Ethanol-induced Hypoglycemia: II. Mechanism of Suppression of Hepatic Gluconeogenesis

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Abstract
The postulation that the increased NADH2/NAD ratio generated in the liver cell during ethanol metabolism causes the suppression of hepatic gluconeogenesis has been tested in several ways in 28 fasted glycogen-depleted dogs in whom hepatic gluconeogenesis was inhibited by infusions of ethanol. First, it was shown that fructose, a non-NAD-dependent precursor of glucose, produced a rapid restoration of hepatic glucose output during ethanol-induced suppression of hepatic gluconeogenesis. Second, in contrast, the infusion of glutamate and [alpha]-ketoglutarate, both NAD-dependent precursors of glucose, failed to augment the depressed rate of hepatic gluconeogenesis induced by ethanol. Finally, the administration of methylene blue, a redox dye which oxidizes NADH2 to NAD, not only prevented the expected fall in hepatic glucose output when infused simultaneously with ethanol, but also produced a rapid restoration of hepatic glucose output previously depressed by ethanol administration in fasting dogs. These data are consonant with the thesis that the increased NADH2/NAD ratio, which characterizes ethanol oxidation by the liver cell, causes a partial block at several points in the gluconeogenic pathway and is responsible for the ethanol-induced suppression of hepatic gluconeogenesis.