Metabolomics and Metabolic Diseases: Where Do We Stand?

Metabolomics, or the comprehensive profiling of small molecule metabolites in cells, tissues, or whole organisms, has undergone a rapid technological evolution in the past two decades. These advances have led to the application of metabolomics to defining predictive biomarkers for incident cardiometabolic diseases and, increasingly, as a blueprint for understanding those diseases' pathophysiologic mechanisms. Progress in this area and challenges for the future are reviewed here.

[1]  R. Kreisberg,et al.  Insulin secretion in obesity. , 1967, The New England journal of medicine.

[2]  P. Clifton Diabetes: Treatment of type 2 diabetes mellitus with bariatric surgery , 2010, Nature Reviews Endocrinology.

[3]  Nicholette D. Palmer,et al.  Metabolomic profile associated with insulin resistance and conversion to diabetes in the Insulin Resistance Atherosclerosis Study. , 2015, The Journal of clinical endocrinology and metabolism.

[4]  Thomas J. Wang,et al.  A diabetes-predictive amino acid score and future cardiovascular disease. , 2013, European heart journal.

[5]  J. Clemente,et al.  Gut Microbiota from Twins Discordant for Obesity Modulate Metabolism in Mice , 2013, Science.

[6]  M. Jensen,et al.  Metabolic cycling in control of glucose-stimulated insulin secretion. , 2008, American journal of physiology. Endocrinology and metabolism.

[7]  Svati H Shah,et al.  Differential Metabolic Impact of Gastric Bypass Surgery Versus Dietary Intervention in Obese Diabetic Subjects Despite Identical Weight Loss , 2011, Science Translational Medicine.

[8]  William L. Lowe,et al.  Metabolic Networks and Metabolites Underlie Associations Between Maternal Glucose During Pregnancy and Newborn Size at Birth , 2016, Diabetes.

[9]  S. Klein,et al.  Effect of Roux-en-Y Gastric Bypass and Laparoscopic Adjustable Gastric Banding on Branched-Chain Amino Acid Metabolism , 2013, Diabetes.

[10]  A. Dyer,et al.  Metabolomics Reveals Broad-Scale Metabolic Perturbations in Hyperglycemic Mothers During Pregnancy , 2013, Diabetes Care.

[11]  P. Bork,et al.  Human gut microbes impact host serum metabolome and insulin sensitivity , 2016, Nature.

[12]  R. Gerszten,et al.  Metabolomic profiling in the prediction of gestational diabetes mellitus , 2015, Diabetologia.

[13]  M. Blüher,et al.  A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism , 2012, Nature.

[14]  S. Hazen,et al.  Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis , 2015, Cell.

[15]  John P. Overington,et al.  An atlas of genetic influences on human blood metabolites , 2014, Nature Genetics.

[16]  S. O’Rahilly,et al.  Human genetics illuminates the paths to metabolic disease , 2009, Nature.

[17]  R. Vasan,et al.  2-Aminoadipic acid is a biomarker for diabetes risk. , 2013, The Journal of clinical investigation.

[18]  M. Orešič,et al.  Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease. , 2016, Journal of hepatology.

[19]  H. Yki-Järvinen,et al.  Non-alcoholic fatty liver disease and risk of type 2 diabetes. , 2016, Best practice & research. Clinical endocrinology & metabolism.

[20]  Shuzhao Li,et al.  Amino Acid Metabolism is Altered in Adolescents with Nonalcoholic Fatty Liver Disease-An Untargeted, High Resolution Metabolomics Study. , 2016, The Journal of pediatrics.

[21]  Alexander Pertsemlidis,et al.  Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease , 2008, Nature Genetics.

[22]  Chad A. Cowan,et al.  β-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors. , 2014, Cell metabolism.

[23]  Y. Bao,et al.  Branched-chain and aromatic amino acid profiles and diabetes risk in Chinese populations , 2016, Scientific Reports.

[24]  W. Kraus,et al.  Validation of the association between a branched chain amino acid metabolite profile and extremes of coronary artery disease in patients referred for cardiac catheterization. , 2014, Atherosclerosis.

[25]  Svati H Shah,et al.  A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. , 2009, Cell metabolism.

[26]  S. Watkins,et al.  GPR120 Is an Omega-3 Fatty Acid Receptor Mediating Potent Anti-inflammatory and Insulin-Sensitizing Effects , 2010, Cell.

[27]  S. Hazen,et al.  Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk , 2016, Cell.

[28]  Andrea Natali,et al.  α-Hydroxybutyrate Is an Early Biomarker of Insulin Resistance and Glucose Intolerance in a Nondiabetic Population , 2010, PloS one.

[29]  Bryan C. Batch,et al.  Branched-chain amino acid levels are associated with improvement in insulin resistance with weight loss , 2012, Diabetologia.

[30]  Jonathan C. Cohen,et al.  Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis , 2014, Hepatology.

[31]  Olga Ilkayeva,et al.  BMI, RQ, Diabetes, and Sex Affect the Relationships Between Amino Acids and Clamp Measures of Insulin Action in Humans , 2014, Diabetes.

[32]  M. Patti,et al.  Metabolomic profiles and childhood obesity , 2014, Obesity.

[33]  D. Altshuler,et al.  Branched chain and aromatic amino acids change acutely following two medical therapies for type 2 diabetes mellitus. , 2013, Metabolism: clinical and experimental.

[34]  Elias Chaibub Neto,et al.  Genetic Networks of Liver Metabolism Revealed by Integration of Metabolic and Transcriptional Profiling , 2008, PLoS genetics.

[35]  L. Willmitzer,et al.  Identification of an intracellular metabolic signature impairing beta cell function in the rat beta cell line INS-1E and human islets , 2011, Diabetologia.

[36]  Dorothy D. Sears,et al.  Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats. , 2011, American journal of physiology. Endocrinology and metabolism.

[37]  C. Newgard Interplay between lipids and branched-chain amino acids in development of insulin resistance. , 2012, Cell metabolism.

[38]  W. Kraus,et al.  Metabolic profiles predict adverse events after coronary artery bypass grafting. , 2012, The Journal of thoracic and cardiovascular surgery.

[39]  E. Ravussin,et al.  Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility. , 2012, Cell metabolism.

[40]  P. Felig,et al.  Plasma amino acid levels and insulin secretion in obesity. , 1970, The New England journal of medicine.

[41]  Christian Gieger,et al.  A genome-wide perspective of genetic variation in human metabolism , 2010, Nature Genetics.

[42]  G. Bray,et al.  FGF21 is an endocrine signal of protein restriction. , 2014, The Journal of clinical investigation.

[43]  Ping Li,et al.  Peroxisome Proliferator-activated Receptor-γ Co-activator 1α-mediated Metabolic Remodeling of Skeletal Myocytes Mimics Exercise Training and Reverses Lipid-induced Mitochondrial Inefficiency* , 2005, Journal of Biological Chemistry.

[44]  A. Attie,et al.  Getting biological about the genetics of diabetes , 2010, Nature Medicine.

[45]  Olga Ilkayeva,et al.  Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. , 2008, Cell metabolism.

[46]  Brian J. Bennett,et al.  Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease , 2011, Nature.

[47]  Terho Lehtimäki,et al.  Branched-Chain and Aromatic Amino Acids Are Predictors of Insulin Resistance in Young Adults , 2013, Diabetes Care.

[48]  P. Spégel,et al.  Time-resolved metabolomics analysis of β-cells implicates the pentose phosphate pathway in the control of insulin release. , 2013, The Biochemical journal.

[49]  B. Zinman,et al.  Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. , 2015, The New England journal of medicine.

[50]  Alan Saghatelian,et al.  Discovery of a Class of Endogenous Mammalian Lipids with Anti-Diabetic and Anti-inflammatory Effects , 2014, Cell.

[51]  C. Gieger,et al.  Human metabolic individuality in biomedical and pharmaceutical research , 2011, Nature.

[52]  Charles R. Evans,et al.  Increased Glucose Metabolism and Glycerolipid Formation by Fatty Acids and GPR40 Receptor Signaling Underlies the Fatty Acid Potentiation of Insulin Secretion* , 2014, The Journal of Biological Chemistry.

[53]  G. Cline,et al.  Integrated, Step-Wise, Mass-Isotopomeric Flux Analysis of the TCA Cycle. , 2015, Cell metabolism.

[54]  P. MacDonald,et al.  Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism. , 2015, Cell reports.

[55]  David S. Wishart,et al.  HMDB 3.0—The Human Metabolome Database in 2013 , 2012, Nucleic Acids Res..

[56]  O. Ilkayeva,et al.  Branched-chain amino acid restriction in Zucker-fatty rats improves muscle insulin sensitivity by enhancing efficiency of fatty acid oxidation and acyl-glycine export , 2016, Molecular metabolism.

[57]  Ming-Huei Chen,et al.  A genome-wide association study of the human metabolome in a community-based cohort. , 2013, Cell metabolism.

[58]  M. Jensen,et al.  A Pyruvate Cycling Pathway Involving Cytosolic NADP-dependent Isocitrate Dehydrogenase Regulates Glucose-stimulated Insulin Secretion* , 2006, Journal of Biological Chemistry.

[59]  Mei Huang,et al.  Assessment of the metabolic pathways associated with glucose-stimulated biphasic insulin secretion. , 2014, Endocrinology.

[60]  Tuija Tammelin,et al.  Metabolic Signatures of Insulin Resistance in 7,098 Young Adults , 2012, Diabetes.

[61]  W. Kraus,et al.  Baseline metabolomic profiles predict cardiovascular events in patients at risk for coronary artery disease. , 2012, American heart journal.

[62]  Jonathan C. Cohen,et al.  Expression and Characterization of a PNPLA3 Protein Isoform (I148M) Associated with Nonalcoholic Fatty Liver Disease* , 2011, The Journal of Biological Chemistry.

[63]  L. Groop,et al.  α-Hydroxybutyric Acid Is a Selective Metabolite Biomarker of Impaired Glucose Tolerance , 2016, Diabetes Care.

[64]  Geoffrey S Ginsburg,et al.  Association of a Peripheral Blood Metabolic Profile With Coronary Artery Disease and Risk of Subsequent Cardiovascular Events , 2010, Circulation. Cardiovascular genetics.

[65]  W. Kraus,et al.  Impact of combined resistance and aerobic exercise training on branched-chain amino acid turnover, glycine metabolism and insulin sensitivity in overweight humans , 2015, Diabetologia.

[66]  B. Zinman,et al.  Evaluation of Circulating Determinants of Beta-Cell Function in Women With and Without Gestational Diabetes. , 2016, The Journal of clinical endocrinology and metabolism.

[67]  B. Kahn,et al.  Adipose cell hyperplasia and enhanced glucose disposal in transgenic mice overexpressing GLUT4 selectively in adipose tissue. , 1993, The Journal of biological chemistry.

[68]  M. Ravier,et al.  Hierarchy of the β‐cell signals controlling insulin secretion , 2003, European journal of clinical investigation.

[69]  B. Kahn,et al.  Adipose Tissue Branched Chain Amino Acid (BCAA) Metabolism Modulates Circulating BCAA Levels* , 2010, The Journal of Biological Chemistry.

[70]  H. Ashktorab,et al.  Global Epidemiology of Nonalcoholic Fatty Liver Disease and Perspectives on US Minority Populations , 2016, Digestive Diseases and Sciences.

[71]  Y. Liu,et al.  Rapid Elevation in CMPF May Act As a Tipping Point in Diabetes Development. , 2016, Cell reports.

[72]  O. Ilkayeva,et al.  Sex differences in biomarkers associated with insulin resistance in obese adolescents: metabolomic profiling and principal components analysis. , 2014, The Journal of clinical endocrinology and metabolism.

[73]  V. Mootha,et al.  Metabolite profiles and the risk of developing diabetes , 2011, Nature Network Boston.

[74]  G. Siuzdak,et al.  Innovation: Metabolomics: the apogee of the omics trilogy , 2012, Nature Reviews Molecular Cell Biology.

[75]  Qiong Yang,et al.  An exome array study of the plasma metabolome , 2016, Nature Communications.

[76]  P. Toth Lipid profiling identifies a triacylglycerol signature of insulin resistance and improves diabetes prediction in humans , 2011 .

[77]  P. Saha,et al.  Absence of the SRC-2 Coactivator Results in a Glycogenopathy Resembling Von Gierke's Disease , 2008, Science.

[78]  E. Tai,et al.  Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men , 2010, Diabetologia.

[79]  Nicola Zamboni,et al.  Defining the metabolome: size, flux, and regulation. , 2015, Molecular cell.

[80]  R. Quintens,et al.  Redox control of exocytosis: regulatory role of NADPH, thioredoxin, and glutaredoxin. , 2005, Diabetes.

[81]  M. Prentki,et al.  Metabolic Fate of Glucose in Purified Islet Cells , 1997, The Journal of Biological Chemistry.

[82]  Christian Gieger,et al.  Biomarkers for Type 2 Diabetes and Impaired Fasting Glucose Using a Nontargeted Metabolomics Approach , 2013, Diabetes.

[83]  J. Buse,et al.  Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. , 2016, The New England journal of medicine.

[84]  V. Mootha,et al.  Circulating branched‐chain amino acid concentrations are associated with obesity and future insulin resistance in children and adolescents , 2013, Pediatric obesity.

[85]  B. Cox,et al.  A Predictive Metabolic Signature for the Transition From Gestational Diabetes Mellitus to Type 2 Diabetes , 2016, Diabetes.

[86]  M. Kleber,et al.  Childhood Obesity Is Associated with Changes in the Serum Metabolite Profile , 2012, Obesity Facts.

[87]  John B Buse,et al.  Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. , 2016, The New England journal of medicine.

[88]  W. Kraus,et al.  Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis , 2015, PLoS genetics.

[89]  S. A. Arriola Apelo,et al.  Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health. , 2016, Cell reports.

[90]  Pengxiang She,et al.  Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. , 2007, American journal of physiology. Endocrinology and metabolism.

[91]  Brett R. Wenner,et al.  Metabolomics Applied to Diabetes Research , 2009, Diabetes.

[92]  P. Neufer,et al.  Isocitrate-to-SENP1 signaling amplifies insulin secretion and rescues dysfunctional β cells. , 2015, The Journal of clinical investigation.

[93]  Jiandie D. Lin,et al.  Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism , 2008, Proceedings of the National Academy of Sciences.

[94]  Joerg M. Buescher,et al.  A roadmap for interpreting (13)C metabolite labeling patterns from cells. , 2015, Current opinion in biotechnology.

[95]  S. Watkins,et al.  Identification of a Lipokine, a Lipid Hormone Linking Adipose Tissue to Systemic Metabolism , 2008, Cell.

[96]  M. Rewers,et al.  Metabolomics in childhood diabetes , 2016, Pediatric diabetes.

[97]  P. Saha,et al.  The coactivator SRC-1 is an essential coordinator of hepatic glucose production. , 2010, Cell metabolism.

[98]  T. Shlomi,et al.  Quantitative flux analysis reveals folate-dependent NADPH production , 2014, Nature.

[99]  William E. Kraus,et al.  Relationships Between Circulating Metabolic Intermediates and Insulin Action in Overweight to Obese, Inactive Men and Women , 2009, Diabetes Care.

[100]  O. Ilkayeva,et al.  Muscle-Specific Overexpression of PGC-1α Does Not Augment Metabolic Improvements in Response to Exercise and Caloric Restriction , 2014, Diabetes.

[101]  C. Burant,et al.  Metabolome Response to Glucose in the β-Cell Line INS-1 832/13* , 2013, The Journal of Biological Chemistry.

[102]  David Millington,et al.  Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance , 2004, Nature Medicine.

[103]  M. Jensen,et al.  The Mitochondrial Citrate/Isocitrate Carrier Plays a Regulatory Role in Glucose-stimulated Insulin Secretion* , 2006, Journal of Biological Chemistry.

[104]  Xian Chen,et al.  Ablation of steroid receptor coactivator-3 resembles the human CACT metabolic myopathy. , 2012, Cell metabolism.

[105]  William E. Kraus,et al.  Basic Science for Clinicians Metabolomic Profiling for the Identification of Novel Biomarkers and Mechanisms Related to Common Cardiovascular Diseases Form and Function , 2012 .

[106]  G. Shulman,et al.  Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver , 2001, Nature.

[107]  Geoffrey S Ginsburg,et al.  High heritability of metabolomic profiles in families burdened with premature cardiovascular disease , 2009, Molecular systems biology.

[108]  SoJung Lee,et al.  Metabolomic profiling of amino acids and β-cell function relative to insulin sensitivity in youth. , 2012, The Journal of clinical endocrinology and metabolism.

[109]  I. G. Fantus,et al.  The furan fatty acid metabolite CMPF is elevated in diabetes and induces β cell dysfunction. , 2014, Cell metabolism.

[110]  H. Mulder,et al.  13C NMR isotopomer analysis reveals a connection between pyruvate cycling and glucose-stimulated insulin secretion (GSIS) , 2002, Proceedings of the National Academy of Sciences of the United States of America.