Clinical Information

C-peptide (connecting peptide), a 31-amino-acid polypeptide, represents the midportion of the proinsulin molecule. Proinsulin resembles a hairpin structure, with an N-terminal and C-terminal, which correspond to the A and B chains of the mature insulin molecule, oriented parallel to each other and linked by disulfide bonds. The looped portion of the hairpin between the A and B chains is called C-peptide. During insulin secretion, C-peptide is enzymatically cleaved off and cosecreted in equimolar proportion with mature insulin molecules.

Following secretion, insulin and C-peptide enter the portal circulation and are routed through the liver where at least 50% of the insulin binds to receptors, initiates specific hepatic actions (stimulation of hepatic glucose uptake and suppression of glycogenolysis, gluconeogenesis, and ketogenesis), and is subsequently degraded. Most of the insulin molecules that pass through the liver into the main circulation bind to peripheral insulin receptors, promoting glucose uptake, while the remaining molecules undergo renal elimination. Unlike insulin, C-peptide is subject to neither hepatic nor significant peripheral degradation but is mainly removed by the kidneys. As a result, C-peptide has a longer half-life than insulin (30-35 minutes versus 5-10 minutes), and the molar ratio of circulating insulin to circulating C-peptide is generally below 1, despite equimolar secretion. Until recently, C-peptide was thought to have no physiological function, but it now appears that there may be specific C-peptide cell-surface receptors (most likely belonging to the super-family of G-protein coupled receptors), which influence endothelial responsiveness and skeletal and renal blood flow.

In most disease conditions associated with abnormal serum insulin levels, the changes in serum C-peptide levels parallel insulin-related alterations (insulin to C-peptide molar ratio ≤1). Both serum C-peptide and serum insulin levels are elevated in kidney failure and in disease states that lead to augmented primary endogenous insulin secretion (eg, insulinoma, sulfonylurea intoxication). Both also may be raised in any disease states that cause secondary increases in endogenous insulin secretion mediated through insulin resistance, primarily obesity, glucose intolerance, and early type 2 diabetes mellitus (DM), as well as endocrine disorders associated with hypersecretion of insulin-antagonistic hormones (eg, Cushing syndrome, acromegaly). Failing insulin secretion in type 1 DM and longstanding type 2 DM is associated with corresponding reductions in serum C-peptide levels.

Discordant serum insulin and serum C-peptide abnormalities are mainly observed in 2 situations: exogenous insulin administration and the presence of anti-insulin autoantibodies. Factitious hypoglycemia due to surreptitious insulin administration results in appropriate suppression of endogenous insulin and C-peptide secretion. At the same time, the peripherally administered insulin bypasses the hepatic first-pass metabolism. In these situations, insulin levels are elevated and C-peptide levels are decreased. In patients with insulin antibodies, insulin levels are increased because of the prolonged half-life of autoantibody-bound insulin. Some patients with anti-idiotypic anti-insulin autoantibodies experience episodic hypoglycemia caused by displacement of autoantibody-bound insulin.