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Am J Physiol Endocrinol Metab 283: E729-E737, 2002. First published April 2, 2002; doi:10.1152/ajpendo.00485.2001
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Vol. 283, Issue 4, E729-E737, October 2002

Glitazones regulate glutamine metabolism by inducing a cellular acidosis in MDCK cells

Greg Coates1, Itzhak Nissim2, Harold Battarbee1, and Tomas Welbourne1

1 Departments of Molecular and Cellular Physiology, Louisiana State University Health Science Center, Shreveport, Louisiana 71130; and 2 Division of Child Development and Rehabilitation, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

We studied the effect of the antihyperglycemic glitazones, ciglitazone, troglitazone, and rosiglitazone, on glutamine metabolism in renal tubule-derived Madin-Darby canine kidney (MDCK) cells. Troglitazone (25 µM) 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 alanine aminotransferase (ALT) reactants, from close to equilibrium to away from equilibrium, consistent with inhibition of ALT activity. A shift of glutamine's amino nitrogen from alanine into ammonium was confirmed by using L-[2-15N]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 twofold more potent than rosiglitazone and ciglitazone. All three glitazones induced a spontaneous cellular acidosis, reflecting impaired acid extrusion in responding to both an exogenous (NH<UP><SUB>4</SUB><SUP>+</SUP></UP>) and an 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.

rosiglitazone; troglitazone; ciglitazone; L-[2-15N]glutamine; 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein; glutamate; alanine; ammonium; Madin-Darby canine kidney cells; intracellular pH


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