Proinsulin-to-C-peptide ratio versus proinsulin-to-insulin ratio in the prediction of incident diabetes: the Insulin Resistance Atherosclerosis Study (IRAS)

Diabetologia. 2011 Dec;54(12):3047-54. doi: 10.1007/s00125-011-2322-2. Epub 2011 Sep 30.


Aims: Associations of proinsulin-to-insulin ratios with incident type 2 diabetes have been inconsistent. The use of C-peptide as the denominator in the ratio may allow for better prediction because C-peptide concentration is not affected by hepatic insulin clearance. The objective of this paper was to compare fasting intact and split proinsulin-to-insulin ratios (PI/I, SPI/I) with intact and split proinsulin-to-C-peptide ratios (PI/C-pep, SPI/C-pep) in the prediction of type 2 diabetes.

Methods: Prospective data on 818 multi-ethnic adults without diabetes at baseline from the Insulin Resistance Atherosclerosis Study (IRAS) were used. Insulin sensitivity (S(I)) and acute insulin response (AIR) were determined from frequently sampled intravenous glucose tolerance tests, and fasting intact and split proinsulin were measured using specific two-site monoclonal antibody-based immunoradiometric assays. Associations of proinsulin ratios with type 2 diabetes were determined using logistic regression and differences in prediction were assessed by comparing areas under the receiver operating characteristic curve (AROCs).

Results: In logistic regression analyses, PI/C-pep and SPI/C-pep were more strongly associated with incident type 2 diabetes (n = 128) than PI/I and SPI/I, and were significantly better predictors of diabetes in AROC analyses (PI/C-pep = 0.662 vs PI/I = 0.603, p = 0.02; SPI/C-pep = 0.690 vs SPI/I = 0.631, p = 0.01). Both PI/C-pep and SPI/C-pep were associated with type 2 diabetes after adjustment for age, sex, ethnicity, waist circumference, impaired glucose tolerance, lipids and S(I). Both PI/C-pep and SPI/C-pep were significantly associated with incident type 2 diabetes in models that included AIR.

Conclusions: Proinsulin-to-C-peptide ratios were stronger predictors of diabetes in comparison with proinsulin-to-insulin ratios. These findings support the use of C-peptide as the denominator for proinsulin ratios, to more accurately reflect the degree of disproportional hyperproinsulinaemia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Atherosclerosis / blood*
  • C-Peptide / blood*
  • Fasting
  • Female
  • Humans
  • Insulin / blood*
  • Insulin Resistance*
  • Male
  • Middle Aged
  • Prediabetic State / blood*
  • Predictive Value of Tests
  • Proinsulin / blood*
  • Prospective Studies
  • ROC Curve
  • Waist Circumference


  • C-Peptide
  • Insulin
  • Proinsulin