 23;10(1):e0116851. doi: 10.1371/journal.pone.0116851. eCollection 2015.

Beneficial effects of canagliflozin in combination with pioglitazone on insulin sensitivity in rodent models of obese type 2 diabetes.

Author information

1
Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan; Department of Pharmacology, Saitama Medical University, Saitama, Japan.
2
Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan.
3
Safety Research Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan.
4
Department of Pharmacology, Saitama Medical University, Saitama, Japan.

Abstract

BACKGROUND:

Despite its insulin sensitizing effects, pioglitazone may induce weight gain leading to an increased risk of development of insulin resistance. A novel sodium glucose co-transporter 2 (SGLT2) inhibitor, canagliflozin, provides not only glycemic control but also body weight reduction through an insulin-independent mechanism. The aim of this study was to investigate the combined effects of these agents on body weight control and insulin sensitivity.

METHODS:

Effects of combination therapy with canagliflozin and pioglitazone were evaluated in established diabetic KK-Ay mice and prediabetic Zucker diabetic fatty (ZDF) rats.

RESULTS:

In the KK-Ay mice, the combination therapy further improved glycemic control compared with canagliflozin or pioglitazone monotherapy. Furthermore, the combination significantly attenuated body weight and fat gain induced by pioglitazone and improved hyperinsulinemia. In the ZDF rats, early intervention with pioglitazone monotherapy almost completely prevented the progressive development of hyperglycemia, and no further improvement was observed by add-on treatment with canagliflozin. However, the combination significantly reduced pioglitazone-induced weight gain and adiposity and improved the Matsuda index, suggesting improved whole-body insulin sensitivity.

CONCLUSIONS:

Our study indicates that combination therapy with canagliflozin and pioglitazone improves insulin sensitivity partly by preventing glucotoxicity and, at least partly, by attenuating pioglitazone-induced body weight gain in two different obese diabetic animal models. This combination therapy may prove to be a valuable option for the treatment and prevention of obese type 2 diabetes.

PMID:
25615826
PMCID:
PMC4304810
DOI:
10.1371/journal.pone.0116851
[Indexed for MEDLINE]
Free PMC Article

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