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-imida zo[4,5-b]pyridin-1-yl-3-phenyl-acryloyloxy)-cyclohexanecarboxylic acid), a derivative of chlorogenic acid, specifically inhibits the glucose-6-phospha te translocating component T1 of the glucose-6-phosphatase system. Its phar macological effect was studied on carbohydrate and lipid parameters in rats . In starved and fed rats, S 4038 caused a dose-dependent reduction of bloo d glucose levels with a corresponding increase in hepatic and renal glycoge n and glucose-6-phosphate. The major quantitative route of carbon flux in t he liver during S 4048-induced inhibition of the glucose-6-phosphatase acti vity seemed to be glycogenesis. Plasma free fatty acids were increased seco ndarily due to the S 4048-induced hypoglycemia. Hepatic triglycerides were increased possibly due to increased re-esterification of the readily availa ble free fatty acids. Glucose-6-phosphate translocase inhibitors may be use ful for experimentally studying aspects of type 1 glycogen storage disease in laboratory animals as well as for the therapeutic modulation of inapprop riately high rates of hepatic glucose production in type 2 diabetes. (C) 19 99 Elsevier Science B.V. All rights reserved.