title: Circulating metabolite predictors of glycemia in middle-aged men and women.
abstract: OBJECTIVE
  Metabolite predictors of deteriorating glucose tolerance may elucidate the pathogenesis of type 2 diabetes. We investigated associations of circulating metabolites from high-throughput profiling with fasting and postload glycemia cross-sectionally and prospectively on the population level.
  
  
  METHODS
  Oral glucose tolerance was assessed in two Finnish, population-based studies consisting of 1,873 individuals (mean age 52 years, 58% women) and reexamined after 6.5 years for 618 individuals in one of the cohorts. Metabolites were quantified by nuclear magnetic resonance spectroscopy from fasting serum samples. Associations were studied by linear regression models adjusted for established risk factors.
  
  
  RESULTS
  Nineteen circulating metabolites, including amino acids, gluconeogenic substrates, and fatty acid measures, were cross-sectionally associated with fasting and/or postload glucose (P < 0.001). Among these metabolic intermediates, branched-chain amino acids, phenylalanine, and α1-acid glycoprotein were predictors of both fasting and 2-h glucose at 6.5-year follow-up (P < 0.05), whereas alanine, lactate, pyruvate, and tyrosine were uniquely associated with 6.5-year postload glucose (P = 0.003-0.04). None of the fatty acid measures were prospectively associated with glycemia. Changes in fatty acid concentrations were associated with changes in fasting and postload glycemia during follow-up; however, changes in branched-chain amino acids did not follow glucose dynamics, and gluconeogenic substrates only paralleled changes in fasting glucose.
  
  
  CONCLUSIONS
  Alterations in branched-chain and aromatic amino acid metabolism precede hyperglycemia in the general population. Further, alanine, lactate, and pyruvate were predictive of postchallenge glucose exclusively. These gluconeogenic precursors are potential markers of long-term impaired insulin sensitivity that may relate to attenuated glucose tolerance later in life.
authors.affiliation: Computational Medicine, Institute of Clinical Medicine, University of Oulu, Oulu, Finland. peter.wyrtz@computationalmedicine.fi
authors.forename: Peter
authors.initials: P
authors.lastname: Würtz
authors.forename: Mika
authors.initials: M
authors.lastname: Tiainen
authors.forename: Ville-Petteri
authors.initials: VP
authors.lastname: Mäkinen
authors.forename: Antti J
authors.initials: AJ
authors.lastname: Kangas
authors.forename: Pasi
authors.initials: P
authors.lastname: Soininen
authors.forename: Juha
authors.initials: J
authors.lastname: Saltevo
authors.forename: Sirkka
authors.initials: S
authors.lastname: Keinänen-Kiukaanniemi
authors.forename: Pekka
authors.initials: P
authors.lastname: Mäntyselkä
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.forename: Antti
authors.initials: A
authors.lastname: Jula
authors.forename: Mika
authors.initials: M
authors.lastname: Kähönen
authors.forename: Mauno
authors.initials: M
authors.lastname: Vanhala
authors.forename: Mika
authors.initials: M
authors.lastname: Ala-Korpela
mesh_terms: D000409:Alanine / Q000097:blood; D000597:Amino Acids, Branched-Chain / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism*; D005215:Fasting / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009961:Orosomucoid / Q000378:metabolism; D010649:Phenylalanine / Q000097:blood; D019289:Pyruvic Acid / Q000097:blood; D014443:Tyrosine / Q000097:blood
chemical_list: D000597:Amino Acids, Branched-Chain; D001786:Blood Glucose; D009961:Orosomucoid; D014443:Tyrosine; D010649:Phenylalanine; D019289:Pyruvic Acid; D000409:Alanine