Protein Biomarkers for Insulin Resistance and Type 2 Diabetes Risk in Two Large Community Cohorts

Diabetes. 2016 Jan;65(1):276-84. doi: 10.2337/db15-0881. Epub 2015 Sep 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Biomarkers / blood
  • Blood Glucose / metabolism*
  • Cathepsin D / blood*
  • Causality
  • Cohort Studies
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / epidemiology
  • Fatty Acid-Binding Proteins / blood*
  • Female
  • Hepatocyte Growth Factor / blood*
  • High-Throughput Screening Assays
  • Humans
  • Insulin Resistance*
  • Interleukin 1 Receptor Antagonist Protein / blood*
  • Leptin / blood*
  • Linear Models
  • Longitudinal Studies
  • Male
  • Mendelian Randomization Analysis
  • Proportional Hazards Models
  • Prospective Studies
  • Proteomics
  • Renin / blood*
  • Risk Assessment
  • Sweden / epidemiology
  • Tissue Plasminogen Activator / blood*

Substances

  • Biomarkers
  • Blood Glucose
  • FABP4 protein, human
  • Fatty Acid-Binding Proteins
  • HGF protein, human
  • IL1RN protein, human
  • Interleukin 1 Receptor Antagonist Protein
  • Leptin
  • Hepatocyte Growth Factor
  • Tissue Plasminogen Activator
  • Renin
  • CTSD protein, human
  • Cathepsin D