Protein Biomarkers for Insulin Resistance and Type 2 Diabetes Risk in Two Large Community Cohorts
2016 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, no 1, 276-284 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2016. Vol. 65, no 1, 276-284 p.
Endocrinology and Diabetes
IdentifiersURN: urn:nbn:se:uu:diva-270825DOI: 10.2337/db15-0881ISI: 000367424900029PubMedID: 26420861OAI: oai:DiVA.org:uu-270825DiVA: diva2:890616
FunderSwedish Research Council, 2012-1397Swedish Heart Lung Foundation, 20140422Swedish Diabetes Association, 2013-024Knut and Alice Wallenberg FoundationEU, European Research Council