Skip to main content
SpringerLink
Log in

Isotopic Tracers for the Measurement of Metabolic Flux Rates

  • Chapter
  • First Online:
Translational Research Methods for Diabetes, Obesity and Cardiometabolic Drug Development

Abstract

Human metabolism is comprised of complex networks, and objective and reliable measures (biomarkers) are needed to guide drug developers toward the goals of safe and efficacious outcomes. The combination of stable isotope labeling with sensitive mass spectrometric analytic techniques is providing increasingly important tools for drug development and early phase clinical studies. The use of stable isotopes allows the measurement of fluxes through metabolic pathways in vivo and provides information about what is new within a biological system and how rapidly molecules are being synthesized and degraded in disease physiology and in response to treatment. This chapter describes a selection of applications for the in vivo assessment of lipid, glucose, and lipoprotein metabolic flux using deuterated water and other stable isotopes that can be used effectively in early clinical research studies to study disease pathology and drug efficacy.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Buchanan JM. Biochemistry during the life and times of Hans Krebs and Fritz Lipmann. J Biol Chem. 2002;277(37):33531–6.

    Article  CAS  PubMed  Google Scholar 

  2. Waterlow JC. Protein turnover. Hammonds Plains: CABI; 2006; 315 p.

    Google Scholar 

  3. Wolfe RR, Chinkes DL. Isotope tracers in metabolic research: principles and practice of kinetic analysis. Hoboken: Wiley; 2005. 494 p.

    Google Scholar 

  4. Schoenheimer R, Rittenberg D. The study of intermediary metabolism of animals with the aid of isotopes. Physiol Rev. 1940;20:218–48.

    CAS  Google Scholar 

  5. Hellerstein MK, Murphy E. Stable isotope-mass spectrometric measurements of molecular fluxes in vivo: emerging applications in drug development. Curr Opin Mol Ther. 2004;6(3):249–64.

    CAS  PubMed  Google Scholar 

  6. Turner SM, Hellerstein MK. Emerging applications of kinetic biomarkers in preclinical and clinical drug development. Curr Opin Drug Discov Devel. 2005;8(1):115–26.

    CAS  PubMed  Google Scholar 

  7. Klein PD, Klein ER. Stable isotopes: origins and safety. J Clin Pharmacol. 1986;26(6):378–82.

    Article  CAS  PubMed  Google Scholar 

  8. Koletzko B, Sauerwald T, Demmelmair H. Safety of stable isotope use. Eur J Pediatr. 1997;156(1):S12–7.

    Article  CAS  PubMed  Google Scholar 

  9. Koletzko B, Demmelmair H, Hartl W, Kindermann A, Koletzko S, Sauerwald T, et al. The use of stable isotope techniques for nutritional and metabolic research in paediatrics. Early Hum Dev. 1998;53:S77–97.

    Article  CAS  PubMed  Google Scholar 

  10. Dufner D, Previs SF. Measuring in vivo metabolism using heavy water. Curr Opin Clin Nutr Metab Care. 2003;6(5):511–7.

    Article  CAS  PubMed  Google Scholar 

  11. Rachdaoui N, Austin L, Kramer E, Previs MJ, Anderson VE, Kasumov T, et al. Measuring proteome dynamics in vivo: as easy as adding water? Mol Cell Proteomics MCP. 2009;8(12):2653–63.

    Article  CAS  Google Scholar 

  12. Jones PJ, Leatherdale ST. Stable isotopes in clinical research: safety reaffirmed. Clin Sci Lond Engl 1979. 1991;80(4):277–80.

    CAS  Google Scholar 

  13. Di Buono M, Jones PJ, Beaumier L, Wykes LJ. Comparison of deuterium incorporation and mass isotopomer distribution analysis for measurement of human cholesterol biosynthesis. J Lipid Res. 2000;41(9):1516–23.

    PubMed  Google Scholar 

  14. Beysen C, Murphy EJ, McLaughlin T, Riiff T, Lamendola C, Turner HC, et al. Whole-body glycolysis measured by the deuterated-glucose disposal test correlates highly with insulin resistance in vivo. Diabetes Care. 2007;30(5):1143–9.

    Article  CAS  PubMed  Google Scholar 

  15. Beysen C, Murphy EJ, Deines K, Chan M, Tsang E, Glass A, et al. Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study. Diabetologia. 2012;55(2):432–42.

    Article  CAS  PubMed  Google Scholar 

  16. Beysen C, Murphy EJ, Nagaraja H, Decaris M, Riiff T, Fong A, et al. A pilot study of the effects of pioglitazone and rosiglitazone on de novo lipogenesis in type 2 diabetes. J Lipid Res. 2008;49(12):2657–63.

    Article  CAS  PubMed  Google Scholar 

  17. Boren J, Taskinen M-R, Adiels M. Kinetic studies to investigate lipoprotein metabolism. J Intern Med. 2012;271(2):166–73.

    Article  CAS  PubMed  Google Scholar 

  18. Strawford A, Antelo F, Christiansen M, Hellerstein MK. Adipose tissue triglyceride turnover, de novo lipogenesis, and cell proliferation in humans measured with 2H2O. Am J Physiol Endocrinol Metab. 2004;286(4):E577–88.

    Article  CAS  PubMed  Google Scholar 

  19. Previs SF, McLaren DG, Wang S-P, Stout SJ, Zhou H, Herath K, et al. New methodologies for studying lipid synthesis and turnover: looking backwards to enable moving forwards. Biochim Biophys Acta. 2014;1842(3):402–13.

    Article  CAS  PubMed  Google Scholar 

  20. Barrett PHR, Chan DC, Watts GF. Thematic review series: patient-oriented research. Design and analysis of lipoprotein tracer kinetics studies in humans. J Lipid Res. 2006;47(8):1607–19.

    Article  CAS  PubMed  Google Scholar 

  21. Chan DC, Barrett PHR, Watts GF. Recent studies of lipoprotein kinetics in the metabolic syndrome and related disorders. Curr Opin Lipidol. 2006;17(1):28–36.

    Article  CAS  PubMed  Google Scholar 

  22. Gasier HG, Fluckey JD, Previs SF. The application of 2H2O to measure skeletal muscle protein synthesis. Nutr Metab. 2010;7:31.

    Article  Google Scholar 

  23. Robinson MM, Turner SM, Hellerstein MK, Hamilton KL, Miller BF. Long-term synthesis rates of skeletal muscle DNA and protein are higher during aerobic training in older humans than in sedentary young subjects but are not altered by protein supplementation. FASEB J Off Publ Fed Am Soc Exp Biol. 2011;25(9):3240–9.

    CAS  Google Scholar 

  24. Scalzo RL, Peltonen GL, Binns SE, Shankaran M, Giordano GR, Hartley DA, et al. Greater muscle protein synthesis and mitochondrial biogenesis in males compared with females during sprint interval training. FASEB J Off Publ Fed Am Soc Exp Biol. 2014;28(6):2705–14.

    CAS  Google Scholar 

  25. Harwood Jr HJ. Treating the metabolic syndrome: acetyl-CoA carboxylase inhibition. Expert Opin Ther Targets. 2005;9(2):267–81.

    Article  CAS  PubMed  Google Scholar 

  26. Hellerstein MK, Schwarz JM, Neese RA. Regulation of hepatic de novo lipogenesis in humans. Annu Rev Nutr. 1996;16:523–57.

    Article  CAS  PubMed  Google Scholar 

  27. Lambert JE, Ramos-Roman MA, Browning JD, Parks EJ. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology. 2014;146(3):726–35.

    Article  CAS  PubMed  Google Scholar 

  28. Tuvdendorj D, Chandalia M, Batbayar T, Saraf M, Beysen C, Murphy EJ, et al. Altered subcutaneous abdominal adipose tissue lipid synthesis in obese, insulin-resistant humans. Am J Physiol Endocrinol Metab. 2013;305(8):E999–1006.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Hudgins LC, Parker TS, Levine DM, Hellerstein MK. A dual sugar challenge test for lipogenic sensitivity to dietary fructose. J Clin Endocrinol Metab. 2011;96(3):861–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Stanhope KL, Griffen SC, Bremer AA, Vink RG, Schaefer EJ, Nakajima K, et al. Metabolic responses to prolonged consumption of glucose- and fructose-sweetened beverages are not associated with postprandial or 24-h glucose and insulin excursions. Am J Clin Nutr. 2011;94(1):112–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Cramer CT, Goetz B, Hopson KLM, Fici GJ, Ackermann RM, Brown SC, et al. Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome. J Lipid Res. 2004;45(7):1289–301.

    Article  CAS  PubMed  Google Scholar 

  32. Leitch CA, Jones PJ. Measurement of human lipogenesis using deuterium incorporation. J Lipid Res. 1993;34(1):157–63.

    CAS  PubMed  Google Scholar 

  33. Hellerstein MK, Christiansen M, Kaempfer S, Kletke C, Wu K, Reid JS, et al. Measurement of de novo hepatic lipogenesis in humans using stable isotopes. J Clin Invest. 1991;87(5):1841–52.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Schoenheimer R. The dynamic state of body constituents. Cambridge, MA: Harvard University Press; 1946.

    Google Scholar 

  35. Busch R, Neese RA, Awada M, Hayes GM, Hellerstein MK. Measurement of cell proliferation by heavy water labeling. Nat Protoc. 2007;2(12):3045–57.

    Article  CAS  PubMed  Google Scholar 

  36. Price JC, Holmes WE, Li KW, Floreani NA, Neese RA, Turner SM, et al. Measurement of human plasma proteome dynamics with (2)H(2)O and liquid chromatography tandem mass spectrometry. Anal Biochem. 2012;420(1):73–83.

    Article  CAS  PubMed  Google Scholar 

  37. Hellerstein MK, Neese RA. Mass isotopomer distribution analysis at eight years: theoretical, analytic, and experimental considerations. Am J Physiol. 1999;276(6 Pt 1):E1146–70.

    CAS  PubMed  Google Scholar 

  38. Chinkes DL, Aarsland A, Rosenblatt J, Wolfe RR. Comparison of mass isotopomer dilution methods used to compute VLDL production in vivo. Am J Physiol. 1996;271(2 Pt 1):E373–83.

    CAS  PubMed  Google Scholar 

  39. Bederman IR, Reszko AE, Kasumov T, David F, Wasserman DH, Kelleher JK, et al. Zonation of labeling of lipogenic acetyl-CoA across the liver: implications for studies of lipogenesis by mass isotopomer analysis. J Biol Chem. 2004;279(41):43207–16.

    Article  CAS  PubMed  Google Scholar 

  40. Vedala A, Wang W, Neese RA, Christiansen MP, Hellerstein MK. Delayed secretory pathway contributions to VLDL-triglycerides from plasma NEFA, diet, and de novo lipogenesis in humans. J Lipid Res. 2006;47(11):2562–74.

    Article  CAS  PubMed  Google Scholar 

  41. Faix D, Neese R, Kletke C, Wolden S, Cesar D, Coutlangus M, et al. Quantification of menstrual and diurnal periodicities in rates of cholesterol and fat synthesis in humans. J Lipid Res. 1993;34(12):2063–75.

    CAS  PubMed  Google Scholar 

  42. Siler SQ, Neese RA, Hellerstein MK. De novo lipogenesis, lipid kinetics, and whole-body lipid balances in humans after acute alcohol consumption. Am J Clin Nutr. 1999;70(5):928–36.

    CAS  PubMed  Google Scholar 

  43. Schwarz JM, Neese RA, Turner S, Dare D, Hellerstein MK. Short-term alterations in carbohydrate energy intake in humans. Striking effects on hepatic glucose production, de novo lipogenesis, lipolysis, and whole-body fuel selection. J Clin Invest. 1995;96(6):2735–43.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Beysen C, Turner S, Carvajal-Gonzalez S, Buckeridge C, Hellerstein M, Esler W, et al. A new methodology for the reproducible measurement of hepatic de novo lipogenesis in humans. Diabetes. 2014;63(Suppl 1):A461.

    Google Scholar 

  45. Flannery C, Dufour S, Rabøl R, Shulman GI, Petersen KF. Skeletal muscle insulin resistance promotes increased hepatic de novo lipogenesis, hyperlipidemia, and hepatic steatosis in the elderly. Diabetes. 2012;61(11):2711–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Freckmann G, Hagenlocher S, Baumstark A, Jendrike N, Gillen RC, Rössner K, et al. Continuous glucose profiles in healthy subjects under everyday life conditions and after different meals. J Diabetes Sci Technol. 2007;1(5):695–703.

    Article  PubMed Central  PubMed  Google Scholar 

  47. Steele R, Wall JS, De Bodo RC, Altszuler N. Measurement of size and turnover rate of body glucose pool by the isotope dilution method. Am J Physiol. 1956;187(1):15–24.

    CAS  PubMed  Google Scholar 

  48. Gerich JE, Meyer C, Woerle HJ, Stumvoll M. Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care. 2001;24(2):382–91.

    Article  CAS  PubMed  Google Scholar 

  49. Katz J, Rognstad R. Futile cycles in the metabolism of glucose. Curr Top Cell Regul. 1976;10:237–89.

    Article  CAS  PubMed  Google Scholar 

  50. Rigalleau V, Beylot M, Laville M, Guillot C, Deleris G, Aubertin J, et al. Measurement of post-absorptive glucose kinetics in non-insulin-dependent diabetic patients: methodological aspects. Eur J Clin Invest. 1996;26(3):231–6.

    Article  CAS  PubMed  Google Scholar 

  51. Glauber H, Wallace P, Brechtel G. Effects of fasting on plasma glucose and prolonged tracer measurement of hepatic glucose output in NIDDM. Diabetes. 1987;36(10):1187–94.

    Article  CAS  PubMed  Google Scholar 

  52. Chen YD, Swislocki AL, Jeng CY, Juang JH, Reaven GM. Effect of time on measurement of hepatic glucose production. J Clin Endocrinol Metab. 1988;67(5):1084–8.

    Article  CAS  PubMed  Google Scholar 

  53. Hovorka R, Eckland DJ, Halliday D, Lettis S, Robinson CE, Bannister P, et al. Constant infusion and bolus injection of stable-label tracer give reproducible and comparable fasting HGO. Am J Physiol. 1997;273(1 Pt 1):E192–201.

    CAS  PubMed  Google Scholar 

  54. Barrett PH, Bell BM, Cobelli C, Golde H, Schumitzky A, Vicini P, et al. SAAM II: Simulation, Analysis, and Modeling Software for tracer and pharmacokinetic studies. Metabolism. 1998;47(4):484–92.

    Article  CAS  PubMed  Google Scholar 

  55. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999;22(9):1462–70.

    Article  CAS  PubMed  Google Scholar 

  56. Hellerstein MK, Neese RA, Linfoot P, Christiansen M, Turner S, Letscher A. Hepatic gluconeogenic fluxes and glycogen turnover during fasting in humans. A stable isotope study. J Clin Invest. 1997;100(5):1305–19.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Neese RA, Schwarz JM, Faix D, Turner S, Letscher A, Vu D, et al. 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. J Biol Chem. 1995;270(24):14452–66.

    Article  CAS  PubMed  Google Scholar 

  58. Hellerstein MK, Neese RA. Mass isotopomer distribution analysis: a technique for measuring biosynthesis and turnover of polymers. Am J Physiol. 1992;263(5 Pt 1):E988–1001.

    CAS  PubMed  Google Scholar 

  59. Hellerstein MK, Kaempfer S, Reid JS, Wu K, Shackleton CH. Rate of glucose entry into hepatic uridine diphosphoglucose by the direct pathway in fasted and fed states in normal humans. Metabolism. 1995;44(2):172–82.

    Article  CAS  PubMed  Google Scholar 

  60. Basu R, Basu A, Johnson CM, Schwenk WF, Rizza RA. Insulin dose-response curves for stimulation of splanchnic glucose uptake and suppression of endogenous glucose production differ in nondiabetic humans and are abnormal in people with type 2 diabetes. Diabetes. 2004;53(8):2042–50.

    Article  CAS  PubMed  Google Scholar 

  61. Steele R, Bishop JS, Dunn A, Altszuler N, Rathbeb I, Debodo RC. Inhibition by insulin of hepatic glucose production in the normal dog. Am J Physiol. 1965;208:301–6.

    CAS  PubMed  Google Scholar 

  62. Cowan JS, Hetenyi Jr G. Glucoregulatory responses in normal and diabetic dogs recorded by a new tracer method. Metabolism. 1971;20(4):360–72.

    Article  CAS  PubMed  Google Scholar 

  63. Hother-Nielsen O. On the appropriate use of the primed-constant tracer infusion technique. Diabète Metab. 1994;20(6):568–70.

    CAS  PubMed  Google Scholar 

  64. Staehr P, Hojlund K, Hother-Nielsen O, Holst JJ, Beck-Nielsen H. Does overnight normalization of plasma glucose by insulin infusion affect assessment of glucose metabolism in Type 2 diabetes? Diabet Med J Br Diabet Assoc. 2003;20(10):816–22.

    Article  CAS  Google Scholar 

  65. Steele R, Bjerknes C, Rathgeb I, Altszuler N. Glucose uptake and production during the oral glucose tolerance test. Diabetes. 1968;17(7):415–21.

    CAS  PubMed  Google Scholar 

  66. Mari A, Wahren J, DeFronzo RA, Ferrannini E. Glucose absorption and production following oral glucose: comparison of compartmental and arteriovenous-difference methods. Metabolism. 1994;43(11):1419–25.

    Article  CAS  PubMed  Google Scholar 

  67. Dalla Man C, Caumo A, Basu R, Rizza R, Toffolo G, Cobelli C. Minimal model estimation of glucose absorption and insulin sensitivity from oral test: validation with a tracer method. Am J Physiol Endocrinol Metab. 2004;287(4):E637–43.

    Article  CAS  PubMed  Google Scholar 

  68. Taylor R, Magnusson I, Rothman DL, Cline GW, Caumo A, Cobelli C, et al. Direct assessment of liver glycogen storage by 13C nuclear magnetic resonance spectroscopy and regulation of glucose homeostasis after a mixed meal in normal subjects. J Clin Invest. 1996;97(1):126–32.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Basu R, Di Camillo B, Toffolo G, Basu A, Shah P, Vella A, et al. Use of a novel triple-tracer approach to assess postprandial glucose metabolism. Am J Physiol Endocrinol Metab. 2003;284(1):E55–69.

    CAS  PubMed  Google Scholar 

  70. Haidar A, Elleri D, Allen JM, Harris J, Kumareswaran K, Nodale M, et al. Validity of triple- and dual-tracer techniques to estimate glucose appearance. Am J Physiol Endocrinol Metab. 2012;302(12):E1493–501.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Rossetti L, Giaccari A. Relative contribution of glycogen synthesis and glycolysis to insulin-mediated glucose uptake. A dose-response euglycemic clamp study in normal and diabetic rats. J Clin Invest. 1990;85(6):1785–92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Woerle HJ, Meyer C, Dostou JM, Gosmanov NR, Islam N, Popa E, et al. Pathways for glucose disposal after meal ingestion in humans. Am J Physiol Endocrinol Metab. 2003;284(4):E716–25.

    CAS  PubMed  Google Scholar 

  73. Del Prato S, Bonadonna RC, Bonora E, Gulli G, Solini A, Shank M, et al. Characterization of cellular defects of insulin action in type 2 (non-insulin-dependent) diabetes mellitus. J Clin Invest. 1993;91(2):484–94.

    Article  PubMed Central  PubMed  Google Scholar 

  74. Galgani JE, Ravussin E. Postprandial whole-body glycolysis is similar in insulin-resistant and insulin-sensitive non-diabetic humans. Diabetologia. 2012;55(3):737–42.

    Article  CAS  PubMed  Google Scholar 

  75. Christiansen MP, Linfoot PA, Neese RA, Hellerstein MK. Effect of dietary energy restriction on glucose production and substrate utilization in type 2 diabetes. Diabetes. 2000;49(10):1691–9.

    Article  CAS  PubMed  Google Scholar 

  76. Goldberg RB, Kendall DM, Deeg MA, Buse JB, Zagar AJ, Pinaire JA, et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 2005;28(7):1547–54.

    Article  CAS  PubMed  Google Scholar 

  77. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457–71.

    Article  CAS  PubMed  Google Scholar 

  78. Erdmann E, Dormandy JA, Charbonnel B, Massi-Benedetti M, Moules IK, Skene AM, et al. The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) Study. J Am Coll Cardiol. 2007;49(17):1772–80.

    Article  CAS  PubMed  Google Scholar 

  79. Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124(2):509–14.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124(2):499–508.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Welty FK, Lichtenstein AH, Barrett PH, Dolnikowski GG, Schaefer EJ. Human apolipoprotein (Apo) B-48 and ApoB-100 kinetics with stable isotopes. Arterioscler Thromb Vasc Biol. 1999;19(12):2966–74.

    Article  CAS  PubMed  Google Scholar 

  82. Foster DM, Barrett PH, Toffolo G, Beltz WF, Cobelli C. Estimating the fractional synthetic rate of plasma apolipoproteins and lipids from stable isotope data. J Lipid Res. 1993;34(12):2193–205.

    CAS  PubMed  Google Scholar 

  83. Kasumov T, Willard B, Li L, Li M, Conger H, Buffa JA, et al. 2H2O-based high-density lipoprotein turnover method for the assessment of dynamic high-density lipoprotein function in mice. Arterioscler Thromb Vasc Biol. 2013;33(8):1994–2003.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. Lichtenstein AH, Cohn JS, Hachey DL, Millar JS, Ordovas JM, Schaefer EJ. Comparison of deuterated leucine, valine, and lysine in the measurement of human apolipoprotein A-I and B-100 kinetics. J Lipid Res. 1990;31(9):1693–701.

    CAS  PubMed  Google Scholar 

  85. Wong ATY, Chan DC, Pang J, Watts GF, Barrett PHR. Plasma apolipoprotein B-48 transport in obese men: a new tracer kinetic study in the postprandial state. J Clin Endocrinol Metab. 2014;99(1):E122–6.

    Article  PubMed  Google Scholar 

  86. Berthold HK, Mertens J, Birnbaum J, Bramswig S, Sudhop T, Barrett PHR, et al. Influence of simvastatin on apoB-100 secretion in non-obese subjects with mild hypercholesterolemia. Lipids. 2010;45(6):491–500.

    Article  CAS  PubMed  Google Scholar 

  87. Berglund L, Witztum JL, Galeano NF, Khouw AS, Ginsberg HN, Ramakrishnan R. Three-fold effect of lovastatin treatment on low density lipoprotein metabolism in subjects with hyperlipidemia: increase in receptor activity, decrease in apoB production, and decrease in particle affinity for the receptor. Results from a novel triple-tracer approach. J Lipid Res. 1998;39(4):913–24.

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Parhofer KG, Barrett PHR. Thematic review series: patient-oriented research. What we have learned about VLDL and LDL metabolism from human kinetics studies. J Lipid Res. 2006;47(8):1620–30.

    Article  CAS  PubMed  Google Scholar 

  89. Telford DE, Sutherland BG, Edwards JY, Andrews JD, Barrett PHR, Huff MW. The molecular mechanisms underlying the reduction of LDL apoB-100 by ezetimibe plus simvastatin. J Lipid Res. 2007;48(3):699–708.

    Article  CAS  PubMed  Google Scholar 

  90. Ginsberg HN. Changes in lipoprotein kinetics during therapy with fenofibrate and other fibric acid derivatives. Am J Med. 1987;83(5B):66–70.

    Article  CAS  PubMed  Google Scholar 

  91. Watts GF, Barrett PHR, Ji J, Serone AP, Chan DC, Croft KD, et al. Differential regulation of lipoprotein kinetics by atorvastatin and fenofibrate in subjects with the metabolic syndrome. Diabetes. 2003;52(3):803–11.

    Article  CAS  PubMed  Google Scholar 

  92. Lamon-Fava S, Diffenderfer MR, Barrett PHR, Buchsbaum A, Nyaku M, Horvath KV, et al. Extended-release niacin alters the metabolism of plasma apolipoprotein (Apo) A-I and ApoB-containing lipoproteins. Arterioscler Thromb Vasc Biol. 2008;28(9):1672–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  93. Parhofer KG, Hugh P, Barrett R, Bier DM, Schonfeld G. Determination of kinetic parameters of apolipoprotein B metabolism using amino acids labeled with stable isotopes. J Lipid Res. 1991;32(8):1311–23.

    CAS  PubMed  Google Scholar 

  94. Reeds PJ, Hachey DL, Patterson BW, Motil KJ, Klein PD. VLDL apolipoprotein B-100, a potential indicator of the isotopic labeling of the hepatic protein synthetic precursor pool in humans: studies with multiple stable isotopically labeled amino acids. J Nutr. 1992;122(3):457–66.

    CAS  PubMed  Google Scholar 

  95. Price JC, Khambatta CF, Li KW, Bruss MD, Shankaran M, Dalidd M, et al. The effect of long term calorie restriction on in vivo hepatic proteostatis: a novel combination of dynamic and quantitative proteomics. Mol Cell Proteomics MCP. 2012;11(12):1801–14.

    Article  Google Scholar 

  96. Heinecke JW. The HDL, proteome: a marker–and perhaps mediator–of coronary artery disease. J Lipid Res. 2009;50(Suppl):S167–71.

    PubMed Central  PubMed  Google Scholar 

  97. Vaisar T, Pennathur S, Green PS, Gharib SA, Hoofnagle AN, Cheung MC, et al. Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J Clin Invest. 2007;117(3):746–56.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  98. Shah AS, Tan L, Long JL, Davidson WS. Proteomic diversity of high density lipoproteins: our emerging understanding of its importance in lipid transport and beyond. J Lipid Res. 2013;54(10):2575–85.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  99. Bilheimer DW, Grundy SM, Brown MS, Goldstein JL. Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes. Proc Natl Acad Sci U S A. 1983;80(13):4124–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  100. Reyes-Soffer G. Treatment with mipomersen reduces levels of ApoB-containing lipoproteins by increasing fractional removal of VLDL and LDL-apoB without reducing VLDL-apob secretion. ATVB 2014. Abstract 634.

    Google Scholar 

  101. Huff MW, Hegele RA. Apolipoprotein C-III: going back to the future for a lipid drug target. Circ Res. 2013;112(11):1405–8.

    Article  CAS  PubMed  Google Scholar 

  102. Graham MJ, Lee RG, Bell TA, Fu W, Mullick AE, Alexander VJ, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res. 2013;112(11):1479–90.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. KineMed, Inc., Emeryville, CA, USA

    Carine Beysen PhD, Marc K. Hellerstein MD, PhD & Scott M. Turner PhD

Authors
  1. Carine Beysen PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marc K. Hellerstein MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Scott M. Turner PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Scott M. Turner PhD .

Editor information

Editors and Affiliations

  1. Profil Institute for Clinical Research, Chula Vista, California, USA

    Andrew J. Krentz

  2. Profil Institute for Clinical Research, Chula Vista, California, USA

    Lutz Heinemann

  3. Profil Institute for Clinical Research, Chula Vista, California, USA

    Marcus Hompesch

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer-Verlag London

About this chapter

Cite this chapter

Beysen, C., Hellerstein, M.K., Turner, S.M. (2015). Isotopic Tracers for the Measurement of Metabolic Flux Rates. In: Krentz, A., Heinemann, L., Hompesch, M. (eds) Translational Research Methods for Diabetes, Obesity and Cardiometabolic Drug Development. Springer, London. https://doi.org/10.1007/978-1-4471-4920-0_3

Download citation

  • DOI: https://doi.org/10.1007/978-1-4471-4920-0_3

  • Published:

  • Publisher Name: Springer, London

  • Print ISBN: 978-1-4471-4919-4

  • Online ISBN: 978-1-4471-4920-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation