AJS1669, a novel small-molecule muscle glycogen synthase activator, improves glucose metabolism and reduces body fat mass in mice

Nakano,Kazuhiro; Takeshita,Sen; Kawasaki,Noriko; Miyanaga,Wataru; Okamatsu,Yoriko; Dohi,Mizuki; Nakagawa,Tadakiyo

doi:10.3892/ijmm.2017.2909

AJS1669, a novel small-molecule muscle glycogen synthase activator, improves glucose metabolism and reduces body fat mass in mice

Authors:
- Kazuhiro Nakano
- Sen Takeshita
- Noriko Kawasaki
- Wataru Miyanaga
- Yoriko Okamatsu
- Mizuki Dohi
- Tadakiyo Nakagawa
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Affiliations: Innovation Promotion Department, Research Institute, EA Pharma Co., Ltd., Kawasaki, Kanagawa 210-868, Japan, Nutrition and Health Science Group Frontier Research Laboratories, Institute for Innovation, Ajinomoto Co., Inc., Kawasaki, Kanagawa 210-8681, Japan, Business Development Department, EA Pharma Co., Ltd., Chuo-ku, Tokyo 104-0042, Japan, Novel Projects Research Group, Institute for Innovation, Ajinomoto Co., Inc., Kawasaki, Kanagawa 210-8681, Japan, Intellectual Property Department, EA Pharma Co., Ltd., Chuo-ku, Tokyo 104-0042, Japan
Published online on: March 7, 2017 https://doi.org/10.3892/ijmm.2017.2909
Pages: 841-850
Copyright: © Nakano et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Impaired glycogen synthesis and turnover are common in insulin resistance and type 2 diabetes. As glycogen synthase (GS) is a key enzyme involved in the synthetic process, it presents a promising therapeutic target for the treatment of type 2 diabetes. In the present study, we identified a novel, potent and orally available GS activator AJS1669 {sodium 2-[[5-[[4-(4,5-difluoro-2-methylsulfanyl-phenyl)phenoxy] methyl]furan-2-carbonyl]-(2-furylmethyl)amino] acetate}. In vitro, we performed a glycogen synthase 1 (GYS1) activation assay for screening GS activators and identified that the activity of AJS1669 was further potentiated in the presence of glucose-6-phosphate (G6P). In vivo, we used ob/ob mice to evaluate the novel anti-diabetic effects of AJS1669 by measuring basal blood glucose levels, glucose tolerance and body fat mass index. Repeated administration of AJS1669 over 4 weeks reduced blood glucose and hemoglobin A1c (HbA1c) levels in ob/ob mice. AJS1669 also improved glucose tolerance in a dose-dependent manner, and decreased body fat mass. The mRNA levels of genes involved in mitochondrial fatty acid oxidation and mitochondrial biogenesis were elevated in skeletal muscle tissue following AJS1669 treatment. Hepatic tissue of treated mice also exhibited elevated expression of genes associated with fatty acid oxidation. In contrast to ob/ob mice, in C57Bl/6 mice AJS1669 administration did not alter body weight or reduce glucose levels. These results demonstrate that pharmacological agents that activate GYS1, the main GS subtype found in skeletal muscle, have potential for use as novel treatments for diabetes that improve glucose metabolism in skeletal muscle.

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