title: Evidence that multiple defects in lipid regulation occur before hyperglycemia during the prodrome of type-2 diabetes.
abstract: BACKGROUND
  Blood-vessel dysfunction arises before overt hyperglycemia in type-2 diabetes (T2DM). We hypothesised that a metabolomic approach might identify metabolites/pathways perturbed in this pre-hyperglycemic phase. To test this hypothesis and for specific metabolite hypothesis generation, serum metabolic profiling was performed in young women at increased, intermediate and low risk of subsequent T2DM.
  
  
  METHODS
  Participants were stratified by glucose tolerance during a previous index pregnancy into three risk-groups: overt gestational diabetes (GDM; n = 18); those with glucose values in the upper quartile but below GDM levels (UQ group; n = 45); and controls (n = 43, below the median glucose values). Follow-up serum samples were collected at a mean 22 months postnatally. Samples were analysed in a random order using Ultra Performance Liquid Chromatography coupled to an electrospray hybrid LTQ-Orbitrap mass spectrometer. Statistical analysis included principal component (PCA) and multivariate methods.
  
  
  RESULTS
  Significant between-group differences were observed at follow-up in waist circumference (86, 95%CI (79-91) vs 80 (76-84) cm for GDM vs controls, p<0.05), adiponectin (about 33% lower in GDM group, p = 0.004), fasting glucose, post-prandial glucose and HbA1c, but the latter 3 all remained within the 'normal' range. Substantial differences in metabolite profiles were apparent between the 2 'at-risk' groups and controls, particularly in concentrations of phospholipids (4 metabolites with p ≤ 0.01), acylcarnitines (3 with p ≤ 0.02), short- and long-chain fatty acids (3 with p<  = 0.03), and diglycerides (4 with p ≤ 0.05).
  
  
  CONCLUSIONS
  Defects in adipocyte function from excess energy storage as relatively hypoxic visceral and hepatic fat, and impaired mitochondrial fatty acid oxidation may initiate the observed perturbations in lipid metabolism. Together with evidence from the failure of glucose-directed treatments to improve cardiovascular outcomes, these data and those of others indicate that a new, quite different definition of type-2 diabetes is required. This definition would incorporate disturbed lipid metabolism prior to hyperglycemia.
authors.affiliation: Institute of Cardiovascular Sciences, Core Technology Facility, The University of Manchester, Manchester, United Kingdom.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Anderson
authors.affiliation: Manchester Centre for Integrative Systems Biology, Manchester Institute of Biotechnology, The University of Manchester, Manchester, United Kingdom; Centre for Advanced Discovery & Experimental Therapeutics (CADET), Central Manchester NHS Foundation Trust and School of Biomedicine, The University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom; School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Warwick B
authors.initials: WB
authors.lastname: Dunn
authors.affiliation: Institute of Cardiovascular Sciences, Core Technology Facility, The University of Manchester, Manchester, United Kingdom.
authors.forename: Moulinath
authors.initials: M
authors.lastname: Banerjee
authors.affiliation: Manchester Centre for Integrative Systems Biology, Manchester Institute of Biotechnology, The University of Manchester, Manchester, United Kingdom.
authors.forename: Marie
authors.initials: M
authors.lastname: Brown
authors.affiliation: Manchester Centre for Integrative Systems Biology, Manchester Institute of Biotechnology, The University of Manchester, Manchester, United Kingdom; Division of General Internal Medicine, Department of Medicine, 4126A Katz Group Centre for Pharmacy & Health, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: David I
authors.initials: DI
authors.lastname: Broadhurst
authors.affiliation: Manchester Centre for Integrative Systems Biology, Manchester Institute of Biotechnology, The University of Manchester, Manchester, United Kingdom.
authors.forename: Royston
authors.initials: R
authors.lastname: Goodacre
authors.affiliation: Centre for Advanced Discovery & Experimental Therapeutics (CADET), Central Manchester NHS Foundation Trust and School of Biomedicine, The University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom; Maurice Wilkins Centre for Molecular Biodiscovery, Faculty of Science, University of Auckland, Auckland, New Zealand; Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
authors.forename: Garth J S
authors.initials: GJ
authors.lastname: Cooper
authors.affiliation: Manchester Centre for Integrative Systems Biology, Manchester Institute of Biotechnology, The University of Manchester, Manchester, United Kingdom.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Kell
authors.affiliation: Institute of Cardiovascular Sciences, Core Technology Facility, The University of Manchester, Manchester, United Kingdom; Diabetes & Nutritional Sciences Division, King's College London, London, United Kingdom.
authors.forename: J Kennedy
authors.initials: JK
authors.lastname: Cruickshank
mesh_terms: D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D002331:Carnitine / Q000031:analogs & derivatives / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D016640:Diabetes, Gestational / Q000378:metabolism* / Q000473:pathology; D004075:Diglycerides / Q000097:blood; D005215:Fasting; D005260:Female; D005500:Follow-Up Studies; D005951:Glucose Tolerance Test; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism* / Q000473:pathology; D007328:Insulin / Q000097:blood; D050356:Lipid Metabolism; D055442:Metabolome; D010743:Phospholipids / Q000097:blood; D011236:Prediabetic State / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D025341:Principal Component Analysis
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; D004075:Diglycerides; D007328:Insulin; D010743:Phospholipids; C116917:acylcarnitine; D002331:Carnitine