Pioglitazone-induced body weight gain is prevented by combined administration with the lipoprotein lipase activator...

Pioglitazone improves insulin resistance in diabetics but often causes body weight gain. The lipoprotein lipase activator NO-1886 has been shown to exert both anti-obesity and anti-insulin-resistance effects. In this study, we investigated the effect of the combined administration of pioglitazone with NO-1886 (pioglitazone+NO-1886) in preventing body weight gain in insulin-resistant, high-fat fed rats. The rats were fed a standard or high-fat diet for 16 weeks. The high-fat fed rats were randomized at week 9 into 4 groups (i.e., control, pioglitazone (30 mg/kg/day), NO-1886 (100mg/kg/day), and pioglitazone+NO-1886 (30 and 100mg/kg/day, respectively)). The high-fat fed control rats developed obesity and insulin resistance. After 7 weeks of drug treatment, pioglitazone+NO-1886 was found to prevent the body weight gain caused by pioglitazone alone (pioglitazone+NO-1886: Δ76.0 ± 16.8 g vs. pioglitazone: Δ127.8 ± 39.5 g, P<0.05) and to increase glucose infusion rate during insulin clamp, compared with the results in the high-fat fed control group. No differences in plasma nonesterified fatty acid, leptin, adiponectin, glucose, or insulin levels were observed between the pioglitazone+NO-1886 and the pioglitazone-alone groups. However, plasma total cholesterol and HDL-cholesterol levels were significantly increased and plasma triglyceride levels were slightly decreased in the pioglitazone+NO-1886 group, compared with the values in the pioglitazone-alone group. In summary, the combined administration of pioglitazone and NO-1886 prevented the pioglitazone-induced body weight gains and ameliorated insulin resistance observed in high-fat fed rats. These results indicate that combined therapy with pioglitazone and NO-1886 may be beneficial for the treatment of type 2 diabetes.