An active metabolite in the rheumatoid arthritis treatment leflunomide may inhibit a protein that affects insulin-receptor signaling in mice, making the anti-inflammatory drug a potentially effective treatment for type 2 diabetes, according to study findings published in the Journal of Endocrinology.
Individuals with rheumatoid arthritis have a higher risk for developing type 2 diabetes and obesity than those without rheumatoid arthritis, Xiulong Xo, PhD, professor at the Institute of Comparative Medicine at Yangzhou University, China, and colleagues wrote in the study background. Currently, patients with both rheumatoid arthritis and diabetes are treated with diabetes and rheumatoid arthritis drugs separately, they noted, and a treatment targeting both would benefit patients with both conditions.
“We studied how leflunomide works at a molecular level and found that it targets a protein involved in desensitizing the insulin receptor, which is responsible for instructing the cells to start absorbing sugar from the bloodstream,” Xo said in a press release. “We know some inflammatory factors can also desensitize the insulin receptor, and leflunomide is an anti-inflammatory, so it may be that it controls blood sugar partly by its anti-inflammatory effect.”
Xo and colleagues found that the inhibition of S6K1 activity by A77 1726, an active metabolite in leflunomide, led to the inhibition of insulin-receptor signaling in mouse and rat myotubes, as well as in mouse adipocytes under both normal and insulin-resistance conditions.
The researchers also investigated the anti-hyperglycemic effect of leflunomide in obese and high-fat diet-induced diabetes mouse models, as well as mice fed a normal chow diet. They found that leflunomide treatment normalized blood glucose levels and overcame insulin resistance in glucose and insulin tolerance tests in the high-fat-diet mice; however, treatment had no effect on mice fed a normal chow diet.
“Our results suggest that leflunomide sensitizes the [insulin resistance] by inhibiting S6K1 activity in vitro, and that leflunomide could be potentially useful for treating patients with both [rheumatoid arthritis] and diabetes,” the researchers wrote.
The researchers plan to conduct clinical trials with leflunomide in humans. – by Regina Schaffer
Disclosures: The authors report no relevant financial disclosures.