In order to determine whether the
glucose-
alanine cycle regulates rates of hepatic mitochondrial oxidation in humans, we applied positional isotopomer NMR tracer analysis (
PINTA) to assess rates of hepatic mitochondrial oxidation and
pyruvate carboxylase flux in healthy volunteers following both an overnight (12 hours) and a 60-hour fast. Following the 60-hour fast, rates of endogenous
glucose production and mitochondrial oxidation decreased, whereas rates of hepatic
pyruvate carboxylase flux remained unchanged. These reductions were associated with reduced rates of
alanine turnover, assessed by [3-13C]
alanine, in a subgroup of participants under similar fasting conditions. In order to determine whether this reduction in
alanine turnover was responsible for the reduced rates of hepatic mitochondrial oxidation, we infused unlabeled
alanine into another subgroup of 60-hour fasted subjects to increase rates of
alanine turnover, similar to what was measured after a 12-hour fast, and found that this perturbation increased rates of hepatic mitochondrial oxidation. Taken together, these studies demonstrate that 60 hours of
starvation induce marked reductions in rates of hepatic mitochondrial oxidation, which in turn can be attributed to reduced rates of
glucose-
alanine cycling, and reveal a heretofore undescribed role for
glucose-
alanine in the regulation of hepatic mitochondrial oxidation in humans.