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

• Published in: Diabetes care Vol. 39; no. 9; pp. 1519 - 1526
• Main Authors: Sims, Emily K., Chaudhry, Zunaira, Watkins, Renecia, Syed, Farooq, Blum, Janice, Ouyang, Fangqian, Perkins, Susan M., Mirmira, Raghavendra G., Sosenko, Jay, DiMeglio, Linda A., Evans-Molina, Carmella
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.09.2016
• Subjects: Adolescent; Adult; Autoantibodies - blood; Biomarkers; Biomarkers - blood; Blood Banks; C-Peptide - blood; Child; Clinical Care/Education/Nutrition/Psychosocial Research; Diabetes; Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - genetics; Disease Progression; Endoplasmic reticulum; Fasting; Fasting - blood; Female; Humans; Immunoglobulins; Insulin; Longitudinal Studies; Male; Pedigree; Peptides; Proinsulin - blood; Young Adult
• ISSN: 0149-5992; 1935-5548
• DOI: 10.2337/dc15-2849

We tested whether an elevation in the serum proinsulin-to-C-peptide ratio (PI:C), a biomarker of β-cell endoplasmic reticulum (ER) dysfunction, was associated with progression to type 1 diabetes. 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). PI:C ratios were calculated as molar ratios and were multiplied by 100% to obtain PI levels as a percentage of C levels. Although absolute PI levels did not differ between groups, PI:C 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 PI:C ratio was nearly triple that of nonprogressors; 90.0% of subjects in this age group within the upper PI:C quartile progressed to the development of diabetes. Logistic regression analysis, adjusted for age and BMI, demonstrated increased odds of progression for higher natural log PI:C ratio values (odds ratio 1.44, 95% CI 1.02, 2.05). These data suggest that β-cell ER dysfunction precedes type 1 diabetes onset, especially in younger children. Elevations in the serum PI:C ratio may have utility in predicting the onset of type 1 diabetes in the presymptomatic phase.