title: Protein Biomarkers for Insulin Resistance and Type 2 Diabetes Risk in Two Large Community Cohorts.
abstract: Insulin resistance (IR) is a precursor of type 2 diabetes (T2D), and improved risk prediction and understanding of the pathogenesis are needed. We used a novel high-throughput 92-protein assay to identify circulating biomarkers for HOMA of IR in two cohorts of community residents without diabetes (n = 1,367) (mean age 73 ± 3.6 years). Adjusted linear regression identified cathepsin D and confirmed six proteins (leptin, renin, interleukin-1 receptor antagonist [IL-1ra], hepatocyte growth factor, fatty acid-binding protein 4, and tissue plasminogen activator [t-PA]) as IR biomarkers. Mendelian randomization analysis indicated a positive causal effect of IR on t-PA concentrations. Two biomarkers, IL-1ra (hazard ratio [HR] 1.28, 95% CI 1.03-1.59) and t-PA (HR 1.30, 1.02-1.65) were associated with incident T2D, and t-PA predicted 5-year transition to hyperglycemia (odds ratio 1.30, 95% CI 1.02-1.65). Additional adjustment for fasting glucose rendered both coefficients insignificant and revealed an association between renin and T2D (HR 0.79, 0.62-0.99). LASSO regression suggested a risk model including IL-1ra, t-PA, and the Framingham Offspring Study T2D score, but prediction improvement was nonsignificant (difference in C-index 0.02, 95% CI -0.08 to 0.12) over the T2D score only. In conclusion, proteomic blood profiling indicated cathepsin D as a new IR biomarker and suggested a causal effect of IR on t-PA.
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Christoph
authors.initials: C
authors.lastname: Nowak
authors.affiliation: Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Sundström
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gustafsson
authors.affiliation: Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Vilmantas
authors.initials: V
authors.lastname: Giedraitis
authors.affiliation: Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lind
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K. Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA.
authors.forename: Erik
authors.initials: E
authors.lastname: Ingelsson
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden tove.fall@medsci.uu.se.
authors.forename: Tove
authors.initials: T
authors.lastname: Fall
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism*; D002402:Cathepsin D / Q000097:blood*; D015984:Causality; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000453:epidemiology; D050556:Fatty Acid-Binding Proteins / Q000097:blood*; D005260:Female; D017228:Hepatocyte Growth Factor / Q000097:blood*; D057166:High-Throughput Screening Assays; D006801:Humans; D007333:Insulin Resistance; D053590:Interleukin 1 Receptor Antagonist Protein / Q000097:blood*; D020738:Leptin / Q000097:blood*; D016014:Linear Models; D008137:Longitudinal Studies; D008297:Male; D057182:Mendelian Randomization Analysis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D040901:Proteomics; D012083:Renin / Q000097:blood*; D018570:Risk Assessment; D013548:Sweden / Q000453:epidemiology; D010959:Tissue Plasminogen Activator / Q000097:blood*
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; C066855:HGF protein, human; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D020738:Leptin; D017228:Hepatocyte Growth Factor; D010959:Tissue Plasminogen Activator; D012083:Renin; C533922:CTSD protein, human; D002402:Cathepsin D