Alterations of carbohydrate and lipid intermediary metabolism during inhibition of glucose-6-phosphatase in rats.
S 4048 (1-[2-(4-Chloro-phenyl)-cyclopropylmethoxy]-3, 4-dihydroxy-5-(3-imidazo[4, 5-b]pyridin-1-yl-3-phenyl-acryloyloxy)-cyclohexanecarboxylic acid), a derivative of chlorogenic acid, specifically inhibits the glucose-6-phosphate translocating component T1 of the glucose-6-phosphatase system. Its pharmacological effect was studied on carbohydrate and lipid parameters in rats. In starved and fed rats, S 4048 caused a dose-dependent reduction of blood glucose levels with a corresponding increase in hepatic and renal glycogen and glucose-6-phosphate. The major quantitative route of carbon flux in the liver during S 4048-induced inhibition of the glucose-6-phosphatase activity seemed to be glycogenesis. Plasma free fatty acids were increased secondarily due to the S 4048-induced hypoglycemia. Hepatic triglycerides were increased possibly due to increased re-esterification of the readily available free fatty acids. Glucose-6-phosphate translocase inhibitors may be useful for experimentally studying aspects of type 1 glycogen storage disease in laboratory animals as well as for the therapeutic modulation of inappropriately high rates of hepatic glucose production in type 2 diabetes.
Herling
A W
AW
Hoechst Marion Roussel Deutschland GmbH, H 821 Pharmacology, 65926, Frankfurt am Main, Germany. andreas.herling@hmrag.com
Burger
H
H
Schubert
G
G
Hemmerle
H
H
Schaefer
H
H
Kramer
W
W
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D050260:Carbohydrate Metabolism; D002726:Chlorogenic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005943:Gluconeogenesis / Q000187:drug effects; D005952:Glucose-6-Phosphatase / Q000037:antagonists & inhibitors*; D007093:Imidazoles / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007328:Insulin; D008112:Liver Glycogen; D011725:Pyridines; C403582:S 4048; D014280:Triglycerides; D002726:Chlorogenic Acid; D002784:Cholesterol; D005952:Glucose-6-Phosphatase