Proinsulin to C-Peptide Ratio in the First Year After Diagnosis of Type 1 Diabetes

J Clin Endocrinol Metab. 2021 Oct 21;106(11):e4318-e4326. doi: 10.1210/clinem/dgab463.


Objective: The proinsulin to C-peptide (PI:C) ratio is reputedly a biomarker of β-cell endoplasmic reticulum (ER) stress.

Objective: This study examined the natural history of the PI:C ratio and its correlation with residual β-cell function in childhood new-onset type 1 diabetes (T1D). Over the first year of T1D, the temporal trend in fasting and nutrient-stimulated PI data is limited.

Methods: PI was a secondary pre-planned analysis of our 1-year, randomized, double-blind, placebo-controlled gamma aminobutyric acid (GABA) trial in new-onset T1D. Of the 99 participants in the primary study, aged 4 to 18 years, 30 were placebo. This study only involved the 30 placebo patients; all were enrolled within 5 weeks of T1D diagnosis. A liquid mixed meal tolerance test was administered at baseline and 5 and 12 months for determination of C-peptide, PI, glucose, and hemoglobin A1C.

Results: Both the fasting (P = 0.0003) and stimulated (P = 0.00008) PI:C ratios increased from baseline to 12 months, indicating escalating β-cell ER stress. The baseline fasting PI correlated with the fasting change in C-peptide at 12 months (P = 0.004) with a higher PI correlating with greater decline in C-peptide. Patients with an insulin-adjusted A1C >9% (hence, not in remission) had higher fasting PI:C ratios. Younger age at diagnosis correlated with a higher PI:C ratio (P = 0.04).

Conclusion: Children with new-onset T1D undergo progressive β-cell ER stress and aberrant proinsulin processing, as evidenced by increasing PI:C ratios. Moreover, the PI:C ratio reflects more aggressive β-cell onslaught with younger age, as well as diminished glycemic control.

Trial registration: NCT02002130.

Keywords: children; proinsulin to C-peptide ratio; type 1 diabetes.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Biomarkers / blood
  • C-Peptide / blood*
  • Child
  • Child, Preschool
  • Diabetes Mellitus, Type 1 / blood*
  • Diabetes Mellitus, Type 1 / diagnosis*
  • Diabetes Mellitus, Type 1 / drug therapy
  • Double-Blind Method
  • Endoplasmic Reticulum Stress / physiology*
  • Fasting
  • Female
  • Glucose Tolerance Test / methods
  • Glycemic Control / statistics & numerical data
  • Humans
  • Insulin / therapeutic use
  • Insulin-Secreting Cells / physiology
  • Insulin-Secreting Cells / ultrastructure*
  • Male
  • Meals
  • Placebos
  • Proinsulin / blood*


  • Biomarkers
  • C-Peptide
  • Insulin
  • Placebos
  • Proinsulin

Associated data