C-peptide determination in the diagnosis of type of diabetes and its management: A clinical perspective

Abstract

Impaired beta-cell function is a recognized cornerstone of diabetes pathophysiology. Estimates of insulin secretory capacity are useful to inform clinical practice, helping to classify types of diabetes, complication risk stratification and to guide treatment decisions. Because C-peptide secretion mirrors beta-cell function, it has emerged as a valuable clinical biomarker, mainly in autoimmune diabetes and especially in adult-onset diabetes. Nonetheless, the lack of robust evidence about the clinical utility of C-peptide measurement in type 2 diabetes, where insulin resistance is a major confounder, limits its use in such cases. Furthermore, problems remain in the standardization of the assay for C-peptide, raising concerns about comparability of measurements between different laboratories. To approach the heterogeneity and complexity of diabetes, reliable, simple and inexpensive clinical markers are required that can inform clinicians about probable pathophysiology and disease progression, and so enable personalization of management and therapy. This review summarizes the current evidence base about the potential value of C-peptide in the management of the two most prevalent forms of diabetes (type 2 diabetes and autoimmune diabetes) to address how its measurement may assist daily clinical practice and to highlight current limitations and areas of uncertainties to be covered by future research.

Keywords: C-peptide; insulin; insulin deficiency; insulin secretion; pancreatic beta cell.

FIGURE 1

Schematic representation of C‐peptide production and secretion in equimolar amounts with insulin. C‐peptide is a 31 amino acid peptide (molecular weight ~ 3000 g/mol) derived from the cleavage of proinsulin in insulin. Briefly, preproinsulin is synthesized in the granular endoplasmic reticulum, where it is cleaved by microsomal enzymes in proinsulin, which consists of a single chain of 86 amino acids including the A and B insulin chains, the C‐peptide and two dipeptide linkages of basic amino acids. Proinsulin is transported by small transfer vesicles to the Golgi apparatus, where it is packed into clathrin‐coated secretory granules together with prohormone convertases 1 and 2. These enzymes are responsible for cutting proinsulin at the dipeptide linkages, whereas a carboxypeptidase E removes the pairs of basic amino acids, finally resulting in the 51 amino acid insulin molecule and in the 31 amino acid connecting peptide (C‐peptide) residue. C‐peptide is stored in the secretory granules of pancreatic beta cells and then secreted in the bloodstream in equimolar amounts with insulin. In contrast to insulin, C‐peptide has a negligible extraction by the liver and has a constant renal peripheral clearance, which approximates the glomerular filtration rate. However, the urinary excretion of C‐peptide is comparatively low, suggesting that most of the C‐peptide extracted by the kidney is metabolized by renal tissues, with only a small fraction excreted in the urine,