posted on 2021-01-08, 23:42authored byMacKenzie D. Williams, Rhonda Bacher, Daniel J. Perry, C. Ramsey Grace, Kieran M. McGrail, Amanda L. Posgai, Andrew Muir, Srikar Chamala, Michael J. Haller, Desmond A. Schatz, Todd M. Brusko, Mark A. Atkinson, Clive H. Wasserfall
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 (duration median = 4.5
years, range 0-60). Indeed, a combined model incorporating disease duration,
age at onset, GRS, and titers of IA-2A, ZnT8A and GADA provided superior
capacity to predict C-peptide detection (QIC=334.6) compared with 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 seeking to preserve or restore endogenous
β-cell function.
Funding
These studies were supported by funding from the National Institutes of Health (P01 AI042288), the JDRF (1-SRA-2019-764-A-N and 2-PDF-2016-207-A-N), endowments from the American Diabetes Association, the McJunkin Family Charitable Foundation, and the Jeffrey Keene Family Professorship.