title: Trajectories of cardiometabolic risk factors before diagnosis of three subtypes of type 2 diabetes: a post-hoc analysis of the longitudinal Whitehall II cohort study.
abstract: BACKGROUND
  Most clinicians acknowledge that type 2 diabetes is multifactorial and has heterogeneous characteristics, but neither prevention nor treatment is systematically stratified. To address the heterogeneity of the disease, we examined whether patients diagnosed on the basis of fasting glucose concentrations, those diagnosed on the basis of 2 h concentrations, and those diagnosed on the basis of both criteria differed in terms of pathogenesis or cardiovascular risks.
  
  
  METHODS
  Retrospectively, we analysed trajectories of cardiometabolic risk factors and 10 year cardiovascular risks in the prospective Whitehall II study cohort by use of multilevel longitudinal modelling. Participants were diagnosed by 75 g oral glucose-tolerance tests. We classified those diagnosed with type 2 diabetes into three subgroups: diagnosed on the basis of fasting glucose concentrations, diagnosed on the basis of 2 h glucose concentrations, and diagnosed on the basis of both concentrations. We also developed a classification tree for identification of individuals who are likely to have high fasting and 2 h glucose concentrations, but for whom only fasting concentrations are available.
  
  
  RESULTS
  Median follow-up was 14·2 years with 15,826 person-examinations (1991-2009). Of 10,308 individuals, 6843 were included and 6569 remained diabetes free. 274 cases of type 2 diabetes were identified: 55 had high fasting glucose concentrations only, 148 had high 2 h concentrations only, and 71 had high fasting and 2 h concentrations. At diagnosis, participants with high fasting and 2 h glucose concentrations had higher mean body-mass indices (30·9 kg/m(2) [SD 5·7]) than did those with high fasting concentrations (28·4 kg/m(2) [4·4]; p=0·0009) or 2 h concentrations (27·9 kg/m(2) [4·9]; <0·0001). Mean glycated haemoglobin A1c concentrations were also higher in the fasting and 2 h subgroup (7·4% [1·6]) than in the fasting (5·9% [0·5]; <0·0001) or 2 h (5·9% [0·6]; <0·0001) sugroups. Additionally, the fasting and 2 h subgroup had a higher proportion of individuals with moderate or high risk of cardiovascular disease than did the fasting subgroup (p=0·02). A classic pattern of β-cell decompensation before diagnosis was noted only in the fasting and 2 h subgroup. Additionally, glucose concentrations and insulin resistance accelerated more substantially before diagnosis in the fasting and 2 h subgroup than in the fasting subgroup or the 2 h subgroup.
  
  
  CONCLUSIONS
  Patients with type 2 diabetes diagnosed on the basis of increased fasting glucose concentrations or 2 h glucose concentrations, or both, have distinct cardiometabolic risk development before diagnosis.
  
  
  BACKGROUND
  UK Medical Research Council, UK Economic and Social Research Council, British Heart Foundation, UK Health and Safety Executive, UK Department of Health, US National Heart Lung and Blood Institute, US National Institute on Aging, US Agency for Health Care Policy Research, and John D and Catherine T MacArthur Foundation.
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark. Electronic address: krif@steno.dk.
authors.forename: Kristine
authors.initials: K
authors.lastname: Færch
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark; Centre de Recherche Public de la Santé, Strassen, Luxembourg.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Witte
authors.affiliation: Department of Epidemiology and Public Health, University College London, London, UK; First Department of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Adam G
authors.initials: AG
authors.lastname: Tabák
authors.affiliation: University of Colorado, Aurora, CO, USA.
authors.forename: Leigh
authors.initials: L
authors.lastname: Perreault
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Herder
authors.affiliation: Department of Epidemiology and Public Health, University College London, London, UK.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Brunner
authors.affiliation: Department of Epidemiology and Public Health, University College London, London, UK.
authors.forename: Mika
authors.initials: M
authors.lastname: Kivimäki
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Dorte
authors.initials: D
authors.lastname: Vistisen
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000097:blood / Q000453:epidemiology*; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000145:classification* / Q000453:epidemiology*; D005215:Fasting / Q000097:blood; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: D001786:Blood Glucose