title: Contributions of hepatic gluconeogenesis suppression and compensative glycogenolysis on the glucose-lowering effect of CS-917, a fructose 1,6-bisphosphatase inhibitor, in non-obese type 2 diabetes Goto-Kakizaki rats.
abstract: Contributions of gluconeogenesis suppression in liver, kidney, and intestine as major gluconeogenic organs to the glucose-lowering effect of CS-917, a fructose 1,6-bisphosphatase inhibitor, was evaluated in overnight-fasted Goto-Kakizaki (GK) rats. CS-917 decreased plasma glucose by suppressing glucose release and lactate uptake from liver but not from kidney and intestine. These results suggest that hepatic gluconeogenesis suppression predominantly contributes to the glucose-lowering effect of CS-917 in GK rats. Moreover, the mechanism by which CS-917 decreased plasma glucose more in overnight-fasted GK rats than in non-fasted ones was investigated. Lactate uptake from liver was suppressed by 15 mg/kg of CS-917 in both states, but glucose release from liver and plasma glucose were decreased only in the overnight-fasted state. CS-917 at 30 mg/kg decreased hepatic glycogen content in both states and depleted it in the overnight-fasted state. In the non-fasted GK rats, co-administration of CS-917 with CP-91149, a glycogen phosphorylase inhibitor, suppressed hepatic glycogen reduction by CS-917 and decreased plasma glucose more than single administration of CS-917. These results suggest that gluconeogenesis suppression by CS-917 was counteracted by hepatic glycogenolysis especially in the non-fasted state and that combination therapy with CS-917 and CP-91149 is efficacious to decrease plasma glucose in GK rats.
authors.affiliation: Cardiovascular-Metabolics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan. yoshida.taishi.bc@daiichisankyo.co.jp
authors.forename: Taishi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Akira
authors.initials: A
authors.lastname: Okuno
authors.forename: Kanako
authors.initials: K
authors.lastname: Takahashi
authors.forename: Junko
authors.initials: J
authors.lastname: Ogawa
authors.forename: Yuka
authors.initials: Y
authors.lastname: Hagisawa
authors.forename: Shoichi
authors.initials: S
authors.lastname: Kanda
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Fujiwara
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D005215:Fasting / Q000502:physiology; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D050261:Glycogenolysis / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010447:Peptide Hydrolases / Q000378:metabolism; D051381:Rats
chemical_list: D000577:Amides; D001786:Blood Glucose; C110844:CP 91149; D007004:Hypoglycemic Agents; D007211:Indoles; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D019344:Lactic Acid; C502805:N,N'-((5-(2-amino-5-(2-methylpropyl)-4-thiazolyl)-2-furanyl)phosphinylidene)bis(alanine) diethyl ester; D010447:Peptide Hydrolases; C020152:fructose 1,6-bisphosphatase converting enzyme; D005947:Glucose; D000409:Alanine