Intestinal TGR5 agonism improves hepatic steatosis and insulin sensitivity in Western diet-fed mice.

Takeda G protein-coupled receptor 5 (TGR5) agonists induce systemic release of glucagon-like peptides (GLPs) from intestinal L cells, a potentially therapeutic action against metabolic diseases such as nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and Type 2 diabetes. Historically, TGR5 agonist use has been hindered by side effects, including inhibition of gallbladder emptying. Here, we characterize RDX8940, a novel, orally administered TGR5 agonist designed to have minimal systemic effects and investigate its activity in mice fed a Western diet, a model of NAFLD and mild insulin resistance. Agonist activity, binding selectivity, toxicity, solubility, and permeability of RDX8940 were characterized in standard in vitro models. RDX8940 pharmacokinetics and effects on GLP secretion, insulin sensitivity, and liver steatosis were assessed in C57BL/6 mice fed normal or Western diet chow and given single or repeated doses of RDX8940 or vehicle, with or without dipeptidyl peptidase-4 (DPP4) inhibitors. Gallbladder effects were assessed in CD-1 mice fed normal chow and given RDX8940 or a systemic TGR5 agonist or vehicle. Our results showed that RDX8940 is minimally systemic, potent, and selective, and induces incretin (GLP-1, GLP-2, and peptide YY) secretion. RDX8940-induced increases in plasma active GLP-1 (aGLP-1) levels were enhanced by repeated dosing and by coadministration of DPP4 inhibitors. RDX8940 increased hepatic exposure to aGLP-1 without requiring coadministration of a DPP4 inhibitor. In mice fed a Western diet, RDX8940 improved liver steatosis and insulin sensitivity. Unlike systemic TGR5 agonists, RDX8940 did not inhibit gallbladder emptying. These results indicate that RDX8940 may have therapeutic potential in patients with NAFLD/NASH. NEW & NOTEWORTHY Takeda G protein-coupled receptor 5 (TGR5) agonists have potential as a treatment for nonalcoholic steatohepatitis and nonalcoholic fatty liver disease (NAFLD) but have until now been associated with undesirable side effects associated with systemic TGR5 agonism, including blockade of gallbladder emptying. We demonstrate that RDX8940, a potent, selective, minimally systemic oral TGR5 agonist, improves liver steatosis and insulin sensitivity in a mouse model of NAFLD and does not inhibit gallbladder emptying in mice.

Angiomyofibroblastoma of the vulva.

Angiomyofibroblastoma is a rare, recently described, distinctive benign mesenchymal tumor that occurs mainly in the vulvar region of premenopausal women. We report a case of angiomyofibroblastoma of the vulva. A 45-year-old woman reported a small, painless nodule on the left vulva which rapidly enlarged during the 6 months before she visited the hospital. Local examination showed a pedunculated, mobile mass on the superior aspect of the left labium majus (13 x 12 x 10 cm) with elastic texture. Left vulvectomy was performed and the excised specimen revealed a well-defined and multilobulated tumor with edematous changes on gross examination. Microscopically, the tumor had alternate hyper- and hypocellular areas characterized by benign-looking round- to spindle-shaped cells with eosinophilic cytoplasm. The tumor cells were admixed with scattered thin-walled vessels in an edematous stroma. Immunohistochemical analysis was diffusely positive for desmin, estrogen receptor and progesterone receptor; reactive in small focus for actin; and negative for S-100 and CD34. Angiomyofibroblastoma, a mesenchymal tumor, was diagnosed. The postoperative course was smooth with no recurrence during the following 8 months. Simple excision for angiomyofibroblastoma is recommended because local recurrence or metastasis has not been reported.