Selective PPARγ modulator INT131 normalizes insulin signaling defects and improves bone mass in diet-induced obese mice

摘要: INT131 is a potent non-thiazolidinedione (TZD)-selective peroxisome proliferator-activated receptor-γ modulator being developed for the treatment of type 2 diabetes. In preclinical studies and phase II clinical trial, has been shown to lower glucose levels ameliorate insulin resistance without typical TZD side effects. To determine whether insulin-sensitizing action mediated by effects on insulin-mediated homeostasis signaling, high-fat diet-induced obese (DIO) insulin-resistant mice treated with were studied. INT131's bone density also investigated. Treatment enhanced systemic sensitivity, as revealed in fasted state an increase area above curve during tolerance test. These independent changes adiposity. Insulin-stimulated PI3K activity skeletal muscle adipose tissue DIO was significantly reduced ∼50–65%, but this restored completely therapy. The are most likely due increased IRS-1 tyrosine phosphorylation. Concurrently, Akt phosphorylation after mice. Importantly, therapy caused significant mineral alteration circulating osteocalcin these data suggest that newly agent, INT131, normalizes obesity-related defects signaling target tissues mechanism involved glycemic control. If confirmed humans, could be used treating diabetes loss mass.