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: Taishi Yoshida, Akira Okuno, Masanori Izumi, Kanako Takahashi, Yuka Hagisawa, Jun Ohsumi, Toshihiko Fujiwara
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 601 Issue 1-3 Pg. 192-7 (Dec 28 2008) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 19014931 (Publication Type: Journal Article)

Chemical References

• Blood Glucose
• Enzyme Inhibitors
• Fructosediphosphates
• Fructosephosphates
• Organophosphonates
• Organophosphorus Compounds
• N,N'-((5-(2-amino-5-(2-methylpropyl)-4-thiazolyl)-2-furanyl)phosphinylidene)bis(alanine) diethyl ester
• fructose-6-phosphate
• Fructose-Bisphosphatase
• fructose-1,6-diphosphate
• Alanine

Topics

• Alanine (administration & dosage, analogs & derivatives, pharmacology)
• Animals
• Blood Glucose (drug effects)
• Diabetes Mellitus, Type 2 (drug therapy, physiopathology)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Enzyme Inhibitors (administration & dosage, pharmacology)
• Fructose-Bisphosphatase (antagonists & inhibitors)
• Fructosediphosphates (metabolism)
• Fructosephosphates (metabolism)
• Gluconeogenesis (drug effects)
• Hyperglycemia (drug therapy, etiology)
• Liver (drug effects, metabolism)
• Male
• Organophosphonates
• Organophosphorus Compounds (administration & dosage, pharmacology)
• Rats
• Rats, Wistar