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