Genetic Composition and Autoantibody Titers Model the Probability of Detecting C-Peptide Following Type 1 Diabetes Diagnosis

Diabetes. 2021 Apr;70(4):932-943. doi: 10.2337/db20-0937. Epub 2021 Jan 8.


We and others previously demonstrated that a type 1 diabetes genetic risk score (GRS) improves the ability to predict disease progression and onset in at-risk subjects with islet autoantibodies. Here, we hypothesized that GRS and islet autoantibodies, combined with age at onset and disease duration, could serve as markers of residual β-cell function following type 1 diabetes diagnosis. Generalized estimating equations were used to investigate whether GRS along with insulinoma-associated protein-2 autoantibody (IA-2A), zinc transporter 8 autoantibody (ZnT8A), and GAD autoantibody (GADA) titers were predictive of C-peptide detection in a largely cross-sectional cohort of 401 subjects with type 1 diabetes (median duration 4.5 years [range 0-60]). Indeed, a combined model with incorporation of disease duration, age at onset, GRS, and titers of IA-2A, ZnT8A, and GADA provided superior capacity to predict C-peptide detection (quasi-likelihood information criterion [QIC] = 334.6) compared with the capacity of disease duration, age at onset, and GRS as the sole parameters (QIC = 359.2). These findings support the need for longitudinal validation of our combinatorial model. The ability to project the rate and extent of decline in residual C-peptide production for individuals with type 1 diabetes could critically inform enrollment and benchmarking for clinical trials where investigators are seeking to preserve or restore endogenous β-cell function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantibodies / genetics
  • Autoantibodies / metabolism*
  • C-Peptide / genetics
  • C-Peptide / metabolism
  • Cross-Sectional Studies
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / metabolism*
  • Humans
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8 / genetics
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8 / metabolism*
  • Zinc Transporter 8 / genetics
  • Zinc Transporter 8 / metabolism


  • Autoantibodies
  • C-Peptide
  • SLC30A8 protein, human
  • Zinc Transporter 8
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8

Associated data

  • figshare/10.2337/figshare.13516808