In Vivo and In Vitro Quantification of Glucose Kinetics: From Bedside to Bench

다국어 초록 (Multilingual Abstract)

Like other substrates, plasma glucose is in a dynamic state of constant turnover (i.e., rates of glucose appearance [Ra glucose] into and disappearance [Rd glucose] from the plasma) while staying within a narrow range of normal concentrations, a physiological priority. Persistent imbalance of glucose turnover leads to elevations (i.e., hyperglycemia, Ra>Rd) or falls (i.e., hypoglycemia, Ra<Rd) in the pool size, leading to clinical conditions such as diabetes. Endogenous Ra glucose is divided into hepatic glucose production via glycogenolysis and gluconeogenesis (GNG) and renal GNG. On the other hand, Rd glucose, the summed rate of glucose uptake by tissues/organs, involves various intracellular metabolic pathways including glycolysis, the tricarboxylic acid (TCA) cycle, and oxidation at varying rates depending on the metabolic status. Despite the dynamic nature of glucose metabolism, metabolic studies typically rely on measurements of static, snapshot information such as the abundance of mRNAs and proteins and (in)activation of implicated signaling networks without determining actual flux rates. In this review, we will discuss the importance of obtaining kinetic information, basic principles of stable isotope tracer methodology, calculations of in vivo glucose kinetics, and assessments of metabolic flux in experimental models in vivo and in vitro.

참고문헌 (Reference)

• 1 Castillo L, "Wholebody nitric oxide synthesis in healthy men determined from [15N] arginine-to-[15N]citrulline labeling" 93 : 11460-11465, 1996
• 2 Burd NA, "Validation of a single biopsy approach and bolus protein feeding to determine myofibrillar protein synthesis in stable isotope tracer studies in humans" 8 : 15-, 2011
• 3 Fabbrini E, "Validation of a novel index to assess insulin resistance of adipose tissue lipolytic activity in obese subjects" 53 : 321-324, 2012
• 4 Kim IY, "Update on maximal anabolic response to dietary protein" 37 : 411-418, 2018
• 5 Il-Young Kim, "Understanding Muscle Protein Dynamics: Technical Considerations for Advancing Sarcopenia Research" 대한노인병학회 24 (24): 157-165, 2020
• 6 Qiao Q, "Two-hour glucose is a better risk predictor for incident coronary heart disease and cardiovascular mortality than fasting glucose" 23 : 1267-1275, 2002
• 7 Chubukov V, "Transcriptional regulation is insufficient to explain substrate-induced flux changes in Bacillus subtilis" 9 : 709-, 2013
• 8 Cobelli C, "Tracer kinetics in biomedical research" Springer 2002
• 9 Qi J, "The use of stable isotope-labeled glycerol and oleic acid to differentiate the hepatic functions of DGAT1 and-2" 53 : 1106-1116, 2012
• 10 Wolfe RR, "The underappreciated role of muscle in health and disease" 84 : 475-482, 2006
• 11 Ackermans MT, "The quantification of gluconeogenesis in healthy men by(2)H2O and [2-(13)C]glycerol yields different results : rates of gluconeogenesis in healthy men measured with(2)H2O are higher than those measured with [2-(13)C]glycerol" 86 : 2220-2226, 2001
• 12 Brooks GA, "The precious few grams of glucose during exercise" 21 : 5733-, 2020
• 13 Park S, "The impact of Hayward green kiwifruit on dietary protein digestion and protein metabolism" 24 : 2020
• 14 Park S, "The anabolic response to dietary protein is not limited by the maximal stimulation of protein synthesis in healthy older adults : a randomized crossover trial" 12 : E3276-, 2020
• 15 Kim IY, "The anabolic response to a meal containing different amounts of protein is not limited by the maximal stimulation of protein synthesis in healthy young adults" 310 : E73-80, 2016
• 16 Romijn JA, "Substrate metabolism during different exercise intensities in endurance-trained women" 88 : 1707-1714, 2000
• 17 Chaumeil MM, "Studies of metabolism using(13)C MRS of hyperpolarized probes" 561 : 1-71, 2015
• 18 Romijn JA, "Strenuous endurance training increases lipolysis and triglyceride-fatty acid cycling at rest" 75 : 108-113, 1993
• 19 Kouw IW, "Sodium nitrate co-ingestion with protein does not augment postprandial muscle protein synthesis rates in older, type 2 diabetes patients" 311 : E325-34, 2016
• 20 Groennebaek T, "Skeletal muscle mitochondrial protein synthesis and respiration increase with low-load blood flow restricted as well as high-load resistance training" 9 : 1796-, 2018
• 21 Deja S, "Simultaneous tracers and a unified model of positional and mass isotopomers for quantification of metabolic flux in liver" 59 : 1-14, 2020
• 22 Kaplan W, "Short-term effects of recombinant human growth hormone and feeding on gluconeogenesis in humans" 57 : 725-732, 2008
• 23 Kim IY, "Short term elevation in dietary protein intake does not worsen insulin resistance or lipids in older adults with metabolic syndrome : a randomized-controlled trial" 3 : 33-, 2017
• 24 Berryman CE, "Severe negative energy balance during 21 d at high altitude decreases fat-free mass regardless of dietary protein intake : a randomized controlled trial" 32 : 894-905, 2018
• 25 Weber JM, "Role of the glucose cycle in control of net glucose flux in exercising humans" 68 : 1815-1819, 1990
• 26 Meyer C, "Role of human liver, kidney, and skeletal muscle in postprandial glucose homeostasis" 282 : E419-27, 2002
• 27 Wolfe RR, "Role of changes in insulin and glucagon in glucose homeostasis in exercise" 77 : 900-907, 1986
• 28 Romijn JA, "Regulation of endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration" 265 (265): E380-91, 1993
• 29 Kim IY, "Quantity of dietary protein intake, but not pattern of intake, affects net protein balance primarily through differences in protein synthesis in older adults" 308 : E21-8, 2015
• 30 Neinast MD, "Quantitative analysis of the whole-body metabolic fate of branched-chain amino acids" 29 : 417-429, 2019
• 31 Liu S, "Quantitative analysis of the physiological contributions of glucose to the TCA cycle" 32 : 619-628, 2020
• 32 Wang SP, "Quantifying rates of glucose production in vivo following an intraperitoneal tracer bolus" 311 : E911-21, 2016
• 33 김일영, "Quantifications of Lipid Kinetics In Vivo Using Stable Isotope Tracer Methodology" 한국지질동맥경화학회 9 (9): 110-123, 2020
• 34 Asghar R, "Quantification of muscle triglyceride synthesis rate requires an adjustment for total triglyceride content" 59 : 2018-2024, 2018
• 35 Martini WZ, "Quantification of DNA synthesis from different pathways in cultured human fibroblasts and myocytes" 53 : 128-133, 2004
• 36 Kim IY, "Quality of meal protein determines anabolic response in older adults" 37 (37): 2076-2083, 2018
• 37 Henderson GC, "Pyruvate shuttling during rest and exercise before and after endurance training in men" 97 : 317-325, 2004
• 38 Waterlow JC, "Protein turnover in mammalian tissues and in the whole body" North-Holland Pub. Co 1978
• 39 Kim IY, "Protein intake distribution pattern does not affect anabolic response, lean body mass, muscle strength or function over 8 weeks in older adults : a randomizedcontrolled trial" 37 : 488-493, 2018
• 40 Chopra S, "Obstructive sleep apnea dynamically increases nocturnal plasma free fatty acids, glucose, and cortisol during sleep" 102 : 3172-3181, 2017
• 41 Sun RC, "Noninvasive liquid diet delivery of stable isotopes into mouse models for deep metabolic network tracing" 8 : 1646-, 2017
• 42 Perry RJ, "Non-invasive assessment of hepatic mitochondrial metabolism by positional isotopomer NMR tracer analysis(PINTA)" 8 : 798-, 2017
• 43 Hellerstein MK, "New stable isotope-mass spectrometric techniques for measuring fluxes through intact metabolic pathways in mammalian systems : introduction of moving pictures into functional genomics and biochemical phenotyping" 6 : 85-100, 2004
• 44 Burd NA, "Muscle time under tension during resistance exercise stimulates differential muscle protein subfractional synthetic responses in men" 590 : 351-362, 2012
• 45 Brooks GA, "Muscle accounts for glucose disposal but not blood lactate appearance during exercise after acclimatization to 4, 300m" 72 : 2435-2445, 1992
• 46 Miller BF, "Modeling the contribution of individual proteins to mixed skeletal muscle protein synthetic rates over increasing periods of label incorporation" 118 : 655-661, 2015
• 47 Drake JC, "Mitophagy in maintaining skeletal muscle mitochondrial proteostasis and metabolic health with ageing" 595 : 6391-6399, 2017
• 48 Previs SF, "Methods for measuring gluconeogenesis in vivo" 1 : 461-465, 1998
• 49 Jang C, "Metabolomics and isotope tracing" 173 : 822-837, 2018
• 50 Bowe JE, "Metabolic phenotyping guidelines : assessing glucose homeostasis in rodent models" 222 : G13-25, 2014
• 51 Tigas S, "Metabolic adaptation to feeding and fasting during lactation in humans" 87 : 302-307, 2002
• 52 Katanik J, "Measuring gluconeogenesis using a low dose of 2H2O : advantage of isotope fractionation during gas chromatography" 284 : E1043-8, 2003
• 53 Chung ST, "Measurements of gluconeogenesis and glycogenolysis : a methodological review" 64 : 3996-4010, 2015
• 54 Zhang XJ, "Measurement of precursor enrichment for calculating intramuscular triglyceride fractional synthetic rate" 53 : 119-125, 2012
• 55 Reaven GM, "Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients with NIDDM" 37 : 1020-1024, 1988
• 56 Lee WN, "Mass isotopomer study of the nonoxidative pathways of the pentose cycle with [1, 2-13C2]glucose" 274 : E843-51, 1998
• 57 Hellerstein MK, "Mass isotopomer distribution analysis at eight years : theoretical, analytic, and experimental considerations" 276 : E1146-70, 1999
• 58 Hellerstein MK, "Mass isotopomer distribution analysis : a technique for measuring biosynthesis and turnover of polymers" 263 (263): E988-1001, 1992
• 59 Suh SH, "Luteal and follicular glucose fluxes during rest and exercise in 3-h postabsorptive women" 93 : 42-50, 2002
• 60 Coyle EF, "Low-fat diet alters intramuscular substrates and reduces lipolysis and fat oxidation during exercise" 280 : E391-8, 2001
• 61 Horowitz JF, "Lipolytic suppression following carbohydrate ingestion limits fat oxidation during exercise" 273 : E768-75, 1997
• 62 Perry RJ, "Leptin mediates a glucose-fatty acid cycle to maintain glucose homeostasis in starvation" 172 : 234-248, 2018
• 63 Romijn JA, "Lactatepyruvate interconversion in blood : implications for in vivo tracer studies" 266 (266): E334-40, 1994
• 64 Messonnier LA, "Lactate kinetics at the lactate threshold in trained and untrained men" 114 : 1593-1602, 2013
• 65 Miller BF, "Lactate and glucose interactions during rest and exercise in men : effect of exogenous lactate infusion" 544 : 963-975, 2002
• 66 Wolfe RR, "Isotope tracers in metabolic research: principles and practice of kinetic analysis" Wiley-Liss 2005
• 67 Wojtaszewski JF, "Invited review:effect of acute exercise on insulin signaling and action in humans" 93 : 384-392, 2002
• 68 Schricker T, "Integrated analysis of protein and glucose metabolism during surgery: effects of anesthesia" 91 : 2523-2530, 2001
• 69 Bukhari SS, "Intake of low-dose leucine-rich essential amino acids stimulates muscle anabolism equivalently to bolus whey protein in older women at rest and after exercise" 308 : E1056-65, 2015
• 70 Vatner DF, "Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids" 112 : 1143-1148, 2015
• 71 van Haeften TW, "Insulin secretion in normal glucose-tolerant relatives of type 2 diabetic subjects. Assessments using hyperglycemic glucose clamps and oral glucose tolerance tests" 21 : 278-282, 1998
• 72 Steele R, "Influences of glucose loading and of injected insulin on hepatic glucose output" 82 : 420-430, 1959
• 73 Jaleel A, "In vivo measurement of synthesis rate of individual skeletal muscle mitochondrial proteins" 295 : E1255-68, 2008
• 74 Lee WN, "In vivo measurement of fatty acids and cholesterol synthesis using D2O and mass isotopomer analysis" 266 (266): E699-708, 1994
• 75 Pietzsch J, "In vivo evidence for increased apolipoprotein A-I catabolism in subjects with impaired glucose tolerance" 47 : 1928-1934, 1998
• 76 Hasenour CM, "In vivo estimates of liver metabolic flux assessed by 13c-propionate and 13clactate are impacted by tracer recycling and equilibrium assumptions" 32 : 107986-, 2020
• 77 Marjanska M, "In vivo 13C spectroscopy in the rat brain using hyperpolarized [1-(13)C]pyruvate and [2-(13)C]pyruvate" 206 : 210-218, 2010
• 78 Nathan DM, "Impaired fasting glucose and impaired glucose tolerance : implications for care" 30 : 753-759, 2007
• 79 Kim JK, "Hyperinsulinemic-euglycemic clamp to assess insulin sensitivity in vivo" 560 : 221-238, 2009
• 80 Umpierrez GE, "Hyperglycemia : an independent marker of inhospital mortality in patients with undiagnosed diabetes" 87 : 978-982, 2002
• 81 Wardle SL, "Human skeletal muscle metabolic responses to 6 days of high-fat overfeeding are associated with dietary n-3PUFA content and muscle oxidative capacity" 8 : e14529-, 2020
• 82 Hellerstein MK, "Hepatic gluconeogenic fluxes and glycogen turnover during fasting in humans. A stable isotope study" 100 : 1305-1319, 1997
• 83 Biolo G, "Harry M. Vars Research Award. A new model to determine in vivo the relationship between amino acid transmembrane transport and protein kinetics in muscle" 16 : 305-315, 1992
• 84 MacDonald AJ, "Habitual myofibrillar protein synthesis is normal in patients with upper GI cancer cachexia" 21 : 1734-1740, 2015
• 85 Wang Y, "Glycerol not lactate is the major net carbon source for gluconeogenesis in mice during both short and prolonged fasting" 31 : 36-44, 2020
• 86 Baba H, "Glycerol gluconeogenesis in fasting humans" 11 : 149-153, 1995
• 87 Sidossis LS, "Glucose plus insulin regulate fat oxidation by controlling the rate of fatty acid entry into the mitochondria" 98 : 2244-2250, 1996
• 88 Jeukendrup AE, "Glucose kinetics during prolonged exercise in highly trained human subjects : effect of glucose ingestion" 515 (515): 579-589, 1999
• 89 Hui S, "Glucose feeds the TCA cycle via circulating lactate" 551 : 115-118, 2017
• 90 Jacobs KA, "Fatty acid reesterification but not oxidation is increased by oral contraceptive use in women" 98 : 1720-1731, 2005
• 91 Fernandez-Calleja JMS, "Extended indirect calorimetry with isotopic CO2 sensors for prolonged and continuous quantification of exogenous vs. total substrate oxidation in mice" 9 : 11507-, 2019
• 92 Sunny NE, "Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease" 14 : 804-810, 2011
• 93 Coker RH, "Essential amino acid-enriched meal replacement promotes superior net protein balance in older, overweight adults" 38 : 2821-2826, 2019
• 94 Robinson MM, "Enhanced protein translation underlies improved metabolic and physical adaptations to different exercise training modes in young and old humans" 25 : 581-592, 2017
• 95 Coggan AR, "Endurance training decreases plasma glucose turnover and oxidation during moderate-intensity exercise in men" 68 : 990-996, 1990
• 96 Gumbiner B, "Effects of weight loss and reduced hyperglycemia on the kinetics of insulin secretion in obese noninsulin dependent diabetes mellitus" 70 : 1594-1602, 1990
• 97 Suh SH, "Effects of oral contraceptives on glucose flux and substrate oxidation rates during rest and exercise" 94 : 285-294, 2003
• 98 Goodpaster BH, "Effects of obesity on substrate utilization during exercise" 10 : 575-584, 2002
• 99 Klein S, "Effect of endurance training on glycerol kinetics during strenuous exercise in humans" 45 : 357-361, 1996
• 100 Song JD, "Dissociation of muscle insulin resistance from alterations in mitochondrial substrate preference" 32 : 726-735, 2020
• 101 Mazzeo RS, "Disposal of blood [1-13C]lactate in humans during rest and exercise" 60 : 232-241, 1986
• 102 Greenhaff PL, "Disassociation between the effects of amino acids and insulin on signaling, ubiquitin ligases, and protein turnover in human muscle" 295 : E595-604, 2008
• 103 Antoniewicz MR, "Determination of confidence intervals of metabolic fluxes estimated from stable isotope measurements" 8 : 324-337, 2006
• 104 Ekberg K, "Contributions by kidney and liver to glucose production in the postabsorptive state and after 60 h of fasting" 48 : 292-298, 1999
• 105 Kim IY, "Consumption of a specially-formulated mixture of essential amino acids promotes gain in whole-body protein to a greater extent than a complete meal replacement in older women with heart failure" 11 : 1360-, 2019
• 106 Romijn JA, "Comparison of indirect calorimetry and a new breath 13C/12C ratio method during strenuous exercise" 263 (263): E64-71, 1992
• 107 Shankaran M, "Circulating protein synthesis rates reveal skeletal muscle proteome dynamics" 126 : 288-302, 2016
• 108 Toffolo G, "Assessment of postprandial glucose metabolism : conventional dual-vs. triple-tracer method" 291 : E800-6, 2006
• 109 Lau T, "Arginine, citrulline, and nitric oxide metabolism in end-stage renal disease patients" 105 : 1217-1225, 2000
• 110 Luiking YC, "Arginine infusion in patients with septic shock increases nitric oxide production without haemodynamic instability" 128 : 57-67, 2015
• 111 Marini JC, "Arginine and ornithine are the main precursors for citrulline synthesis in mice" 142 : 572-580, 2012
• 112 김일영, "Applications of stable, nonradioactive isotope tracers in in vivo human metabolic research" 생화학분자생물학회 48 : 1-10, 2016
• 113 Hines KM, "Application of high-resolution mass spectrometry to measure low abundance isotope enrichment in individual muscle proteins" 407 : 4045-4052, 2015
• 114 Kowalski GM, "Application of dynamic metabolomics to examine in vivo skeletal muscle glucose metabolism in the chronically high-fat fed mouse" 462 : 27-32, 2015
• 115 Park S, "Anabolic response to essential amino acid plus whey protein composition is greater than whey protein alone in young healthy adults" 17 : 9-, 2020
• 116 Rosen ED, "Adipocytes as regulators of energy balance and glucose homeostasis" 444 : 847-853, 2006
• 117 Kim IY, "Acute lysine supplementation does not improve hepatic or peripheral insulin sensitivity in older, overweight individuals" 11 : 49-, 2014
• 118 Kim IY, "Acute ingestion of citrulline stimulates nitric oxide synthesis but does not increase blood flow in healthy young and older adults with heart failure" 309 : E915-24, 2015
• 119 Buescher JM, "A roadmap for interpreting(13)C metabolite labeling patterns from cells" 34 : 189-201, 2015
• 120 Brook MS, "A novel D2O tracer method to quantify RNA turnover as a biomarker of de novo ribosomal biogenesis, in vitro, in animal models, and in human skeletal muscle" 313 : E681-9, 2017
• 121 Gasier HG, "A comparison of 2H2O and phenylalanine flooding dose to investigate muscle protein synthesis with acute exercise in rats" 297 : E252-9, 2009
• 122 Antoniewicz MR, "13C metabolic flux analysis : optimal design of isotopic labeling experiments" 24 : 1116-1121, 2013
• 123 Young JD, "(13)C metabolic flux analysis of recombinant expression hosts" 30 : 238-245, 2014