C-peptide

C-peptide is a protein that is produced in the body along with insulin. First preproinsulin is secreted with an A-chain, C-peptide, a B-chain, and a signal sequence. The signal sequence is cut off, leaving proinsulin. Then the C-peptide is cut off, leaving the A-chain and B-chain to form insulin.

C-peptide should not be confused with c-reactive protein or Protein C.

History

Proinsulin C-peptide was first described in 1967 in connection with the discovery of the insulin biosynthesis.^[2] It serves as an important linker between the A- and the B- chains of insulin and facilitates the efficient assembly, folding, and processing of insulin in the endoplasmic reticulum. Equimolar amounts of C-peptide and insulin are then stored in secretory granules of the pancreatic beta cells and both are eventually released to the portal circulation. Initially, the sole interest in C-peptide was as a marker of insulin secretion and has as such been of great value in furthering the understanding of the pathophysiology of type 1 and type 2 diabetes. The first documented use of the C-peptide test was in 1972. During the past decade, however, C-peptide has been found to be a bioactive peptide in its own right, with effects on microvascular blood flow and tissue health.

Function

Cellular effects of C-peptide: C-peptide has been shown to bind to the surface of a number of cell types such as neuronal, endothelial, fibroblast and renal tubular, at nanomolar concentrations to a receptor that is likely G-protein-coupled. The signal activates Ca²⁺-dependent intracellular signaling pathways such as MAPK, PLCγ, and PKC, leading to upregulation of a range of transcription factors as well as eNOS and Na+K+ATPase activities.^[3] The latter two enzymes are known to have reduced activities in patients with type I diabetes and have been implicated in the development of long-terms complications of type I diabetes such as peripheral and autonomic neuropathy. In vivo studies in animal models of type 1 diabetes have established that C-peptide administration results in significant improvements in nerve and kidney function. Thus, in animals with early signs of diabetes-induced neuropathy, C peptide treatment in replacement dosage results in improved peripheral nerve function, as evidenced by increased nerve conduction velocity, increased nerve Na+,K+ ATPase activity, and significant amelioration of nerve structural changes.^[4] Likewise, C-peptide administration in animals that had C-peptide deficiency (type 1 model) with nephropathy improves renal function and structure; it decreases urinary albumin excretion and prevents or decreases diabetes-induced glomerular changes secondary to mesangial matrix expansion.^[5][6][7][8] C-peptide also has been reported to have anti-inflammatory effects as well as aid repair of smooth muscle cells.^[9][10]

Uses

• Newly diagnosed diabetes patients often get their C-peptide levels measured as a means of distinguishing type 1 diabetes and type 2 diabetes. C-peptide levels are measured instead of insulin levels because insulin concentration in the portal vein ranges from two to ten times higher than in the peripheral circulation. The liver extracts about half the insulin reaching it in the plasma, but this varies with the nutritional state. The pancreas of patients with type 1 diabetes is unable to produce insulin, and, therefore, they will usually have a decreased level of C-peptide, whereas C-peptide levels in type 2 patients are normal or higher than normal. Measuring C-peptide in patients injecting synthetic insulin can help to determine how much of their own natural insulin these patients are still producing, or if they produce any at all.

• C-peptide is also used for determining the possibility of gastrinomas associated with Multiple Endocrine Neoplasm syndromes (MEN 1). Since a significant number of gastrinomas are associated with MEN involving other hormone producing organs (pancreas, parathyroids, and pituitary), higher levels of C-peptide together with the presence of a gastrinoma suggest that organs besides the stomach may harbor neoplasms.

• C-peptide levels are checked in women with Polycystic Ovarian Syndrome (PCOS) to determine degree of insulin resistance.

Both excess body weight and a high plasma concentration of C-peptide predispose men with a subsequent diagnosis of prostate cancer to an increased likelihood of dying of the disease, according to the results of a long-term survival analysis reported in the October 6, 2008 Online First issue of Lancet Oncology.

Therapeutics

Several physiological effects have been observed in several Phase 1 and exploratory Phase 2 studies in almost 300 type 1 diabetes patients, who lacked endogenous C-peptide. Improvements were seen on diabetic peripheral neuropathy, nephropathy and other decrements associated with long-term complications of type I diabetes.^{[11] [12] [13] [14] [15] [16] [17] [18]} .^[19] So far, dosing with C-peptide has shown to be safe and there were no effects of C-peptide demonstrated in healthy subjects (who make their own C-peptide).

References