Elevations in the Fasting Serum Proinsulin-to-C-Peptide Ratio Precede the Onset of Type 1 Diabetes.

ABSTRACT

OBJECTIVE: We tested whether an elevation in the serum proinsulin-to-C-peptide ratio (PIC), a biomarker of ß-cell endoplasmic reticulum (ER) dysfunction, was associated with progression to type 1 diabetes. RESEARCH DESIGN AND METHODS: Fasting total PI and C levels were measured in banked serum samples obtained from TrialNet Pathway to Prevention (PTP) participants, a cohort of autoantibody-positive relatives without diabetes of individuals with type 1 diabetes. Samples were obtained ∼12 months before diabetes onset from PTP progressors in whom diabetes developed (n = 60), and were compared with age-, sex-, and BMI-matched nonprogressors who remained normoglycemic (n = 58). PIC ratios were calculated as molar ratios and were multiplied by 100% to obtain PI levels as a percentage of C levels. RESULTS: Although absolute PI levels did not differ between groups, PIC ratios were significantly increased in antibody-positive subjects in whom there was progression to diabetes compared with nonprogressors (median 1.81% vs. 1.17%, P = 0.03). The difference between groups was most pronounced in subjects who were ≤10 years old, where the median progressor PIC ratio was nearly triple that of nonprogressors; 90.0% of subjects in this age group within the upper PIC quartile progressed to the development of diabetes. Logistic regression analysis, adjusted for age and BMI, demonstrated increased odds of progression for higher natural log PIC ratio values (odds ratio 1.44, 95% CI 1.02, 2.05). CONCLUSIONS: These data suggest that ß-cell ER dysfunction precedes type 1 diabetes onset, especially in younger children. Elevations in the serum PIC ratio may have utility in predicting the onset of type 1 diabetes in the presymptomatic phase.