Metabolomics in human type 2 diabetes research

Abstract

The high prevalence of diabetes and diabetic complications has caused a huge burden on the modern society. Although scientific advances have led to effective strategies for preventing and treating diabetes over the past several decades, little progress has been made toward curing the disease or even getting it under control, from a public health and overall societal standpoint. There is still a lack of reliable biomarkers indicative of metabolic alterations associated with diabetes and different drug responses, highlighting the need for the development of early diagnostic and prognostic markers for diabetes and diabetic complications. The emergence of metabolomics has allowed researchers to systemically measure the small molecule metabolites, which are sensitive to the changes of both environmental and genetic factors and therefore, could be regarded as the link between genotypes and phenotypes. During the last decade, the progression made in metabolomics has provided insightful information on disease development and disease onset prediction. Recent studies using metabolomics approach coupled with statistical tools to predict incident diabetes revealed a number of metabolites that are significantly altered, including branched-chain and aromatic amino acids, such as isoleucine, leucine, valine, tyrosine and phenylalanine, as diagnostic or highly-significant predictors of future diabetes. This review summarizes the current findings of metabolomic studies in human investigations with the most common form of diabetes, type 2 diabetes.

Keywords

metabolomics / type 2 diabetes / metabolic pathway / mass spectrometry / nuclear magnetic resonance (NMR)

References

[1] World Health Organization. Diabetes: Fact sheet N°312. 2011

[2] National Diabetes Information Clearinghouse (NDIC). Complications of Diabetes. 2012

[3] Friedrich N. Metabolomics in diabetes research. J Endocrinol2012; 215(1): 29-42

[4] Pal A, McCarthy M . The genetics of type 2 diabetes and its clinical relevance. Clin Genet 2012 Nov 20. [Epub ahead of print]

[5] Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G, McCulloch LJ, Ferreira T, Grallert H, Amin N, Wu G, Willer CJ, Raychaudhuri S, McCarroll SA, Langenberg C, Hofmann OM, Dupuis J, Qi L, Segrè AV, van Hoek M, Navarro P, Ardlie K, Balkau B, Benediktsson R, Bennett AJ, Blagieva R, Boerwinkle E, Bonnycastle LL, Bengtsson Boström K, Bravenboer B, Bumpstead S, Burtt NP, Charpentier G, Chines PS, Cornelis M, Couper DJ, Crawford G, Doney AS, Elliott KS, Elliott AL, Erdos MR, Fox CS, Franklin CS, Ganser M, Gieger C, Grarup N, Green T, Griffin S, Groves CJ, Guiducci C, Hadjadj S, Hassanali N, Herder C, Isomaa B, Jackson AU, Johnson PR, Jørgensen T, Kao WH, Klopp N, Kong A, Kraft P, Kuusisto J, Lauritzen T, Li M, Lieverse A, Lindgren CM, Lyssenko V, Marre M, Meitinger T, Midthjell K, Morken MA, Narisu N, Nilsson P, Owen KR, Payne F, Perry JR, Petersen AK, Platou C, Proença C, Prokopenko I, Rathmann W, Rayner NW, Robertson NR, Rocheleau G, Roden M, Sampson MJ, Saxena R, Shields BM, Shrader P, Sigurdsson G, Sparsø T, Strassburger K, Stringham HM, Sun Q, Swift AJ, Thorand B, Tichet J, Tuomi T, van Dam RM, van Haeften TW, van Herpt T, van Vliet-Ostaptchouk JV, Walters GB, Weedon MN, Wijmenga C, Witteman J, Bergman RN, Cauchi S, Collins FS, Gloyn AL, Gyllensten U, Hansen T, Hide WA, Hitman GA, Hofman A, Hunter DJ, Hveem K, Laakso M, Mohlke KL, Morris AD, Palmer CN, Pramstaller PP, Rudan I, Sijbrands E, Stein LD, Tuomilehto J, Uitterlinden A, Walker M, Wareham NJ, Watanabe RM, Abecasis GR, Boehm BO, Campbell H, Daly MJ, Hattersley AT, Hu FB, Meigs JB, Pankow JS, Pedersen O, Wichmann HE, Barroso I, Florez JC, Frayling TM, Groop L, Sladek R, Thorsteinsdottir U, Wilson JF, Illig T, Froguel P, van Duijn CM, Stefansson K, Altshuler D, Boehnke M, McCarthy MI ; MAGIC investigators; GIANT Consortium. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet2010; 42(7): 579-589

[6] Fiehn O. Combining genomics, metabolome analysis, and biochemical modelling to understand metabolic networks. Comp Funct Genomics2001; 2(3): 155-168

[7] Nicholson JK, Lindon JC, Holmes E. ‘Metabonomics’: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica1999; 29(11): 1181-1189

[8] Lucio M, Fekete A, Weigert C, Wägele B, Zhao X, Chen J, Fritsche A, Häring HU, Schleicher ED, Xu G, Schmitt-Kopplin P, Lehmann R. Insulin sensitivity is reflected by characteristic metabolic fingerprints—a Fourier transform mass spectrometric non-targeted metabolomics approach. PLoS ONE2010; 5(10): e13317

[9] Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, Haqq AM, Shah SH, Arlotto M, Slentz CA, Rochon J, Gallup D, Ilkayeva O, Wenner BR, Yancy WS Jr, Eisenson H, Musante G, Surwit RS, Millington DS, Butler MD, Svetkey LP. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab2009; 9(4): 311-326

[10] Qiu Y, Cai G, Su M, Chen T, Zheng X, Xu Y, Ni Y, Zhao A, Xu LX, Cai S, Jia W. Serum metabolite profiling of human colorectal cancer using GC-TOFMS and UPLC-QTOFMS. J Proteome Res2009; 8(10): 4844-4850

[11] Lanza IR, Zhang S, Ward LE, Karakelides H, Raftery D, Nair KS. Quantitative metabolomics by H-NMR and LC-MS/MS confirms altered metabolic pathways in diabetes. PLoS ONE2010; 5(5): e10538

[12] Bernini P, Bertini I, Luchinat C, Tenori L, Tognaccini A. The cardiovascular risk of healthy individuals studied by NMR metabonomics of plasma samples. J Proteome Res2011; 10(11): 4983-4992

[13] Xie G, Zheng X, Qi X, Cao Y, Chi Y, Su M, Ni Y, Qiu Y, Liu Y, Li H, Zhao A, Jia W. Metabonomic evaluation of melamine-induced acute renal toxicity in rats. J Proteome Res2010; 9(1): 125-133

[14] Chen T, Xie G, Wang X, Fan J, Qiu Y, Zheng X, Qi X, Cao Y, Su M, Xu LX, Yen Y, Liu P, Jia W. Serum and urine metabolite profiling reveals potential biomarkers of human hepatocellular carcinoma. Mol Cell Proteomics2011;10(7):M110.004945

[15] Lenz EM, Wilson ID. Analytical strategies in metabonomics. J Proteome Res2007; 6(2): 443-458

[16] Beckonert O, Keun HC, Ebbels TM, Bundy J, Holmes E, Lindon JC, Nicholson JK. Metabolic profiling, metabolomic and metabonomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts. Nat Protoc2007; 2(11): 2692-2703

[17] Bictash M, Ebbels TM, Chan Q, Loo RL, Yap IK, Brown IJ, de Iorio M, Daviglus ML, Holmes E, Stamler J, Nicholson JK, Elliott P. Opening up the “Black Box”: metabolic phenotyping and metabolome-wide association studies in epidemiology. J Clin Epidemiol2010; 63(9): 970-979

[18] Büscher JM, Czernik D, Ewald JC, Sauer U, Zamboni N. Cross-platform comparison of methods for quantitative metabolomics of primary metabolism. Anal Chem2009; 81(6): 2135-2143

[19] Kim HK, Choi YH, Verpoorte R. NMR-based plant metabolomics: where do we stand, where do we go? Trends Biotechnol2011; 29(6): 267-275

[20] Blumich B. Essential NMR: For Scientists and Engineers. Springer-Verlag Berlin and Heidelberg GmbH & Co. K, 2005

[21] Lu J, Zhou J, Bao Y, Chen T, Zhang Y, Zhao A, Qiu Y, Xie G, Wang C, Jia W, Jia W. Serum metabolic signatures of fulminant type 1 diabetes. J Proteome Res2012; 11(9): 4705-4711

[22] Messana I, Forni F, Ferrari F, Rossi C, Giardina B, Zuppi C. Proton nuclear magnetic resonance spectral profiles of urine in type II diabetic patients. Clin Chem1998; 44(7): 1529-1534

[23] Salek RM, Maguire ML, Bentley E, Rubtsov DV, Hough T, Cheeseman M, Nunez D, Sweatman BC, Haselden JN, Cox RD, Connor SC, Griffin JL. A metabolomic comparison of urinary changes in type 2 diabetes in mouse, rat, and human. Physiol Genomics2007; 29(2): 99-108

[24] Yamanouchi T, Tachibana Y, Akanuma H, Minoda S, Shinohara T, Moromizato H, Miyashita H, Akaoka I. Origin and disposal of 1,5-anhydroglucitol, a major polyol in the human body. Am J Physiol1992; 263(2 Pt 1): E268-E273

[25] Yamanouchi T, Akanuma H, Asano T, Konishi C, Akaoka I, Akanuma Y. Reduction and recovery of plasma 1,5-anhydro-D-glucitol level in diabetes mellitus. Diabetes1987; 36(6): 709-715

[26] Dungan KM, Buse JB, Largay J, Kelly MM, Button EA, Kato S, Wittlin S. 1,5-anhydroglucitol and postprandial hyperglycemia as measured by continuous glucose monitoring system in moderately controlled patients with diabetes. Diabetes Care2006; 29(6): 1214-1219

[27] Yamanouchi T, Inoue T, Ogata E, Kashiwabara A, Ogata N, Sekino N, Yoshimura T, Ichiyanagi K, Kawasaki T. Post-load glucose measurements in oral glucose tolerance tests correlate well with 1,5-anhydroglucitol, an indicator of overall glycaemic state, in subjects with impaired glucose tolerance. Clin Sci (Lond)2001; 101(3): 227-233

[28] Yamanouchi T, Ogata N, Tagaya T, Kawasaki T, Sekino N, Funato H, Akaoka L, Miyashita H. Clinical usefulness of serum 1,5-anhydroglucitol in monitoring glycaemic control. Lancet1996; 347(9014): 1514-1518

[29] Hanefeld M, Fischer S, Julius U, Schulze J, Schwanebeck U, Schmechel H, Ziegelasch HJ, Lindner J. Risk factors for myocardial infarction and death in newly detected NIDDM: the Diabetes Intervention Study, 11-year follow-up. Diabetologia1996; 39(12): 1577-1583

[30] Muggeo M, Zoppini G, Bonora E, Brun E, Bonadonna RC, Moghetti P, Verlato G. Fasting plasma glucose variability predicts 10-year survival of type 2 diabetic patients: the Verona Diabetes Study. Diabetes Care2000; 23(1): 45-50

[31] Temelkova-Kurktschiev TS, Koehler C, Henkel E, Leonhardt W, Fuecker K, Hanefeld M. Postchallenge plasma glucose and glycemic spikes are more strongly associated with atherosclerosis than fasting glucose or HbA1c level. Diabetes Care2000; 23(12): 1830-1834

[32] Erlinger TP, Brancati FL. Postchallenge hyperglycemia in a national sample of U.S. adults with type 2 diabetes. Diabetes Care2001; 24(10): 1734-1738

[33] Kannel WB. Lipids, diabetes, and coronary heart disease: insights from the Framingham Study. Am Heart J1985; 110(5): 1100-1107

[34] Krauss RM, Siri PW. Dyslipidemia in type 2 diabetes. Med Clin North Am2004; 88(4): 897-909, x

[35] Taskinen MR. Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia2003; 46(6): 733-749

[36] Fiehn O, Garvey WT, Newman JW, Lok KH, Hoppel CL, Adams SH. Plasma metabolomic profiles reflective of glucose homeostasis in non-diabetic and type 2 diabetic obese African-American women. PLoS ONE2010; 5(12): e15234

[37] Balasse EO, Féry F. Ketone body production and disposal: effects of fasting, diabetes, and exercise. Diabetes Metab Rev1989; 5(3): 247-270

[38] Suhre K, Meisinger C, Döring A, Altmaier E, Belcredi P, Gieger C, Chang D, Milburn MV, Gall WE, Weinberger KM, Mewes HW, Hrabé de Angelis M, Wichmann HE, Kronenberg F, Adamski J, Illig T. Metabolic footprint of diabetes: a multiplatform metabolomics study in an epidemiological setting. PLoS ONE2010; 5(11): e13953

[39] Blaak EE, van Aggel-Leijssen DP, Wagenmakers AJ, Saris WH, van Baak MA. Impaired oxidation of plasma-derived fatty acids in type 2 diabetic subjects during moderate-intensity exercise. Diabetes2000; 49(12): 2102-2107

[40] Kelley DE. Skeletal muscle fat oxidation: timing and flexibility are everything. J Clin Invest2005; 115(7): 1699-1702

[41] Kelley DE, Goodpaster B, Wing RR, Simoneau JA. Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. Am J Physiol1999; 277(6 Pt 1): E1130-E1141

[42] Adams SH, Hoppel CL, Lok KH, Zhao L, Wong SW, Minkler PE, Hwang DH, Newman JW, Garvey WT. Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African-American women. J Nutr2009; 139(6): 1073-1081

[43] Kramer HF, Goodyear LJ. Exercise, MAPK, and NF-kappaB signaling in skeletal muscle. J Appl Physiol2007; 103(1): 388-395

[44] Tilg H, Moschen AR. Inflammatory mechanisms in the regulation of insulin resistance. Mol Med2008; 14(3-4): 222-231

[45] Mihalik SJ, Goodpaster BH, Kelley DE, Chace DH, Vockley J, Toledo FG, DeLany JP. Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity. Obesity (Silver Spring)2010; 18(9): 1695-1700

[46] Ha CY, Kim JY, Paik JK, Kim OY, Paik YH, Lee EJ, Lee JH. The association of specific metabolites of lipid metabolism with markers of oxidative stress, inflammation and arterial stiffness in men with newly diagnosed type 2 diabetes. Clin Endocrinol (Oxf)2012; 76(5): 674-682

[47] Mihalik SJ, Michaliszyn SF, de las Heras J, Bacha F, Lee S, Chace DH, DeJesus VR, Vockley J, Arslanian SA. Metabolomic profiling of fatty acid and amino acid metabolism in youth with obesity and type 2 diabetes: evidence for enhanced mitochondrial oxidation. Diabetes Care2012; 35(3): 605-611

[48] Cole LK, Vance JE, Vance DE. Phosphatidylcholine biosynthesis and lipoprotein metabolism. Biochim Biophys Acta2012; 1821(5): 754-761

[49] Floegel A, Stefan N, Yu Z, Mühlenbruch K, Drogan D, Joost HG, Fritsche A, Häring HU, Hrabe de Angelis M, Peters A, Roden M, Prehn C, Wang-Sattler R, Illig T, Schulze MB, Adamski J, Boeing H, Pischon T. Identification of Serum Metabolites Associated With Risk of Type 2 Diabetes Using a Targeted Metabolomic Approach. Diabetes2012 Oct 4. [Epub ahead of print]

[50] Wang-Sattler R, Yu Z, Herder C, Messias AC, Floegel A, He Y, Heim K, Campillos M, Holzapfel C, Thorand B, Grallert H, Xu T, Bader E, Huth C, Mittelstrass K, Döring A, Meisinger C, Gieger C, Prehn C, Roemisch-Margl W, Carstensen M, Xie L, Yamanaka-Okumura H, Xing G, Ceglarek U, Thiery J, Giani G, Lickert H, Lin X, Li Y, Boeing H, Joost HG, de Angelis MH, Rathmann W, Suhre K, Prokisch H, Peters A, Meitinger T, Roden M, Wichmann HE, Pischon T, Adamski J, Illig T. Novel biomarkers for pre-diabetes identified by metabolomics. Mol Syst Biol2012; 8: 615

[51] Felig P, Marliss E, Cahill GF Jr. Plasma amino acid levels and insulin secretion in obesity. N Engl J Med1969; 281(15): 811-816

[52] Felig P, Wahren J, Hendler R, Brundin T. Splanchnic glucose and amino acid metabolism in obesity. J Clin Invest1974; 53(2): 582-590

[53] Luetscher JA Jr. The Metabolism of Amino Acids in Diabetes Mellitus. J Clin Invest1942; 21(3): 275-279

[54] Huffman KM, Shah SH, Stevens RD, Bain JR, Muehlbauer M, Slentz CA, Tanner CJ, Kuchibhatla M, Houmard JA, Newgard CB, Kraus WE. Relationships between circulating metabolic intermediates and insulin action in overweight to obese, inactive men and women. Diabetes Care2009; 32(9): 1678-1683

[55] Tai ES, Tan ML, Stevens RD, Low YL, Muehlbauer MJ, Goh DL, Ilkayeva OR, Wenner BR, Bain JR, Lee JJ, Lim SC, Khoo CM, Shah SH, Newgard CB. Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men. Diabetologia2010; 53(4): 757-767

[56] Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, McCabe E, Lewis GD, Fox CS, Jacques PF, Fernandez C, O’Donnell CJ, Carr SA, Mootha VK, Florez JC, Souza A, Melander O, Clish CB, Gerszten RE. Metabolite profiles and the risk of developing diabetes. Nat Med2011; 17(4): 448-453

[57] Zhang X, Wang Y, Hao F, Zhou X, Han X, Tang H, Ji L. Human serum metabonomic analysis reveals progression axes for glucose intolerance and insulin resistance statuses. J Proteome Res2009; 8(11): 5188-5195

[58] Bao Y, Zhao T, Wang X, Qiu Y, Su M, Jia W, Jia W. Metabonomic variations in the drug-treated type 2 diabetes mellitus patients and healthy volunteers. J Proteome Res2009; 8(4): 1623-1630

[59] Mochida T, Tanaka T, Shiraki Y, Tajiri H, Matsumoto S, Shimbo K, Ando T, Nakamura K, Okamoto M, Endo F. Time-dependent changes in the plasma amino acid concentration in diabetes mellitus. Mol Genet Metab2011; 103(4): 406-409

[60] Phillips JD, Kushner JP. Fast track to the porphyrias. Nat Med2005; 11(10): 1049-1050

[61] Gall WE, Beebe K, Lawton KA, Adam KP, Mitchell MW, Nakhle PJ, Ryals JA, Milburn MV, Nannipieri M, Camastra S, Natali A, Ferrannini E;βRISC Study Group. alpha-hydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population. PLoS ONE2010; 5(5): e10883

[62] Li X, Xu Z, Lu X, Yang X, Yin P, Kong H, Yu Y, Xu G. Comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry for metabonomics: Biomarker discovery for diabetes mellitus. Anal Chim Acta2009; 633(2): 257-262

[63] Mosharov E, Cranford MR, Banerjee R. The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the transsulfuration pathway and its regulation by redox changes. Biochemistry2000; 39(42): 13005-13011

[64] Persa C, Pierce A, Ma Z, Kabil O, Lou MF. The presence of a transsulfuration pathway in the lens: a new oxidative stress defense system. Exp Eye Res2004; 79(6): 875-886

[65] Kostolanská J, Jakus V, Barák L. HbA1c and serum levels of advanced glycation and oxidation protein products in poorly and well controlled children and adolescents with type 1 diabetes mellitus. J Pediatr Endocrinol Metab; 22(5): 433-442

[66] Bennion LJ, Grundy SM. Effects of diabetes mellitus on cholesterol metabolism in man. N Engl J Med1977; 296(24): 1365-1371

[67] Schwartz SL, Lai YL, Xu J, Abby SL, Misir S, Jones MR, Nagendran S. The effect of colesevelam hydrochloride on insulin sensitivity and secretion in patients with type 2 diabetes: a pilot study. Metab Syndr Relat Disord2010; 8(2): 179-188

[68] Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature2011; 472(7341): 57-63

[69] McGill HC Jr, McMahan CA. Determinants of atherosclerosis in the young. Am J Cardiol1998; 82(10B): 30T-36T

[70] Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation1998; 97(18): 1837-1847

[71] al-Waiz M, Mikov M, Mitchell SC, Smith RL. The exogenous origin of trimethylamine in the mouse. Metabolism1992; 41(2): 135-136

[72] Swann JR, Want EJ, Geier FM, Spagou K, Wilson ID, Sidaway JE, Nicholson JK, Holmes E. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc Natl Acad Sci USA2011; 108(Suppl 1): 4523-4530

[73] Nicholson JK, Holmes E, Wilson ID. Gut microorganisms, mammalian metabolism and personalized health care. Nat Rev Microbiol2005; 3(5): 431-438

[74] Fujimura KE, Slusher NA, Cabana MD, Lynch SV. Role of the gut microbiota in defining human health. Expert Rev Anti Infect Ther2010; 8(4): 435-454

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