Proinsulin:C-peptide ratio trajectories over time in relatives at increased risk of progression to type 1 diabetes

Taylor M Triolo; Laura Pyle; Sona Seligova; Liping Yu; Kimber Simmons; Peter Gottlieb; Carmella Evans-Molina; Andrea K Steck

doi:10.1016/j.jtauto.2021.100089

Proinsulin:C-peptide ratio trajectories over time in relatives at increased risk of progression to type 1 diabetes

J Transl Autoimmun. 2021 Feb 19:4:100089. doi: 10.1016/j.jtauto.2021.100089. eCollection 2021.

Authors

Taylor M Triolo¹, Laura Pyle^{1

2}, Sona Seligova¹, Liping Yu¹, Kimber Simmons¹, Peter Gottlieb¹, Carmella Evans-Molina^{3

4}, Andrea K Steck¹

Affiliations

¹ University of Colorado Denver School of Medicine - the Barbara Davis Center for Diabetes, Aurora, CO, USA.
² University of Colorado Anschutz Medical Campus, Pediatrics, Aurora, CO, USA.
³ Indiana University School of Medicine, Indianapolis, IN, USA.
⁴ Indiana University Center for Diabetes and Metabolic Diseases. Indianapolis, IN, USA.

Abstract

Objective: Biomarkers are needed to characterize heterogeneity within populations at risk for type 1 diabetes. The ratio of proinsulin to C-peptide (PI:C ratio), has been proposed as a biomarker of beta cell dysfunction and is associated with progression to type 1 diabetes. However, relationships between PI:C ratios and autoantibody type and number have not been examined. We sought to characterize PI:C ratios in multiple islet autoantibody positive, single autoantibody positive and autoantibody negative relatives of individuals with type 1 diabetes.

Methods: We measured PI:C ratios and autoantibodies with both electrochemiluminescence (ECL) assays (ECL-IAA, ECL-GADA and ECL-IA2A) and radiobinding (RBA) assays (mIAA, GADA, IA2A and ZnT8A) in 98 relatives of individuals with type 1 diabetes followed in the TrialNet Pathway to Prevention Study at the Barbara Davis Center for a mean of 7.4 ± 4.1 years. Of these subjects, eight progressed to T1D, 31 were multiple autoantibody (Ab) positive, 37 were single Ab positive and 22 were Ab negative (by RBA).

Results: In cross-sectional analyses, there were no significant differences in PI:C ratios between type 1 diabetes and/or multiple Ab positive subjects (4.16 ± 4.06) compared to single Ab positive subjects (4.08 ± 4.34) and negative Ab subjects (3.72 ± 3.78) (p = 0.92) overall or after adjusting for age, sex and BMI. Higher PI:C ratios were associated with mIAA titers (p = 0.03) and showed an association with ECL-IA2A titers (p = 0.09), but not with ECL-IAA, GADA, ECL-GADA, IA2A nor ZnT8A titers. In mixed-effects longitudinal models, the trajectories of PI:C ratio over time were significantly different between the Ab negative and multiple Ab positive/type 1 diabetes groups, after adjusting for sex, age, and BMI (p = 0.04).

Conclusions: PI:C ratio trajectories increase over time in subjects who have multiple Ab or develop type 1 diabetes and may be a helpful biomarker to further characterize and stratify risk of progression to type 1 diabetes over time.

Abstract

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