title: AJS1669, a novel small-molecule muscle glycogen synthase activator, improves glucose metabolism and reduces body fat mass in mice.
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.
authors.affiliation: Innovation Promotion Department, Research Institute, EA Pharma Co., Ltd., Kawasaki, Kanagawa 210-868, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakano
authors.affiliation: Innovation Promotion Department, Research Institute, EA Pharma Co., Ltd., Kawasaki, Kanagawa 210-868, Japan.
authors.forename: Sen
authors.initials: S
authors.lastname: Takeshita
authors.affiliation: Nutrition and Health Science Group Frontier Research Laboratories, Institute for Innovation, Ajinomoto Co., Inc., Kawasaki, Kanagawa 210-8681, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Kawasaki
authors.affiliation: Business Development Department, EA Pharma Co., Ltd., Chuo-ku, Tokyo 104-0042, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Miyanaga
authors.affiliation: Novel Projects Research Group, Institute for Innovation, Ajinomoto Co., Inc., Kawasaki, Kanagawa 210-8681, Japan.
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Okamatsu
authors.affiliation: Innovation Promotion Department, Research Institute, EA Pharma Co., Ltd., Kawasaki, Kanagawa 210-868, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Dohi
authors.affiliation: Intellectual Property Department, EA Pharma Co., Ltd., Chuo-ku, Tokyo 104-0042, Japan.
authors.forename: Tadakiyo
authors.initials: T
authors.lastname: Nakagawa
mesh_terms: D050154:Adiposity / Q000187:drug effects*; D000284:Administration, Oral; D000818:Animals; D020536:Enzyme Activators / Q000737:chemistry / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D019298:Glucose-6-Phosphate / Q000378:metabolism*; D006006:Glycogen Synthase / Q000378:metabolism*; D008099:Liver / Q000201:enzymology; D051379:Mice; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000201:enzymology*
chemical_list: D020536:Enzyme Activators; D019298:Glucose-6-Phosphate; D006006:Glycogen Synthase