Complementary effects of dapagliflozin and lobeglitazone on metabolism in a diet-induced obese mouse model.

ABSTRACT

Thiazolidinedione, an insulin sensitizer, has beneficial effects on glucose metabolism; however, there are concerns regarding weight gain and heart failure. Sodium-glucose co-transporter 2 (SGLT2) inhibitors can reduce body weight, increase diuresis, and play a protective role in heart failure. We examined the complementary effects of dapagliflozin, an SGLT2 inhibitor, and lobeglitazone, a thiazolidinedione, in high-fat diet (HFD)-induced obese mice. We treated HFD-induced obese mice with vehicle, dapagliflozin, lobeglitazone, and their combination for 12 weeks. Oral glucose tolerance and insulin tolerance tests were performed after 12-week treatment, and body composition was measured by dual-energy X-ray absorptiometry before and after treatment. We analyzed oxygen consumption rate (OCR) using 3T3-L1 cells after treatment of ß-hydroxybutyrate and/or lobeglitazone. Treatment with a combination of dapagliflozin and lobeglitazone resulted in a significant decrease in postprandial hyperglycemia compared with dapagliflozin monotherapy, but not compared with lobeglitazone monotherapy. The addition of dapagliflozin to lobeglitazone treatment did not attenuate weight gain compared with lobeglitazone monotherapy in this study. However, this combination prevented the increase of organ weight of liver and heart, and OCR in 3T3-L1 cells was increased after treatment with a combination of ß-hydroxybutyrate and lobeglitazone compared to lobeglitazone monotherapy. We confirmed the beneficial effect of lobeglitazone on glucose metabolism; however, we did not find any beneficial effect of dapagliflozin on body weight in HFD-induced obese mice. However, the protective effects of dapagliflozin and lobeglitazone combined therapy on the liver, heart, energy consumption, and ß-cell senescence are worth investigating in clinical trials.