Emerging applications of metabolomic and genomic profiling in diabetic clinical medicine

Aine M McKillop, Peter R Flatt, Aine M McKillop, Peter R Flatt

Abstract

Clinical and epidemiological metabolomics provides a unique opportunity to look at genotype-phenotype relationships as well as the body\x{2019}s responses to environmental and lifestyle factors. Fundamentally, it provides information on the universal outcome of influencing factors on disease states and has great potential in the early diagnosis, therapy monitoring, and understanding of the pathogenesis of disease. Diseases, such as diabetes, with a complex set of interactions between genetic and environmental factors, produce changes in the body\x{2019}s biochemical profile, thereby providing potential markers for diagnosis and initiation of therapies. There is clearly a need to discover new ways to aid diagnosis and assessment of glycemic status to help reduce diabetes complications and improve the quality of life. Many factors, including peptides, proteins, metabolites, nucleic acids, and polymorphisms, have been proposed as putative biomarkers for diabetes. Metabolomics is an approach used to identify and assess metabolic characteristics, changes, and phenotypes in response to influencing factors, such as environment, diet, lifestyle, and pathophysiological states. The specificity and sensitivity using metabolomics to identify biomarkers of disease have become increasingly feasible because of advances in analytical and information technologies. Likewise, the emergence of high-throughput genotyping technologies and genome-wide association studies has prompted the search for genetic markers of diabetes predisposition or susceptibility. In this review, we consider the application of key metabolomic and genomic methodologies in diabetes and summarize the established, new, and emerging metabolomic and genomic biomarkers for the disease. We conclude by summarizing future insights into the search for improved biomarkers for diabetes research and human diagnostics.

References

    1. 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 ONE 2010;5:e10538.
    1. Li LO, Hu YF, Wang L, Mitchell M, Berger A, Coleman RA. Early hepatic insulin resistance in mice: a metabolomics analysis. Mol Endocrinol 2010;24:657–666
    1. Bain JR, Stevens RD, Wenner BR, Ilkayeva O, Muoio DM, Newgard CB. Metabolomics applied to diabetes research: moving from information to knowledge. Diabetes 2009;58:2429–2443
    1. Meisinger C, Löwel H, Heier M, Schneider A, Thorand B; KORA Study Group Serum gamma-glutamyltransferase and risk of type 2 diabetes mellitus in men and women from the general population. J Intern Med 2005;258:527–535
    1. Schindhelm RK, Diamant M, Dekker JM, Tushuizen ME, Teerlink T, Heine RJ. Alanine aminotransferase as a marker of non-alcoholic fatty liver disease in relation to type 2 diabetes mellitus and cardiovascular disease. Diabetes Metab Res Rev 2006;22:437–443
    1. Sattar N, Wannamethee SG, Forouhi NG. Novel biochemical risk factors for type 2 diabetes: pathogenic insights or prediction possibilities? Diabetologia 2008;51:926–940
    1. Kolberg JA, Jørgensen T, Gerwien RW, et al. Development of a type 2 diabetes risk model from a panel of serum biomarkers from the Inter99 cohort. Diabetes Care 2009;32:1207–1212
    1. Salomaa V, Havulinna A, Saarela O, et al. Thirty-one novel biomarkers as predictors for clinically incident diabetes. PLoS ONE 2010;5:e10100.
    1. Christ A, Evers S, Krapfenbauer K, Sebokova E. Pancreatic polypeptide as target/marker of beta cell failure. US patent 2009/0215069. 27 August 2009
    1. Amrein K, Berndt P, Evers S, Foster S, Fountoulakis M, Sebokova E. Fibronectin as target/marker for insulin resistance. International patent WO/2007/06278. 7 June 2007
    1. Stefan N, Fritsche A, Weikert C, et al. Plasma fetuin-A levels and the risk of type 2 diabetes. Diabetes 2008;57:2762–2767
    1. Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 2006;295:1288–1299
    1. Sandhu MS. Insulin-like growth factor-I and risk of type 2 diabetes and coronary heart disease: molecular epidemiology. Endocr Dev 2005;9:44–54
    1. Armbruster DA. Fructosamine: structure, analysis, and clinical usefulness. Clin Chem 1987;33:2153–2163
    1. Nowatzke W, Sarno MJ, Birch NC, Stickle DF, Eden T, Cole TG. Evaluation of an assay for serum 1,5-anhydroglucitol (GlycoMark) and determination of reference intervals on the Hitachi 917 analyzer. Clin Chim Acta 2004;350:201–209
    1. Kouzuma T, Usami T, Yamakoshi M, Takahashi M, Imamura S. An enzymatic method for the measurement of glycated albumin in biological samples. Clin Chim Acta 2002;324:61–71
    1. Lindsay JR, McKillop AM, Mooney MH, O’Harte FPM, Bell PM, Flatt PR. Demonstration of increased concentrations of circulating glycated insulin in human type 2 diabetes using a novel and specific radioimmunoassay. Diabetologia 2003;46:475–478
    1. Rittenhouse J, Koda J, Fineman M, Percy A. Glycosylated amylins. International patent WO/1997/035600. 2 October 1997
    1. Cohen MP. Monoclonal antibodies against glycated low density lipoprotein. US patent 5,494,791. 27 February 1996
    1. Maritim AC, Sanders RA, Watkins JB., 3rd Diabetes, oxidative stress, and antioxidants: a review. J Biochem Mol Toxicol 2003;17:24–38
    1. Sargeant LA, Wareham NJ, Bingham S, et al. Vitamin C and hyperglycemia in the European Prospective Investigation into Cancer—Norfolk (EPIC-Norfolk) study: a population-based study. Diabetes Care 2000;23:726–732
    1. Zhao G, Ford ES, Li C. Associations of serum concentrations of 25-hydroxyvitamin D and parathyroid hormone with surrogate markers of insulin resistance among U.S. adults without physician-diagnosed diabetes: NHANES, 2003-2006. Diabetes Care 2010;33:344–347
    1. Wang TJ, Larson MG, Vasan RS, et al. Metabolite profiles and the risk of developing diabetes. Nat Med 2011;17:448–453
    1. Koyama H, Yamamoto H, Nishizawa Y. Endogenous secretory RAGE as a novel biomarker for metabolic syndrome and cardiovascular diseases. Biomark Insights 2007;2:331–339
    1. Thorand B, Zierer A, Baumert J, Meisinger C, Herder C, Koenig W. Associations between leptin and the leptin/adiponectin ratio and incident type 2 diabetes in middle-aged men and women: results from the MONICA/KORA Augsburg study 1984-2002. Diabet Med 2010;27:1004–1011
    1. Freeman DJ, Norrie J, Caslake MJ, et al. ; West of Scotland Coronary Prevention Study C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes 2002;51:1596–1600
    1. Thorand B, Kolb H, Baumert J, et al. Elevated levels of interleukin-18 predict the development of type 2 diabetes: results from the MONICA/KORA Augsburg Study, 1984-2002. Diabetes 2005;54:2932–2938
    1. Herder C, Brunner EJ, Rathmann W, et al. Elevated levels of the anti-inflammatory interleukin-1 receptor antagonist precede the onset of type 2 diabetes: the Whitehall II study. Diabetes Care 2009;32:421–423
    1. Festa A, D’Agostino R, Jr, Tracy RP, Haffner SM; Insulin Resistance Atherosclerosis Study Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes 2002;51:1131–1137
    1. Song Y, Manson JE, Tinker L, et al. Circulating levels of endothelial adhesion molecules and risk of diabetes in an ethnically diverse cohort of women. Diabetes 2007;56:1898–1904
    1. Wannamethee SG, Sattar N, Rumley A, Whincup PH, Lennon L, Lowe GD. Tissue plasminogen activator, von Willebrand factor, and risk of type 2 diabetes in older men. Diabetes Care 2008;31:995–1000
    1. Voight BF, Scott LJ, Steinthorsdottir V, et al. ; MAGIC investigators; GIANT Consortium Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 2010;42:579–589
    1. Grant SF, Thorleifsson G, Reynisdottir I, et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 2006;38:320–323
    1. Scott LJ, Mohlke KL, Bonnycastle LL, et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 2007;316:1341–1345
    1. Sandhu MS, Weedon MN, Fawcett KA, et al. Common variants in WFS1 confer risk of type 2 diabetes. Nat Genet 2007;39:951–953
    1. Winckler W, Weedon MN, Graham RR, et al. Evaluation of common variants in the six known maturity-onset diabetes of the young (MODY) genes for association with type 2 diabetes. Diabetes 2007;56:685–693
    1. Zeggini E, Scott LJ, Saxena R, et al. ; Wellcome Trust Case Control Consortium Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 2008;40:638–645
    1. Saxena R, Hivert MF, Langenberg C, et al. ; GIANT consortium; MAGIC investigators Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Genet 2010;42:142–148
    1. Salonen JT, Uimari P, Aalto JM, et al. Type 2 diabetes whole-genome association study in four populations: the DiaGen consortium. Am J Hum Genet 2007;81:338–345
    1. Zeggini E, Weedon MN, Lindgren CM, et al. ; Wellcome Trust Case Control Consortium (WTCCC) Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 2007;316:1336–1341
    1. Rung J, Cauchi S, Albrechtsen A, et al. Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia. Nat Genet 2009;41:1110–1115
    1. Soranzo N, Sanna S, Wheeler E, et al. ; WTCCC Common variants at 10 genomic loci influence hemoglobin A1c levels via glycemic and nonglycemic pathways. Diabetes 2010;59:3229–3239
    1. Schleinitz D, Tönjes A, Böttcher Y, et al. Lack of significant effects of the type 2 diabetes susceptibility loci JAZF1, CDC123/CAMK1D, NOTCH2, ADAMTS9, THADA, and TSPAN8/LGR5 on diabetes and quantitative metabolic traits. Horm Metab Res 2010;42:14–22
    1. Boraska V, Rayner NW, Groves CJ, et al. Large-scale association analysis of TNF/LTA gene region polymorphisms in type 2 diabetes. BMC Med Genet 2010;11:69.
    1. Arora P, Garcia-Bailo B, Dastani Z, et al. Genetic polymorphisms of innate immunity-related inflammatory pathways and their association with factors related to type 2 diabetes. BMC Med Genet 2011;12:95.
    1. McDonald TJ, Shields BM, Lawry J, Owen KR, Gloyn AL, Ellard S, Hattersley AT. High-sensitivity CRP discriminates HNF1A-MODY from other subtypes of diabetes. Diabetes Care 2011;34:1860–1862
    1. Psychogios N, Hau DD, Peng J, et al. The human serum metabolome. PLoS ONE 2011;6:e16957.
    1. Erlich H, Valdes AM, Noble J, et al. ; Type 1 Diabetes Genetics Consortium HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes 2008;57:1084–1092
    1. Varney MD, Valdes AM, Carlson JA, et al. ; Type 1 Diabetes Genetics Consortium HLA DPA1, DPB1 alleles and haplotypes contribute to the risk associated with type 1 diabetes: analysis of the type 1 diabetes genetics consortium families. Diabetes 2010;59:2055–2062
    1. Pugliese A, Gianani R, Moromisato R, et al. HLA-DQB1*0602 is associated with dominant protection from diabetes even among islet cell antibody-positive first-degree relatives of patients with IDDM. Diabetes 1995;44:608–613
    1. Steck AK, Armstrong TK, Babu SR, Eisenbarth GS; Type 1 Diabetes Genetics Consortium Stepwise or linear decrease in penetrance of type 1 diabetes with lower-risk HLA genotypes over the past 40 years. Diabetes 2011;60:1045–1049
    1. Noble JA, Martin A, Valdes AM, et al. Type 1 diabetes risk for human leukocyte antigen (HLA)-DR3 haplotypes depends on genotypic context: association of DPB1 and HLA class I loci among DR3- and DR4-matched Italian patients and controls. Hum Immunol 2008;69:291–300
    1. Valdes AM, Erlich HA, Noble JA. Human leukocyte antigen class I B and C loci contribute to Type 1 Diabetes (T1D) susceptibility and age at T1D onset. Hum Immunol 2005;66:301–313
    1. Steck AK, Rewers MJ. Genetics of type 1 diabetes. Clin Chem 2011;57:176–185
    1. Bell GI, Horita S, Karam JH. A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes 1984;33:176–183
    1. Concannon P, Chen WM, Julier C, et al. ; Type 1 Diabetes Genetics Consortium Genome-wide scan for linkage to type 1 diabetes in 2,496 multiplex families from the Type 1 Diabetes Genetics Consortium. Diabetes 2009;58:1018–1022
    1. Bottini N, Musumeci L, Alonso A, et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 2004;36:337–338
    1. Barrett JC, Clayton DG, Concannon P, et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 2009;41:703–707
    1. Concannon P, Onengut-Gumuscu S, Todd JA, et al. ; Type 1 Diabetes Genetics Consortium A human type 1 diabetes susceptibility locus maps to chromosome 21q22.3. Diabetes 2008;57:2858–2861
    1. Guo D, Li M, Zhang Y, et al. A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes. Nat Genet 2004;36:837–841

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe