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Regulation of Hepatic Mitochondrial Oxidation by Glucose- Alanine Cycling During Starvation in Humans

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Regulation of Hepatic Mitochondrial Oxidation by Glucose- Alanine Cycling During Starvation in Humans Regulation of hepatic mitochondrial oxidation by glucose- alanine cycling during starvation in humans Kitt Falk Petersen, … , Gary W. Cline, Gerald I. Shulman J Clin Invest. 2019. https://doi.org/10.1172/JCI129913. Concise Communication Endocrinology Metabolism 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. Find the latest version: https://jci.me/129913/pdf The Journal of Clinical Investigation CONCISE COMMUNICATION Regulation of hepatic mitochondrial oxidation by glucose-alanine cycling during starvation in humans Kitt Falk Petersen,1,2 Sylvie Dufour,1,2 Gary W. Cline,1,2 and Gerald I. Shulman1,2,3 1Department of Medicine, 2Yale Diabetes Research Center, and 3Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, USA. 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. Introduction Furthermore, we found that reduced rates of hepatic mitochondrial The glucose-alanine cycle represents a critical link between car- oxidation during prolonged starvation could be attributed to a 40% bohydrate and amino acid metabolism and comprises a series of reduction in rates of glucose-alanine cycling. However, whether alter- reactions in which pyruvate, derived mostly from intramyocellular ations in the rates of glucose-alanine cycles have similar effects in the glycolysis, is transaminated with ammonia, derived from muscle regulation of hepatic mitochondrial oxidation in humans during star- protein catabolism, to form l-alanine (1, 2). Alanine is subsequent- vation is not known. ly transported to the liver, where the amino group is transferred In order to determine whether starvation promotes reduced to α-ketoglutarate by alanine transaminase to form glutamate and rates of hepatic mitochondrial oxidation (rate of citrate synthase pyruvate. The amino group, which was transferred from alanine flux [VCS]) in humans, we applied positional isotopomer NMR to glutamate, is subsequently converted to urea, and the newly tracer analysis (PINTA) to assess rates of hepatic VCS and pyruvate generated pyruvate is converted to glucose. Besides transferring carboxylase flux (VPC) as well as the hepatic mitochondrial redox potentially toxic ammonia, derived from muscle protein catabo- state by measuring the ratio of plasma concentrations of β-hy- lism, to the liver for conversion to urea, this cycle also transfers droxybutyrate to acetoacetate ([β-OHB]/[AcAc]) (4–7) in healthy energy from the liver to the muscle by the generation of 2 moles volunteers following a 12-hour overnight fast and again following a of ATP for every mole of glucose that is glycolyzed and recycles 60-hour fast (8). In order to determine whether alanine turnover is 3-carbon units back to the liver for conversion to glucose. How- reduced during starvation, we assessed rates of [3-13C]alanine turn- ever, it is unknown whether the glucose-alanine cycle participates over in another subgroup of individuals under the same 12-hour in other critical functions of hepatic metabolism during prolonged and 60-hour fasted conditions. Finally, in order to determine (60 hours) starvation. whether decreased rates of alanine turnover during starvation play We have recently demonstrated a critical role for decreased glu- a causal role in promoting decreased rates of hepatic mitochondrial cose-alanine cycling, due to hepatic glycogen depletion, in promot- oxidation, we infused alanine in a subgroup of 60-hour fasted sub- ing marked reductions in rates of hepatic mitochondrial oxidative jects to approximately match rates of alanine turnover in 12-hour metabolism in awake rats during prolonged (48 hours) starvation (3). fasted subjects and reassessed rates of hepatic VPC and VCS flux by PINTA under these conditions. Related Commentary: https://doi.org/10.1172/JCI131931 Results and Discussion Sixty hours of starvation promoted an approximately 25% reduction Conflict of interest: The authors have declared that no conflict of interest exists. in plasma glucose and insulin concentrations, compared with the Copyright: © 2019, American Society for Clinical Investigation. overnight (12 hours) fast (Table 1), which could be attributed to sim- Submitted: May 14, 2019; Accepted: July 18, 2019; Published: September 23, 2019. Reference information: J Clin Invest. https://doi.org/10.1172/JCI129913. ilar reductions in the rates of endogenous glucose production (Fig- ure 1A). As expected, these changes were associated with marked jci.org 1 CONCISE COMMUNICATION The Journal of Clinical Investigation ma leptin and thyroid-stimulating hormone (TSH) concentrations, Table 1. Anthropometric data, plasma metabolite, and hormone but were independent of changes in plasma T3 concentrations or concentrations in healthy volunteers after 12-hour and changes in whole body energy expenditure (Table 1). 60-hour fasts In order to determine whether 60 hours of starvation altered rates of glucose-alanine cycling, we next measured endogenous 12-Hour fast 60-Hour fast P value (n = 15) (n = 15) rates of alanine turnover in a similar group of young, lean individ- 13 Age (years) 26 ± 2 – uals following 12 hours and 60 hours of fasting assessed by [3- C] Body weight (kg) 73.8 ± 3.1 72.1 ± 3.3 0.0003 alanine turnover. Rates of alanine turnover in plasma following a BMI (kg/m2) 23.6 ± 0.9 23.1 ± 0.9 0.0002 12-hour fast were approximately 425 μmol/min (Figure 1F), which Glucose (mmol/L) 5.01 ± 0.11 3.73 ± 0.09 <0.0001 is in good agreement with rates of alanine turnover previously Lactate (mmol/L) 0.90 ± 0.08 1.03 ± 0.05 0.241 measured in overnight-fasted humans using similar methodolo- NEFAs (mmol/L) 0.50 ± 0.066 1.36 ± 0.10 <0.0001 gy (10). Following 60 hours of fasting, rates of alanine turnover Alanine (mmol/L) 0.27 ± 0.02 0.23 ± 0.02 0.125 decreased by approximately 30% (Figure 1F) despite no signifi- Glycine (mmol/L) 0.19 ± 0.02 0.15 ± 0.02 0.051 cant alterations in plasma alanine concentrations (Table 1). This Serine (mmol/L) 0.021 ± 0.002 0.020 ± 0.002 0.879 starvation-induced reduction in rates of whole body alanine turn- Leucine (mmol/L) 0.15 ± 0.01 0.24 ± 0.01 0.009 over is consistent with the observed 75% reduction in net alanine Isoleucine (mmol/L) 0.06 ± 0.01 0.11 ± 0.01 0.0001 release across the forearm that occurs in humans during prolonged Aspartate+asparagine (mmol/L) 0.041 ± 0.004 0.037 ± 0.003 0.131 starvation (1). Previous studies in awake rats found that reduced Phenylalanine (mmol/L) 0.056 ± 0.004 0.055 ± 0.003 0.787 rates of glucose-alanine cycling following 48 hours of starvation Glutamate+glutamine (mmol/L) 0.51 ± 0.04 0.46 ± 0.03 0.145 were associated with reduced rates of net hepatic glycogenolysis, β-hydroxybutyrate (mmol/L) 0.26 ± 0.11 3.31 ± 0.30 <0.0001 resulting in decreased rates of hepatic glucose production and AcAc (mmol/L) 0.17 ± 0.02 0.72 ± 0.10 <0.0001 reductions of plasma glucose
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