Febuxostat Improves Insulin Resistance in the Skeletal Muscle In Vitro and In Vivo

Abstract

Hyperuricemia is closely associated with various metabolic disorders such as diabetes, hypertension, dyslipidemia, and cardiovascular diseases. Xanthine oxidoreductase (XOR) is a key enzyme known to catalyze purines to uric acid. Febuxostat is an orally-active, potent, non-purine, selective XOR inhibitor. However, the effect of febuxostat on glucose and insulin metabolism has not been fully elucidated. Therefore, we investigated the effect of febuxostat on insulin sensitivity in male Wistar rats. Insulin sensitivity was evaluated by the hyperinsulinemic-euglycemic glucose clamp studies (at 25 mU/kg/min insulin infusion rate) after an 8-hour fast. Male Wistar rats were 60% high fat diet containing with either febuxostat (∼4 mg/kg/day) or not, for 4 weeks. The glucose infusion rate and insulin-stimulated glucose disposal rate were significantly increased by 12% and 17%, respectively. But hepatic glucose output was no significant change between two groups. Consistent with the clamp data, the insulin-stimulated phosphorylation of Akt and AMPK were significantly increased by 90% and 53%, respectively, only in skeletal muscle of febuxostat treated rats. Next, to investigate whether this effect is direct or indirect, we examined the effect of febuxostat in the differentiated C2C12 cells. The treatment of 10 μM febuxostat for 48 hours significantly increased the phosphorylation of Akt and AMPK by 65% (P=0.017) and 43% (P=0.028) in the differentiated C2C12 cells, respectively. These results suggest that this effect of febuxostat is direct. In conclusion, these findings indicate the possibility that febuxostat acts directly on the skeletal muscle and improves insulin resistance. Disclosure C.T. Moriya: None. H. Satoh: None. H. Watada: Advisory Panel; Self; AstraZeneca. Consultant; Self; Astellas Pharma US, Inc., AstraZeneca, Boehringer Ingelheim GmbH, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Novartis AG, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Takeda Development Center Asia, Pte. Ltd.. Research Support; Self; Abbott, Astellas Pharma US, Inc., AstraZeneca, Bayer AG, Benefit One Health Care Co., Ltd., Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Johnson & Johnson Diabetes Institute, LLC., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nitto Boseki Co., Ltd., Novartis AG, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Terumo Medical Corporation.