Proinsulin is a single-chain protein molecule produced exclusively by the beta cells within the pancreatic islets of Langerhans. This precursor molecule is the starting point for the body’s production of insulin, the hormone that regulates blood glucose levels. Proinsulin’s primary role is to ensure the correct folding and assembly of the final, functional insulin molecule before its release into the bloodstream. It represents an intermediate step in a complex biological manufacturing process.
The Biological Journey: Synthesis and Conversion to Insulin
Proinsulin begins as a single, long polypeptide chain, an 86-residue structure in humans, which is synthesized on the ribosomes of the rough endoplasmic reticulum (ER) inside the pancreatic beta cells. The unique structure of proinsulin, which includes the C-peptide connecting the future A and B chains of insulin, is necessary for the proper formation of the three disulfide bonds that stabilize the mature hormone. The presence of the C-peptide ensures the A and B chains are correctly aligned, allowing for the subsequent creation of two inter-chain and one intra-chain disulfide bond.
Once folded in the ER, the proinsulin molecule is transported to the Golgi apparatus, where it is packaged into immature secretory granules. It is within these granules that the conversion process takes place, transforming the precursor into active insulin. This conversion is an enzymatic cleavage process carried out by proteases, primarily prohormone convertase 1/3 (PC1/3) and prohormone convertase 2 (PC2).
These prohormone convertases act like molecular scissors, cutting the proinsulin chain at specific pairs of basic amino acids—arginine and lysine residues—that flank the C-peptide section. The initial cleavage is typically performed by PC1/3 at the junction between the B-chain and the C-peptide. Subsequent cleavage by PC2, along with carboxypeptidase E (CPE), removes the C-peptide completely. This proteolytic processing yields three separate components: the A-chain and B-chain, which remain connected by the disulfide bonds to form mature insulin, and the free C-peptide.
The Significance of C-Peptide
The connecting peptide, or C-peptide, is a 31-amino-acid polypeptide that is released into the bloodstream at the same time as insulin, resulting in equimolar concentrations of both molecules. While C-peptide was once considered an inactive byproduct of insulin synthesis, research has revealed that it is a valuable marker and may possess its own biological activity. Because C-peptide and insulin are secreted in a one-to-one ratio, measuring C-peptide provides an accurate assessment of the body’s own, or endogenous, insulin production.
This measurement is particularly useful in people who are receiving insulin therapy, as injected insulin preparations do not contain C-peptide. By measuring C-peptide levels, clinicians can differentiate between insulin produced naturally by the pancreas and insulin that has been administered as medication. This distinction helps classify the type of diabetes, such as distinguishing between Type 1, where C-peptide levels are typically very low or absent, and Type 2, where some endogenous insulin production is usually still present.
Beyond its utility as a diagnostic marker, emerging evidence suggests C-peptide has minor biological effects, particularly on microvascular complications often associated with diabetes. It appears to bind to cell surfaces, potentially activating pathways that stimulate enzymes like the sodium-potassium pump and endothelial nitric oxide synthase. This action has been shown to improve nerve function, enhance blood flow in the skin and muscle, and reduce urinary albumin excretion in patients with Type 1 diabetes.
Proinsulin as a Biomarker in Metabolic Health
Under normal metabolic conditions, the conversion of proinsulin to insulin is highly efficient, meaning only a small amount, typically between 1% and 3%, of intact proinsulin is released into circulation. An increase in circulating intact proinsulin or, more specifically, the proinsulin-to-insulin ratio, is a strong indicator of beta-cell dysfunction and metabolic stress. This high level suggests that the pancreatic beta cells are struggling to process proinsulin efficiently, overwhelming the capacity of the converting enzymes like PC1/3 and PC2.
Elevated proinsulin levels are a recognized sign of insulin resistance, a condition where the body’s cells do not respond effectively to insulin. As insulin resistance develops, the beta cells must work harder to secrete more insulin to maintain normal glucose levels, leading to cellular overwork and eventual failure of the processing machinery. This phenomenon often precedes a diagnosis of Type 2 diabetes, making proinsulin an early predictor of disease progression.
Measuring intact proinsulin can therefore serve as a way to stage the degree of beta-cell impairment and monitor the effectiveness of treatments aimed at improving insulin sensitivity. High concentrations of proinsulin are also independently associated with increased cardiovascular risk, even in individuals who have not yet been diagnosed with diabetes. This link suggests that impaired proinsulin processing may be a part of the broader metabolic disturbance that contributes to heart disease and all-cause mortality, regardless of traditional risk factors.