title: MASP1, THBS1, GPLD1 and ApoA-IV are novel biomarkers associated with prediabetes: the KORA F4 study.
abstract: Individuals at a high risk of type 2 diabetes demonstrate moderate impairments in glucose metabolism years before the clinical manifestation of type 2 diabetes, a state called 'prediabetes'. In order to elucidate the pathophysiological processes leading to type 2 diabetes, we aimed to identify protein biomarkers associated with prediabetes.
  
  
  
  In a proteomics study, we used targeted selected reaction monitoring (SRM)-MS to quantify 23 candidate proteins in the plasma of 439 randomly selected men and women aged 47-76 years from the population-based German KORA F4 study. Cross-sectional associations of protein levels with prediabetes (impaired fasting glucose and/or impaired glucose tolerance), type 2 diabetes, glucose levels in both the fasting state and 2 h after an OGTT, fasting insulin and insulin resistance were investigated using regression models adjusted for technical covariables, age, sex, BMI, smoking, alcohol intake, physical inactivity, actual hypertension, triacylglycerol levels, total cholesterol/HDL-cholesterol ratio, and high-sensitivity C-reactive protein levels.
  
  
  
  Mannan-binding lectin serine peptidase 1 (MASP1; OR per SD 1.77 [95% CI 1.26, 2.47]), thrombospondin 1 (THBS1; OR per SD 1.55 [95% CI 1.16, 2.07]) and glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1; OR per SD 1.40 [95% CI 1.01, 1.94]) were positively associated with prediabetes, and apolipoprotein A-IV (ApoA-IV; OR per SD 0.75 [95% CI 0.56, 1.00]) was inversely associated with prediabetes. MASP1 was positively associated with fasting and 2 h glucose levels. ApoA-IV was inversely and THBS1 was positively associated with 2 h glucose levels. MASP1 associations with prediabetes and fasting glucose resisted Bonferroni correction. Type 2 diabetes associations were partly influenced by glucose-lowering medication.
  
  
  
  We discovered novel and independent associations of prediabetes and related traits with MASP1, and some evidence for associations with THBS1, GPLD1 and ApoA-IV, suggesting a role for these proteins in the pathophysiology of type 2 diabetes.
authors.affiliation: Research Unit Protein Science, Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Ingolstaedter Landstraße 1, D-85764, München, Germany. vontoerne@helmholtz-muenchen.de.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany. vontoerne@helmholtz-muenchen.de.
authors.forename: Christine
authors.initials: C
authors.lastname: von Toerne
authors.affiliation: German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Huth
authors.affiliation: Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
authors.forename: Tonia
authors.initials: T
authors.lastname: de Las Heras Gala
authors.affiliation: Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Kronenberg
authors.affiliation: German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Herder
authors.affiliation: Department of Internal Medicine II - Cardiology, University of Ulm Medical Center, Ulm, Germany.|Deutsches Herzzentrum München, Technische Universität München, München, Germany.|German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, München, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Koenig
authors.affiliation: German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Neuherberg, Germany.|MONICA/KORA Myocardial Infarction Registry, Central Hospital of Augsburg, Augsburg, Germany.
authors.forename: Christa
authors.initials: C
authors.lastname: Meisinger
authors.affiliation: German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rathmann
authors.affiliation: Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Neuherberg, Germany.|Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Waldenberger
authors.affiliation: German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.|Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Roden
authors.affiliation: German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.affiliation: German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Thorand
authors.affiliation: Research Unit Protein Science, Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Ingolstaedter Landstraße 1, D-85764, München, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Hauck
mesh_terms: D000368:Aged; D001054:Apolipoproteins A / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism*; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000378:metabolism*; D008875:Middle Aged; D010739:Phospholipase D / Q000378:metabolism*; D011236:Prediabetic State / Q000378:metabolism*; D040901:Proteomics; D019699:Thrombospondins / Q000378:metabolism*; D000099262:Thrombospondin 2
chemical_list: D001054:Apolipoproteins A; D015415:Biomarkers; D050606:Mannose-Binding Protein-Associated Serine Proteases; D010739:Phospholipase D; D019699:Thrombospondins; D000099262:Thrombospondin 2; C022205:apolipoprotein A-IV; C065017:glycoprotein phospholipase D; C084067:MASP1 protein, human
keywords: Epidemiology; Prediction and prevention of type 2 diabetes; Proteomics