title: Impact of the adipokine adiponectin and the hepatokine fetuin-A on the development of type 2 diabetes: prospective cohort- and cross-sectional phenotyping studies.
abstract: BACKGROUND
  Among adipokines and hepatokines, adiponectin and fetuin-A were consistently found to predict the incidence of type 2 diabetes, both by regulating insulin sensitivity.
  
  
  OBJECTIVE
  To determine to what extent circulating adiponectin and fetuin-A are independently associated with incident type 2 diabetes in humans, and the major mechanisms involved.
  
  
  METHODS
  Relationships with incident diabetes were tested in two cohort studies: within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study (628 cases) and the Nurses' Health Study (NHS; 470 cases). Relationships with body fat compartments, insulin sensitivity and insulin secretion were studied in the Tübingen Lifestyle Intervention Program (TULIP; N = 358).
  
  
  RESULTS
  Circulating adiponectin and fetuin-A, independently of several confounders and of each other, associated with risk of diabetes in EPIC-Potsdam (RR for 1 SD: adiponectin: 0.45 [95% CI 0.37-0.54], fetuin-A: 1.18 [1.05-1.32]) and the NHS (0.51 [0.42-0.62], 1.35 [1.16-1.58]). Obesity measures considerably attenuated the association of adiponectin, but not of fetuin-A. Subjects with low adiponectin and concomitantly high fetuin-A had the highest risk. Whereas both proteins were independently (both p<1.8×10(-7)) associated with insulin sensitivity, circulating fetuin-A (r = -0.37, p = 0.0004), but not adiponectin, associated with insulin secretion in subjects with impaired glucose tolerance.
  
  
  CONCLUSIONS
  We provide novel information that adiponectin and fetuin-A independently of each other associate with the diabetes risk. Furthermore, we suggest that they are involved in the development of type 2 diabetes via different mechanisms, possibly by mediating effects of their source tissues, expanded adipose tissue and nonalcoholic fatty liver.
authors.affiliation: Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases, Member of the German Center for Diabetes Research (DZD), Tübingen, Germany; Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, München, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Stefan
authors.affiliation: Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, United States of America; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Qi
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases, Member of the German Center for Diabetes Research (DZD), Tübingen, Germany; Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, München, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
authors.affiliation: Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, München, Germany; Section on Experimental Radiology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Machann
authors.affiliation: Section on Experimental Radiology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Fritz
authors.initials: F
authors.lastname: Schick
authors.affiliation: Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases, Member of the German Center for Diabetes Research (DZD), Tübingen, Germany; Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, München, Germany.
authors.forename: Felicia
authors.initials: F
authors.lastname: Gerst
authors.affiliation: Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, München, Germany.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Jeppesen
authors.affiliation: Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, München, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Joost
authors.affiliation: Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, United States of America; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Frank B
authors.initials: FB
authors.lastname: Hu
authors.affiliation: Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
authors.forename: Heiner
authors.initials: H
authors.lastname: Boeing
authors.affiliation: Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases, Member of the German Center for Diabetes Research (DZD), Tübingen, Germany; Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, München, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Ullrich
authors.affiliation: Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases, Member of the German Center for Diabetes Research (DZD), Tübingen, Germany; Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, München, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.affiliation: Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, München, Germany.
authors.forename: Matthias B
authors.initials: MB
authors.lastname: Schulze
mesh_terms: D052242:Adiponectin / Q000097:blood*; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D015992:Body Mass Index; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D005260:Female; D018149:Glucose Intolerance / Q000097:blood; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010641:Phenotype; D011446:Prospective Studies; D012306:Risk; D055105:Waist Circumference; D060749:alpha-2-HS-Glycoprotein / Q000378:metabolism*
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin; D015415:Biomarkers; D060749:alpha-2-HS-Glycoprotein