Elevations in the fasting serum Proinsulin-to-C-peptide ratio precede the onset of type 1 diabetes

Emily K. Sims, Zunaira Chaudhry, Renecia Watkins, Farooq Syed, Janice Blum, Fangqian Ouyang, Susan Perkins, Raghu Mirmira, Jay Sosenko, Linda DiMeglio, Carmella Evans-Molina

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE 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. 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 autoantibodypositive 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 BMImatched 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. RESULTS 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). CONCLUSIONS 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.

Original languageEnglish (US)
Pages (from-to)1519-1526
Number of pages8
JournalDiabetes Care
Volume39
Issue number9
DOIs
StatePublished - Sep 1 2016

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C-Peptide
Type 1 Diabetes Mellitus
Fasting
Serum
Endoplasmic Reticulum
Age Groups
Biomarkers
Logistic Models
Odds Ratio
Regression Analysis
Antibodies

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)
  • Advanced and Specialized Nursing

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Elevations in the fasting serum Proinsulin-to-C-peptide ratio precede the onset of type 1 diabetes. / Sims, Emily K.; Chaudhry, Zunaira; Watkins, Renecia; Syed, Farooq; Blum, Janice; Ouyang, Fangqian; Perkins, Susan; Mirmira, Raghu; Sosenko, Jay; DiMeglio, Linda; Evans-Molina, Carmella.

In: Diabetes Care, Vol. 39, No. 9, 01.09.2016, p. 1519-1526.

Research output: Contribution to journalArticle

Sims, Emily K. ; Chaudhry, Zunaira ; Watkins, Renecia ; Syed, Farooq ; Blum, Janice ; Ouyang, Fangqian ; Perkins, Susan ; Mirmira, Raghu ; Sosenko, Jay ; DiMeglio, Linda ; Evans-Molina, Carmella. / Elevations in the fasting serum Proinsulin-to-C-peptide ratio precede the onset of type 1 diabetes. In: Diabetes Care. 2016 ; Vol. 39, No. 9. pp. 1519-1526.
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AU - Sims, Emily K.

AU - Chaudhry, Zunaira

AU - Watkins, Renecia

AU - Syed, Farooq

AU - Blum, Janice

AU - Ouyang, Fangqian

AU - Perkins, Susan

AU - Mirmira, Raghu

AU - Sosenko, Jay

AU - DiMeglio, Linda

AU - Evans-Molina, Carmella

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N2 - OBJECTIVE 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. 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 autoantibodypositive 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 BMImatched 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. RESULTS 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). CONCLUSIONS 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.

AB - OBJECTIVE 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. 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 autoantibodypositive 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 BMImatched 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. RESULTS 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). CONCLUSIONS 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.

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