title: Elevations in the Fasting Serum Proinsulin-to-C-Peptide Ratio Precede the Onset of Type 1 Diabetes.
abstract: 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.
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Sims
authors.affiliation: Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Zunaira
authors.initials: Z
authors.lastname: Chaudhry
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Renecia
authors.initials: R
authors.lastname: Watkins
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Farooq
authors.initials: F
authors.lastname: Syed
authors.affiliation: Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Janice
authors.initials: J
authors.lastname: Blum
authors.affiliation: Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Fangqian
authors.initials: F
authors.lastname: Ouyang
authors.affiliation: Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Perkins
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN Department of Medicine, Indiana University School of Medicine, Indianapolis, IN Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Raghavendra G
authors.initials: RG
authors.lastname: Mirmira
authors.affiliation: Division of Endocrinology, University of Miami, Miami, FL.
authors.forename: Jay
authors.initials: J
authors.lastname: Sosenko
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Linda A
authors.initials: LA
authors.lastname: DiMeglio
authors.affiliation: Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN Department of Medicine, Indiana University School of Medicine, Indianapolis, IN Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN Richard L. Roudebush VA Medical Center, Indianapolis, IN cevansmo@iu.edu.
authors.forename: Carmella
authors.initials: C
authors.lastname: Evans-Molina
mesh_terms: D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000097:blood; D015415:Biomarkers / Q000097:blood; D001771:Blood Banks; D002096:C-Peptide / Q000097:blood*; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000235:genetics; D018450:Disease Progression; D005215:Fasting / Q000097:blood*; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D010375:Pedigree; D011384:Proinsulin / Q000097:blood*; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D002096:C-Peptide; D011384:Proinsulin