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. ⁵ 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. ¹³⁰ 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 ¹³⁰ , ¹³¹