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Use of stable isotopes to study carbohydrate and fat metabolism at the whole-body level

Published online by Cambridge University Press:  12 June 2007

Andrew R. Coggan*
Affiliation:
Biomedical Mass Spectrometry Facility, University of Maryland School of Medicine, Department of Medicine, Division of Gerontology, VA Medical Center (BT18GR), 10 N Greene Street, Baltimore, MD 21201, USA
*
Corresponding Author: Dr Andrew R. Coggan, fax +1 410 605 7913, email coggan@grecc.umaryland.edu
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Abstract

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The present review discusses the advantages and limitations of using stable-isotope tracers to assess carbohydrate and fat metabolism at the whole-body level. One advantage of stable-(v. radioactive-) isotope tracers is the relative ease with which the location of a label within a molecule can be determined using selected-ion-monitoring GC-mass spectrometry (SIM-GC- MS). This technique minimizes potential problems due to label recycling, allows the use of multiple-labelled compounds simultaneously (e.g. to quantify glucose cycling), and perhaps most importantly, has led to the development of unique stable-isotope methods for, for example, quantifying gluconeogenesis. However, the limited sensitivity of SIM-GC-MS sometimes requires that relatively large amounts of a stable-isotope tracer be used, thus increasing cost and potentially altering metabolism. At least theoretically, stable- (or radioactive-) isotope tracers can also be used in conjunction with indirect calorimetry to estimate utilization of muscle glycogen or triacylglycerol stores, thus potentially circumventing the need to obtain muscle biopsies. These calculations, however, require certain critical assumptions, which if incorrect could lead to major errors in the values obtained. Despite such limitations, stable-isotope tracers provide a powerful and sometimes unique tool for investigating carbohydrate and fat metabolism at the whole-body level. With continuing advances in availability, instrumentation and methods, it is likely that stable-isotope tracers will become increasingly important in the immediate future.

Type
Meeting Report
Copyright
The Nutrition Society

References

Argoud, GM, Schade, DS & Eaton, RP (1987) Underestimation of hepatic glucose production by radioactive and stable tracers.American Journal of Physiology 252, E606E615.Google ScholarPubMed
Arner, P & Ostman, J (1974) Mono- and diacylglycerols in human adipose tissue. Biochimica et Biophysica Acta 369, 209221.Google Scholar
Baba, H, Zhang, XJ & Wolfe, RR (1995) Glycerol gluconeogenesis in fasting humans. Nutrition 11, 149153.Google Scholar
Bier, DM, Arnold, KJ, Sherman, WR, Holland, WH, Holmes, WF & Kipnis, DM (1977a) In-vivo measurement of glucose and alanine metabolism with stable isotopic tracers. Diabetes 26, 10051015.Google Scholar
Bier, DM, Leake, RD, Haymond, MW, Arnold, KJ, Gruenke, LD, Sperling, MD & Kipnis, DM (1977b) Measurement of ‘true’ glucose production rates in infancy and childhood with 6,6-dideuteroglucose. Diabetes 26, 10161023.CrossRefGoogle ScholarPubMed
Bougneres, PF, Karl, IE, Hillman, LS & Bier, DM (1982) Lipid transport in the human newborn. Palmitate and glycerol turnover and the contribution of glycerol to neonatal hepatic glucose output. Journal of Clinical Investigation 70, 262270.Google ScholarPubMed
Brunengraber, H, Kelleher, JK & Des, Rosiers C (1997) Applications of mass isotopomer analysis to nutrition research. Annual Review of Nutrition 17, 559596.Google Scholar
Burke, JF, Wolfe, RR, Mullany, CJ, Matthews, DE & Bier, DM (1979) Glucose requirements following burn injury. Annals of Surgery 190, 274285.CrossRefGoogle ScholarPubMed
Coggan, AR, Kohrt, WM, Spina, RJ, Bier, DM & Holloszy, JO (1990) Endurance training decreases plasma glucose turnover and oxidation during moderate intensity exercise in men. Journal of Applied Physiology 68, 990996.CrossRefGoogle ScholarPubMed
Coggan, AR, Spina, RJ, Kohrt, WM, Kirwan, JP, Bier, DM & Holloszy, JO (1992) Plasma glucose kinetics during exercise in subjects with high and low lactate thresholds. Journal of Applied Physiology 73, 18731880.Google Scholar
Coggan, AR, Swanson, SC, Mendenhall, LA, Habash, DL & Kien, CL (1995) Effect of endurance training on hepatic glycogenolysis and gluconeogenesis during prolonged exercise in men. American Journal of Physiology 268, E375E383.Google ScholarPubMed
Coppack, SW, Persson, M, Judd, RL & Miles, JM (1999) Glycerol and nonesterified fatty acid metabolism in human muscle and adipose tissue in vivo. American Journal of Physiology 276, E233E240.Google ScholarPubMed
Coyle, EF, Jeukendrup, AE, Wagenmakers, AJM & Saris, WHM (1997) Fatty acid oxidation is directly regulated by carbohydrate metabolism during exercise. American Journal of Physiology 273, E268E275.Google ScholarPubMed
Elia, M, Kahn, K, Calder, G & Kurpad, A (1993) Glycerol exchange across the human forearm assessed by a combination of tracer and arteriovenous exchange techniques. Clinical Science 84, 99104.Google Scholar
Galster, AD, Clutter, WE, Cryer, PE, Collins, JA & Bier, DM (1981) Epinephrine plasma thresholds for lipolytic effects in man: measurements of fatty acid transport with [1-13C\palmitic acid. Journal of Clinical Investigation 67, 17291738.Google Scholar
Goromaru, T, Matsuki, K & Matsuki, Y (1994) Gas chromatographic-mass spectrometric determination of 13C-glucose level for evaluating the effect of alpha-glucosidase inhibitor acarbose on the digestion of [U-13C] starch in rat. Biological and Pharmacological Bulletin 17, 156159.CrossRefGoogle ScholarPubMed
Guo, Z, Nielsen, S, Burguera, B & Jensen, MD (1997) Free fatty acid turnover measured using ultralow doses of [U-13C\palmitate. Journal of Lipid Research 38, 18881895.CrossRefGoogle ScholarPubMed
Haesler, E, Schneiter, P, Temler, E, Jequier, E & Tappy, L (1994) Effects of infused amino acids and lipids on glucose metabolism in healthy lean humans. International Journal of Obesity and Related Metabolic Disorders 18, 307312.Google Scholar
Hagenfeldt, L & Wahren, J (1968) Human forearm metabolism during exercise. III. Uptake, release, and oxidation of individual fatty acids and glycerol. Scandinavian Journal of Clinical and Laboratory Investigation 21, 263276.CrossRefGoogle Scholar
Haigh, JW, Johnston, DG, McCulloch, AJ, Laker, MF, Welby, J & Evans, S (1982) Assessment of glucose turnover in normal man with the use of a non-radioactive isotopically labelled preparation, [6,6-2H\glucose, as tracer. Clinical Science 63, 437440.CrossRefGoogle Scholar
Hellerstein, MK, Kletke, C, Kaempfer, S, Wu, K & Shackleton, CH (1991) Use of mass isotopomer distributions in secreted lipids to sample lipogenic acetyl-CoA pool in vivo in humans. American Journal of Physiology 261, E479E486.Google ScholarPubMed
Hovorka, R, Eckland, DJ, Halliday, D, Lettis, S, Robinson, CE, Bannister, P, Young, MA & Bye, A (1997) Constant infusion and bolus injection of stable-label tracer give reproducible and comparable fasting HGO. American Journal of Physiology 273, E192E201.Google ScholarPubMed
Jeukendrup, AE, Raben, A, Gijsen, A, Stegen, JH, Brouns, F, Saris, WH & Wagenmakers, AJ (1999) Glucose kinetics during prolonged exercise in highly trained human subjects: effect of glucose ingestion. Journal of Physiology 515, 579589.CrossRefGoogle ScholarPubMed
Judd, RL, Nelson, R, Klein, S, Jensen, MD & Miles, JM (1998) Measurement of plasma glycerol specific activity by high performance liquid chromatography to determine glycerol flux. Journal of Lipid Research 39, 11061110.CrossRefGoogle ScholarPubMed
Kalhan, SC, D'Angelo, LJ, Savin, SM & Adam, PAJ (1979) Glucose production in pregnant women at term gestation. Sources of glucose for human fetus. Journal of Clinical Investigation 63, 388394.CrossRefGoogle ScholarPubMed
Kalhan, SC, Savin, SM & Adam, PAJ (1977) Estimation of glucose turnover with stable tracer glucose-1-13C. Journal of Laboratory and Clinical Medicine 89, 285294.Google Scholar
Kanaley, JA, Mottram, CD, Scanlon, PD & Jensen, MD (1995) Fatty acid kinetic responses to running above or below lactate threshold. Journal of Applied Physiology 79, 439447.CrossRefGoogle ScholarPubMed
Katz, J & Tayek, JA (1998) Gluconeogenesis and the Cori cycle in 12-, 20-, and 40-h-fasted humans. American Journal of Physiology 275, E537E542.Google ScholarPubMed
Klein, S, Peters, EJ, Holland, OB & Wolfe, RR (1989) Effect of short- and long-term beta-adrenergic blockade on lipolysis during fasting in humans. American Journal of Physiology 257, E65E73.Google Scholar
Kurpad, A, Kahn, K, Calder, AG, Coppack, S, Frayn, K, Macdonald;, I & Elia, M (1994) Effect of noradrenaline on glycerol turnover and lipolysis in the whole body and subcutaneous adipose tissue in humans in vivo. Clinical Science 86, 177184.CrossRefGoogle ScholarPubMed
Landau, BR (1999) Quantifying contributions of gluconeogenesis to glucose production in fasted humans using stable isotopes. Proceedings of the Nutrition Society 58, 963972.Google Scholar
Landau, BR, Fernandez, CA, Previs, SF, Ekberg, K, Chandramouli, V, Wahren, J, Kalhan, SC & Brunengraber, H (1995a) A limitation in the use of mass isotopomer distributions to measure gluconeogenesis in fasting humans. American Journal of Physiology 269, E18E26.Google Scholar
Landau, BR, Wahren, J, Chandramouli, V, Schumann, WC, Ekberg, K & Kalhan, SC (1995b) Use of 2H2O for estimating rates of gluconeogenesis. Application to the fasted state. Journal of Clinical Investigation 95, 172178.Google Scholar
Landau, BR, Wahren, J, Ekberg, K, Previs, SF, Yang, D & Brunengraber, H (1998) Limitations in estimating gluconeogenesis and Cori cycling from mass isotopomer distributions using [U-13C6\glucose. American Journal of Physiology 274, E854E961.Google Scholar
Lin, ECC (1977) Glycerol utilization and its regulation in mammals. Annual Reviews of Biochemistry 46, 765795.CrossRefGoogle ScholarPubMed
Martin, WH III, Dalsky, GP, Hurley, BF, Matthews, DE, Bier, DM, Hagberg, JM & Holloszy, JO (1993) Effect of endurance training on plasma FFA turnover and oxidation during exercise. American Journal of Physiology 265, E708E714.Google ScholarPubMed
Miles, JM & Jensen, MD (1991) Determination of plasma-free fatty acid kinetics with tracers: methodologic considerations. Journal of Parenteral and Enteral Nutrition 15, 90S93S.Google Scholar
Neese, RA, Faix, D, Kletke, C, Wu, K, Wang, AC, Shackleton, CH & Hellerstein, MK (1993) Measurement of endogenous synthesis of plasma cholesterol in rats and humans using MIDA. American Journal of Physiology 264, E136E147.Google ScholarPubMed
Neese, RA, Schwarz, JM, Faix, D, Turner, S, Letscher, A, Vu, D & Hellerstein, MK (1995) Gluconeogenesis and intrahepatic triose phosphate flux in response to fasting or substrate loads. Application of the mass isotopomer distribution analysis technique with testing of assumptions and potential problems. Journal of Biological Chemistry 270, 1445214466.Google Scholar
Phillips, SM, Green, HJ, Tarnopolsky, MA, Heigenhauser, GF, Hill, RE & Grant, SM (1996) Effects of training duration on substrate turnover and oxidation during exercise. Journal of Applied Physiology 81, 21822191.CrossRefGoogle ScholarPubMed
Previs, SF, Fernandez, CA, Yang, D, Soloviev, MV, David, F & Brunengraber, H (1995) Limitations of the mass isotopomer distribution analysis of glucose to study gluconeogenesis. Substrate cycling between glycerol and triose phosphates in liver. Journal of Biological Chemistry 270, 1980619815.Google Scholar
Romijn, JA, Coyle, EF, Sidossis, LS, Gastaldelli, A, Horowitz, JF, Endert, E & Wolfe, RR (1993) Regulation of endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration. American Journal of Physiology 265, E380E391.Google Scholar
Shulman, GI, Ladenson, PW, Wolfe, MH, Ridgeway, EC & Wolfe, RR (1985) Substrate cycling between gluconeogenesis and glycolysis in euthyroid, hypothyroid, and hyperthyroid man. Journal of Clinical Investigation 76, 757764.CrossRefGoogle ScholarPubMed
Sidossis, LS & Coggan, AR (1998) Regulation of fatty acid oxidation in untrained versus trained men during exercise. American Journal of Physiology 274, E510E515.Google Scholar
Sidossis, LS, Coggan, AR, Gastaldelli, A & Wolfe, R (1995) A new correction factor for use in tracer estimations of plasma fatty acid oxidation. American Journal of Physiology 269, E649E656.Google Scholar
Stanley, WC, Wisneski, JA, Gertz, EW, Neese, RA & Brooks, GA (1988) Glucose and lactate interrelations during moderate-intensity exercise in humans. Metabolism 37, 850858.Google Scholar
Tappy, L, Acheson, K, Normand, S, Schneeberger, D, Thelin, A, Pachiaudi, C, Riou, JP & Jequier, E (1992) Effects of infused amino acids on glucose production and utilization in healthy human subjects. American Journal of Physiology 262, E826E833.Google Scholar
Tayek, JA & Katz, J (1996) Glucose production, recycling, and gluconeogenesis in normals and diabetics: a mass isotopomer [U-13C\glucose study. American Journal of Physiology 270, E709E717.Google Scholar
Tayek, JA & Katz, J (1997) Glucose production, recycling, Cori cycle, and gluconeogenesis in humans: relationship to serum cortisol. American Journal of Physiology 272, E476E484.Google ScholarPubMed
Tsering, K-Y & Kalhan, SC (1983) Estimation of glucose carbon recycling and glucose turnover with [U-13C\glucose. American Journal of Physiology 245, E476E482.Google Scholar
Vallerand, AL, Zamecnik, J, Jones, PJ & Jacobs, I (1999) Cold stress increases lipolysis, FFA Ra and TG/FFA cycling in humans. Aviation, Space, and Environmental Medicine 70, 4250.Google Scholar
van Hall, G (1999) Correction factors for 13C-labelled substrate oxidation at whole-body and muscle level. Proceedings of the Nutrition Society 58, 979986.CrossRefGoogle ScholarPubMed
Wajngot, A, Chandramouli, V, Schumann, WC, Kumaran, K, Efendi, S & Landau, BR (1989) Testing of the assumptions made in estimating the extent of futile cycling. American Journal of Physiology 256, E668E675.Google Scholar
Wolfe, RR, Allsop, JR & Burke, JF (1979) Glucose metabolism in man: responses to intravenous glucose infusion. Metabolism 28, 12101220.CrossRefGoogle ScholarPubMed
Wolfe, RR, Evans, JE, Mullany, CJ & Burke, JF (1980) Measurement of plasma free fatty acid turnover and oxidation using [1-13C\palmitic acid. Biomedical Mass Spectrometry 7, 168171.CrossRefGoogle ScholarPubMed
Wolfe, RR & Peters, EJ (1987) Lipolytic response to glucose infusion in human subjects. American Journal of Physiology 252, E218E223.Google ScholarPubMed
Zadwarzki, JK, Wolfe, RR, Mott, DM, Lillioja, S, However, BV & Bogardus, C (1988) Increased rate of Cori-cycle in obese subjects with NIDDM and effect of weight reduction. Diabetes 37, 154159.Google Scholar