title: CS-917, a fructose 1,6-bisphosphatase inhibitor, improves postprandial hyperglycemia after meal loading in non-obese type 2 diabetic Goto-Kakizaki rats.
abstract: Postprandial hyperglycemia is one of the features of type 2 diabetes. Increased hepatic gluconeogenesis is a predominant cause of postprandial hyperglycemia in type 2 diabetes. In this study, we evaluated the effect of gluconeogenesis inhibition on postprandial hyperglycemia using CS-917, a novel inhibitor of fructose 1,6-bisphphosphatase (FBPase) which is one of the rate-limiting enzymes of gluconeogenesis. The suppressive effect of CS-917 on postprandial hyperglycemia was evaluated in a meal loading test in Goto-Kakizaki (GK) rats, non-obese type 2 diabetic animal model characterized by impaired insulin secretion. In addition, we describe acute effect of CS-917 on fasting hyperglycemia in overnight-fasted GK rats and chronic effect of CS-917 in multiple dosing GK rats.CS-917 suppressed plasma glucose elevation after meal loading in a dose-dependent manner at doses ranging from 10 to 40 mg/kg. In an overnight-fasted state, CS-917 decreased the plasma glucose levels dose-dependently at doses ranging from 2.5 to 40 mg/kg. Consistent with the inhibition of FBPase, glucose-lowering was associated with an accumulation of hepatic d-fructose 1,6-bisphosphate and a reduction in hepatic d-fructose 6-phosphate. Chronic treatment of CS-917 decreased plasma glucose significantly, and no significant increase in plasma lactate and no profound elevation in plasma triglycerides were observed by both acute and chronic treatment of CS-917 in GK rats.These findings suggest that enhanced gluconeogenesis contributes to hyperglycemia in postprandial conditions as well as in fasting conditions, and that CS-917 as an FBPase inhibitor corrects postprandial hyperglycemia as well as fasting hyperglycemia.
authors.affiliation: Biological Research Laboratories II, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, 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: Masanori
authors.initials: M
authors.lastname: Izumi
authors.forename: Kanako
authors.initials: K
authors.lastname: Takahashi
authors.forename: Yuka
authors.initials: Y
authors.lastname: Hagisawa
authors.forename: Jun
authors.initials: J
authors.lastname: Ohsumi
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Fujiwara
mesh_terms: D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006597:Fructose-Bisphosphatase / Q000037:antagonists & inhibitors; D005635:Fructosediphosphates / Q000378:metabolism; D005636:Fructosephosphates / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects; D006943:Hyperglycemia / Q000188:drug therapy* / Q000209:etiology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D005635:Fructosediphosphates; D005636:Fructosephosphates; D063065:Organophosphonates; D009943:Organophosphorus Compounds; C502805:N,N'-((5-(2-amino-5-(2-methylpropyl)-4-thiazolyl)-2-furanyl)phosphinylidene)bis(alanine) diethyl ester; C027618:fructose-6-phosphate; D006597:Fructose-Bisphosphatase; C029063:fructose-1,6-diphosphate; D000409:Alanine