Glitazones regulate glutamine metabolism by inducing a cellular acidosis in MDCK cells.
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 microM) 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-(15)N]glutamine and measuring the [(15)N]alanine and [(15)N]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) 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.
Coates
Greg
G
Departments of Molecular and Cellular Physiology, Louisiana State University Health Science Center, Shreveport, Louisiana 71130, USA.
Nissim
Itzhak
I
Battarbee
Harold
H
Welbourne
Tomas
T
D000138:Acidosis / Q000378:metabolism*; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005973:Glutamine / Q000493:pharmacokinetics*; D006863:Hydrogen-Ion Concentration; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007668:Kidney / Q000166:cytology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009584:Nitrogen / Q000378:metabolism; D009587:Nitrogen Isotopes; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone
D002839:Chromans; D007004:Hypoglycemic Agents; D009587:Nitrogen Isotopes; D013844:Thiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D005973:Glutamine; D007770:L-Lactate Dehydrogenase; D000410:Alanine Transaminase; D000077288:Troglitazone; D009584:Nitrogen; C039671:ciglitazone