Christine von Toerne1,2, Cornelia Huth3,4, Tonia de Las Heras Gala4, Florian Kronenberg5, Christian Herder3,6, Wolfgang Koenig7,8,9, Christa Meisinger3,4,10, Wolfgang Rathmann3,11, Melanie Waldenberger4,12, Michael Roden3,6,13, Annette Peters3,4, Barbara Thorand3,4, Stefanie M Hauck14,3. 1. 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. 2. German Center for Diabetes Research (DZD), München-Neuherberg, Germany. vontoerne@helmholtz-muenchen.de. 3. German Center for Diabetes Research (DZD), München-Neuherberg, Germany. 4. Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Neuherberg, Germany. 5. Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria. 6. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany. 7. Department of Internal Medicine II - Cardiology, University of Ulm Medical Center, Ulm, Germany. 8. Deutsches Herzzentrum München, Technische Universität München, München, Germany. 9. German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, München, Germany. 10. MONICA/KORA Myocardial Infarction Registry, Central Hospital of Augsburg, Augsburg, Germany. 11. Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University Düsseldorf, Düsseldorf, Germany. 12. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Neuherberg, Germany. 13. Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany. 14. Research Unit Protein Science, Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Ingolstaedter Landstraße 1, D-85764, München, Germany.
Abstract
AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS/ INTERPRETATION: 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.
AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: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. CONCLUSIONS/ INTERPRETATION: 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.
Entities:
Keywords:
Epidemiology; Prediction and prevention of type 2 diabetes; Proteomics
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