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Regulation of hepatic mitochondrial oxidation by glucose-alanine cycling during starvation in humans
Kitt Falk Petersen, … , Gary W. Cline, Gerald I. Shulman
Kitt Falk Petersen, … , Gary W. Cline, Gerald I. Shulman
Published September 23, 2019
Citation Information: J Clin Invest. 2019;129(11):4671-4675. https://doi.org/10.1172/JCI129913.
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Concise Communication Endocrinology Metabolism

Regulation of hepatic mitochondrial oxidation by glucose-alanine cycling during starvation in humans

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Abstract

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.

Authors

Kitt Falk Petersen, Sylvie Dufour, Gary W. Cline, Gerald I. Shulman

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Figure 1

Hepatic glucose and mitochondrial metabolism in healthy, young lean subjects after 12 hours and 60 hours of starvation.

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Hepatic glucose and mitochondrial metabolism in healthy, young lean subj...
(A) Rates of endogenous glucose production (VEGP) (n = 15). (B) Ratio of plasma concentrations of β-OHB to plasma concentrations of AcAc (n = 15). (C) Rates of hepatic pyruvate carboxylase flux (VPC) (n = 15). (D) Relative rates of hepatic pyruvate carboxylase flux vs. citrate synthase flux (VPC/VCS) (n = 15). (E) Rates of hepatic mitochondrial oxidation (VCS) (n = 15). (F) Rates of alanine turnover in a subgroup of healthy volunteers (n = 5). All rates are shown at 12 hours and 60 hours of starvation. Comparisons between the 12-hour and 60-hour fast were performed using a paired, 2-tailed Student’s t test, and P < 0.05 was considered statistically significant. The corresponding plasma enrichments for glucose, lactate, and B-OHB are shown in Supplemental Figures 1, 2, and 3.
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