Abstract
Children with gain‐of‐function mutations in Glutamate Dehydrogenase (GDH) display hyperinsulinemia (HI) and hyperammonemia (HA). The HI has been clearly linked to an effect of increased GDH flux on insulin secretion. However, the origin of the HA is uncertain, particularly because hepatic GDH is considered to be close to thermodynamic equilibrium in vivo. We found increased ammonia release into the renal vein of rats infused with β‐2‐aminobicyclo[2.2.1]heptane‐2‐carboxylic acid (BCH), an activator of GDH. BCH infusion had no effect on the hepatic handling of ammonia as portal venous ammonia was effectively removed by the liver. BCH also caused increased ammonia production by isolated rat proximal tubules incubated with glutamine. BCH also increased ammonia production and flux through GDH in isolated rat kidney mitochondria incubated with glutamine. We conclude that activation of renal GDH may be responsible, at least in part, for the HA of the HI/HA Syndrome. (Supported by IGTC and CIHR).
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