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Articles in PresS, published online ahead of print April 2, 2002
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00485.2001
Submitted on October 31, 2001
Accepted on March 31, 2002
1 Departments of Molecular and Cellular Physiology, Louisiana State University Health Science Center, Shreveport, LA, USA
2 Division of Child Development and Rehabilitation, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
* To whom correspondence should be addressed. E-mail: twelbo{at}lsumc.edu.
We studied the effect of the antihyperglycemic glitazones, ciglitazone, troglitazone, and rosiglitazone, on glutamine metabolism in renal tubule-derived MDCK cells. Troglitazone, 25µM, enhanced glucose uptake and lactate production by 108 and 92% (both p<0.001). Glutamine utilization was not inhibited but alanine formation decreased and ammonium formation increased (both p<0.005). The decrease in net alanine formation occurred with a change in ALT reactants from close to equilibrium to away from equilibrium condition consistent with inhibition of ALT activity. A shift of glutamine's amino nitrogen from alanine into ammonium was confirmed using [2-15N] L-glutamine and measuring the [15N]-alanine and [15N]-ammonium production. The glitazone-induced shift from alanine to ammonium in glutamate metabolism was dose dependent with troglitazone being 2 fold more potent than rosiglitazone and ciglitazone. All three glitazones induced a spontaneous cellular acidosis reflecting impaired acid extrusion in responding to both an exogenous (NH4+) and endogenous (lactic acid) load. Our findings are consistent with glitazones inducing a spontaneous cellular acidosis associated with a shift in glutamine amino nitrogen metabolism from predominantly anabolic into a catabolic pathway.
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