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Diabetologia
Published in: Diabetologia 9/2016

01-09-2016 | Article

MASP1, THBS1, GPLD1 and ApoA-IV are novel biomarkers associated with prediabetes: the KORA F4 study

Authors: Christine von Toerne, Cornelia Huth, Tonia de las Heras Gala, Florian Kronenberg, Christian Herder, Wolfgang Koenig, Christa Meisinger, Wolfgang Rathmann, Melanie Waldenberger, Michael Roden, Annette Peters, Barbara Thorand, Stefanie M. Hauck

Published in: Diabetologia | Issue 9/2016

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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.
Appendix
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Literature
1.
2.
Huth C, Beuerle S, Zierer A et al (2015) Biomarkers of iron metabolism are independently associated with impaired glucose metabolism and type 2 diabetes: the KORA F4 study. Eur J Endocrinol 173:643–653
3.
Kluppelholz B, Thorand B, Koenig W et al (2015) Association of subclinical inflammation with deterioration of glycaemia before the diagnosis of type 2 diabetes: the KORA S4/F4 study. Diabetologia 58:2269–2277CrossRefPubMed
4.
Herder C, Karakas M, Koenig W (2011) Biomarkers for the prediction of type 2 diabetes and cardiovascular disease. Clin Pharmacol Ther 90:52–66CrossRefPubMed
5.
Herder C, Kowall B, Tabak AG, Rathmann W (2014) The potential of novel biomarkers to improve risk prediction of type 2 diabetes. Diabetologia 57:16–29CrossRefPubMed
6.
Shao S, Guo T, Aebersold R (2015) MS-based proteomic quest for diabetes biomarkers. Biochim Biophys Acta 1854:519–527CrossRefPubMed
7.
8.
Yokoi N, Beppu M, Yoshida E et al (2015) Identification of putative biomarkers for prediabetes by metabolome analysis of rat models of type 2 diabetes. Metabolomics 11:1277–1286
9.
10.
Picotti P, Bodenmiller B, Aebersold R (2013) Proteomics meets the scientific method. Nat Methods 10:24–27CrossRefPubMed
11.
12.
von Toerne C, Kahle M, Schafer A et al (2013) Apoe, Mbl2, and Psp plasma protein levels correlate with diabetic phenotype in NZO Mice – an optimized rapid workflow for SRM-based quantification. J Proteome Res 12:1331–1343CrossRef
13.
Rathmann W, Kowall B, Tamayo T et al (2012) Hemoglobin A1c and glucose criteria identify different subjects as having type 2 diabetes in middle-aged and older populations: the KORA S4/F4 Study. Ann Med 44:170–177CrossRefPubMed
14.
Ruckert IM, Heier M, Rathmann W, Baumeister SE, Doring A, Meisinger C (2011) Association between markers of fatty liver disease and impaired glucose regulation in men and women from the general population: the KORA-F4-study. PLoS One 6:e22932CrossRefPubMedPubMedCentral
15.
Stangl S, Kollerits B, Lamina C et al (2015) Association between apolipoprotein A-IV concentrations and chronic kidney disease in two large population-based cohorts: results from the KORA studies. J Intern Med 278:410–423CrossRefPubMed
16.
Meisinger C, Ruckert IM, Rathmann W et al (2011) Retinol-binding protein 4 is associated with prediabetes in adults from the general population: the Cooperative Health Research in the Region of Augsburg (KORA) F4 Study. Diabetes Care 34:1648–1650CrossRefPubMedPubMedCentral
17.
WHO (1999) Definition, diagnosis and classification of diabetes mellitus and its complications. Report of a WHO consultation Part 1: Diagnosis and classification of diabetes mellitus. WHO Department of Noncommunicable Disease Surveillance, Geneva, pp 1–59
18.
MacLean B, Tomazela DM, Shulman N et al (2010) Skyline: an open source document editor for creating and analyzing targeted proteomics experiments. Bioinformatics 26:966–968CrossRefPubMedPubMedCentral
19.
R Development Core Team (2014) R: a language and environment for statistical computing. R Foundation for Statistical Computing, available from www.​r-project.​org/​
20.
Abbatiello SE, Mani DR, Keshishian H, Carr SA (2010) Automated detection of inaccurate and imprecise transitions in peptide quantification by multiple reaction monitoring MS. Clin Chem 56:291–305CrossRefPubMed
21.
Mani DR, Abbatiello SE, Carr SA (2012) Statistical characterization of multiple-reaction monitoring mass spectrometry (MRM-MS) assays for quantitative proteomics. BMC Bioinformatics 13(Suppl 16):S9
22.
Thiel S (2007) Complement activating soluble pattern recognition molecules with collagen-like regions, mannan-binding lectin, ficolins and associated proteins. Mol Immunol 44:3875–3888CrossRefPubMed
23.
Dobo J, Schroeder V, Jenny L, Cervenak L, Zavodszky P, Gal P (2014) Multiple roles of complement MASP-1 at the interface of innate immune response and coagulation. Mol Immunol 61:69–78CrossRefPubMed
24.
Frauenknecht V, Thiel S, Storm L et al (2013) Plasma levels of mannan-binding lectin (MBL)-associated serine proteases (MASPs) and MBL-associated protein in cardio- and cerebrovascular diseases. Clin Exp Immunol 173:112–120CrossRefPubMedPubMedCentral
25.
Sildorf SM, Eising S, Hougaard DM et al (2014) Differences in MBL levels between juvenile patients newly diagnosed with type 1 diabetes and their healthy siblings. Mol Immunol 62:71–76CrossRefPubMed
26.
Bouwman LH, Eerligh P, Terpstra OT et al (2005) Elevated levels of mannose-binding lectin at clinical manifestation of type 1 diabetes in juveniles. Diabetes 54:3002–3006CrossRefPubMed
27.
Hansen TK, Thiel S, Knudsen ST et al (2003) Elevated levels of mannan-binding lectin in patients with type 1 diabetes. J Clin Endocrinol Metab 88:4857–4861CrossRefPubMed
28.
Hansen TK, Tarnow L, Thiel S et al (2004) Association between mannose-binding lectin and vascular complications in type 1 diabetes. Diabetes 53:1570–1576CrossRefPubMed
29.
Fernandez-Real JM, Straczkowski M, Vendrell J et al (2006) Protection from inflammatory disease in insulin resistance: the role of mannan-binding lectin. Diabetologia 49:2402–2411CrossRefPubMed
30.
Jenny L, Ajjan R, King R, Thiel S, Schroeder V (2015) Plasma levels of mannan-binding lectin-associated serine proteases MASP-1 and MASP-2 are elevated in type 1 diabetes and correlate with glycaemic control. Clin Exp Immunol 180:227–232CrossRefPubMedPubMedCentral
31.
Fortpied J, Vertommen D, Van Schaftingen E (2010) Binding of mannose-binding lectin to fructosamines: a potential link between hyperglycaemia and complement activation in diabetes. Diabetes Metab Res Rev 26:254–260CrossRefPubMed
32.
Hoener MC, Brodbeck U (1992) Phosphatidylinositol-glycan-specific phospholipase D is an amphiphilic glycoprotein that in serum is associated with high-density lipoproteins. Eur J Biochem 206:747–757
33.
Schofield JN, Stephens JW, Hurel SJ, Bell KM, deSouza JB, Rademacher TW (2002) Insulin reduces serum glycosylphosphatidylinositol phospholipase D levels in human type I diabetic patients and streptozotocin diabetic rats. Mol Genet Metab 75:154–161CrossRefPubMed
34.
Suzuki S, Suzuki C, Hinokio Y et al (2014) Insulin-mimicking bioactivities of acylated inositol glycans in several mouse models of diabetes with or without obesity. PLoS One 9:e100466CrossRefPubMedPubMedCentral
35.
36.
Ezeh B, Haiman M, Alber HF et al (2003) Plasma distribution of apoA-IV in patients with coronary artery disease and healthy controls. J Lipid Res 44:1523–1529CrossRefPubMed
37.
38.
Maritim AC, Sanders RA, Watkins JB 3rd (2003) Diabetes, oxidative stress, and antioxidants: a review. J Biochem Mol Toxicol 17:24–38CrossRefPubMed
39.
40.
Wang F, Kohan AB, Kindel TL et al (2012) Apolipoprotein A-IV improves glucose homeostasis by enhancing insulin secretion. Proc Natl Acad Sci U S A 109:9641–9646CrossRefPubMedPubMedCentral
41.
Pressler JW, Haller A, Sorrell J et al (2015) Vertical sleeve gastrectomy restores glucose homeostasis in apolipoprotein A-IV KO mice. Diabetes 64:498–507CrossRefPubMed
42.
Verges B (1995) Apolipoprotein A-IV in diabetes mellitus. Diabete Metab 21:99–105PubMed
43.
Sun Z, Larson IA, Ordovas JM, Barnard JR, Schaefer EJ (2000) Effects of age, sex, and lifestyle factors on plasma apolipoprotein A-IV concentrations. Atherosclerosis 151:381–388CrossRefPubMed
44.
Kong P, Cavalera M, Frangogiannis NG (2014) The role of thrombospondin (TSP)-1 in obesity and diabetes. Adipocytes 3:81–84CrossRef
45.
Varma V, Yao-Borengasser A, Bodles AM et al (2008) Thrombospondin-1 is an adipokine associated with obesity, adipose inflammation, and insulin resistance. Diabetes 57:432–439CrossRefPubMed
46.
Kong P, Gonzalez-Quesada C, Li N, Cavalera M, Lee DW, Frangogiannis NG (2013) Thrombospondin-1 regulates adiposity and metabolic dysfunction in diet-induced obesity enhancing adipose inflammation and stimulating adipocyte proliferation. Am J Physiol Endocrinol Metab 305:E439–E450CrossRefPubMedPubMedCentral
Metadata
Title
MASP1, THBS1, GPLD1 and ApoA-IV are novel biomarkers associated with prediabetes: the KORA F4 study
Authors
Christine von Toerne
Cornelia Huth
Tonia de las Heras Gala
Florian Kronenberg
Christian Herder
Wolfgang Koenig
Christa Meisinger
Wolfgang Rathmann
Melanie Waldenberger
Michael Roden
Annette Peters
Barbara Thorand
Stefanie M. Hauck
Publication date
01-09-2016
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 9/2016
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-016-4024-2

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