IN-VITRO AND IN-VIVO SUPPRESSION OF GLUCONEOGENESIS BY INHIBITION OF PYRUVATE-CARBOXYLASE

The mechanism of inhibition of gluconeogenesis by phenylalkanoic acids was studied in vitro and in vivo. In vitro production of (CO2)-C-14 f rom labeled glucose or palmitate was not inhibited at 4 mM, a concentr ation of phenylacetic acid that inhibited gluconeogenesis from lactate /pyruvate. In vitro studies with isolated mitochondria showed that the CoA ester of phenylacetic acid was formed. The parent phenylalkanoic acid had no effect on purified pyruvate carboxylase activity, but phen ylacetyl CoA ester decreased pyruvate carboxylation in a concentration -dependent manner. Phenylacetic acid inhibited gluconeogenesis in isol ated rat liver cells from 10 mM lactate/1 mM pyruvate (decreased 39%, P < 0.05), but not 10 mM L-glutamine or [C-14]aspartate, showing that the inhibition of gluconeogenesis occurred at the level of pyruvate ca rboxylase. A 20 mg bolus with infusion of 1 mg/min of phenylpropionic acid decreased blood glucose levels of normal [110 +/- 12 to 66 +/- 11 mg/dL, N = 7, P < 0.05 (unpaired Student's t-test vs control)] and st reptozocin diabetic rats [295 +/- 14 to 225 +/- 12 mg/dL, N = 7, P < 0 .01 (paired c-test vs basal)]. Hepatic glucose production in control a nd diabetic rats was suppressed under conditions where liver glycogen was depleted, indicating that gluconeogenesis had been inhibited in do e. The results suggest the possibility that the inappropriate overprod uction of glucose can be controlled by inhibitors of pyruvate carboxyl ase. This class of inhibitors may be useful in the treatment of non-in sulin-dependent diabetes mellitus. Copyright (C) 1996 Elsevier Science Inc.