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Humans express two GDH isoforms, GDH1 and 2, whereas most other mammals express only GDH1. hGDH1 is widely expressed in human brain while hGDH2 is confined to astrocytes. The two isoforms display different enzymatic properties and the nature of these supports that hGDH2 expression in astrocytes potentially increases glutamate oxidation and supports the TCA cycle during energy\u2010demanding processes such as high intensity glutamatergic signaling. However, little is known about how expression of hGDH2 affects the handling of glutamate and TCA cycle metabolism in astrocytes. Therefore, we cultured astrocytes from cerebral cortical tissue of hGDH2\u2010expressing transgenic mice. We measured glutamate uptake and metabolism using [<jats:sup>3<\/jats:sup>H]glutamate, while the effect on metabolic pathways of glutamate and glucose was evaluated by use of <jats:sup>13<\/jats:sup>C and <jats:sup>14<\/jats:sup>C substrates and analysis by mass spectrometry and determination of radioactively labeled metabolites including CO<jats:sub>2<\/jats:sub>, respectively. We conclude that hGDH2 expression increases capacity for uptake and oxidative metabolism of glutamate, particularly during increased workload and aglycemia. Additionally, hGDH2 expression increased utilization of branched\u2010chain amino acids (BCAA) during aglycemia and caused a general decrease in oxidative glucose metabolism. We speculate, that expression of hGDH2 allows astrocytes to spare glucose and utilize BCAAs during substrate shortages. These findings support the proposed role of hGDH2 in astrocytes as an important fail\u2010safe during situations of intense glutamatergic activity. 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