Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes

Abstract

Objective: Abnormally elevated proinsulin secretion has been reported in type 2 and early type 1 diabetes when significant C-peptide is present. We questioned whether individuals with long-standing type 1 diabetes and low or absent C-peptide secretory capacity retained the ability to make proinsulin.

Research design and methods: C-peptide and proinsulin were measured in fasting and stimulated sera from 319 subjects with long-standing type 1 diabetes (≥3 years) and 12 control subjects without diabetes. We considered three categories of stimulated C-peptide: 1) C-peptide positive, with high stimulated values ≥0.2 nmol/L; 2) C-peptide positive, with low stimulated values ≥0.017 but <0.2 nmol/L; and 3) C-peptide <0.017 nmol/L. Longitudinal samples were analyzed from C-peptide-positive subjects with diabetes after 1, 2, and 4 years.

Results: Of individuals with long-standing type 1 diabetes, 95.9% had detectable serum proinsulin (>3.1 pmol/L), while 89.9% of participants with stimulated C-peptide values below the limit of detection (<0.017 nmol/L; n = 99) had measurable proinsulin. Proinsulin levels remained stable over 4 years of follow-up, while C-peptide decreased slowly during longitudinal analysis. Correlations between proinsulin with C-peptide and mixed-meal stimulation of proinsulin were found only in subjects with high stimulated C-peptide values (≥0.2 nmol/L). Specifically, increases in proinsulin with mixed-meal stimulation were present only in the group with high stimulated C-peptide values, with no increases observed among subjects with low or undetectable (<0.017 nmol/L) residual C-peptide.

Conclusions: In individuals with long-duration type 1 diabetes, the ability to secrete proinsulin persists, even in those with undetectable serum C-peptide.

Figure 1

Longitudinal C-peptide and proinsulin values in subjects with long-standing type 1 diabetes. Values are color coded based on stimulated C-peptide values (<0.017 nmol/L [teal], ≥0.017–0.2 nmol/L [light blue], or ≥0.2 nmol/L [royal blue]). A: Individual stimulated (90 min) serum C-peptide (C-pep) levels over 4 years of follow-up. B: Fasting proinsulin values during the initial MMTT, grouped by C-peptide category and type 1 diabetes (T1D) duration. C: Scatterplot of individual proinsulin increments from fasting to stimulated MMTT time points. D: Individual longitudinal proinsulin values for participants with stimulated C-peptide ≥0.017–0.2 nmol/L or ≥0.2 nmol/L. Subjects with undetectable stimulated C-peptide were not invited for longitudinal MMTTs per study protocol. For graphical depiction, values below the assay limit of detection were plotted as one-half the assay limit of detection. Bars in scatterplot graphs represent medians and interquartile range values. *P < 0.05; ***P < 0.001.