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

• Published in: Diabetes (New York, N.Y.) Vol. 70; no. 4; pp. 932 - 943
• Main Authors: Williams, MacKenzie D., Bacher, Rhonda, Perry, Daniel J., Grace, C. Ramsey, McGrail, Kieran M., Posgai, Amanda L., Muir, Andrew, Chamala, Srikar, Haller, Michael J., Schatz, Desmond A., Brusko, Todd M., Atkinson, Mark A., Wasserfall, Clive H.
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.04.2021
• Subjects: Age; Autoantibodies; Autoantibodies - genetics; Autoantibodies - metabolism; Beta cells; C-Peptide - genetics; C-Peptide - metabolism; Clinical trials; Cross-Sectional Studies; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - metabolism; Diagnosis; Glutamate decarboxylase; Humans; Immunology and Transplantation; Insulinoma; Medical diagnosis; Neuroendocrine tumors; Peptides; Receptor-Like Protein Tyrosine Phosphatases, Class 8 - genetics; Receptor-Like Protein Tyrosine Phosphatases, Class 8 - metabolism; Recovery of function; Zinc transporter; Zinc Transporter 8 - genetics; Zinc Transporter 8 - metabolism
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db20-0937

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.