The connecting peptide, or C-peptide, is a short 31-amino-acid polypeptide that connects insulin's A-chain to its B-chain in the proinsulin molecule. In the context of diabetes or hypoglycemia, a measurement of C-peptide blood serum levels can be used to distinguish between different conditions with similar clinical features.
3D model (JSmol)
|Molar mass||3020.29 g/mol|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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In the insulin synthesis pathway, first preproinsulin is translocated into the endoplasmic reticulum of beta cells of the pancreas with an A-chain, a C-peptide, a B-chain, and a signal sequence. The signal sequence is cleaved from the N-terminus of the peptide by a signal peptidase, leaving proinsulin. After proinsulin is packaged into vesicles in the Golgi apparatus (beta-granules), the C-peptide is removed, leaving the A-chain and B-chain bound together by disulfide bonds, that constitute the insulin molecule.
Proinsulin C-peptide was first described in 1967 in connection with the discovery of the insulin biosynthesis pathway. It serves as a 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.
Cellular effects of C-peptideEdit
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. 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-term 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. 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. C-peptide also has been reported to have anti-inflammatory effects as well as aid repair of smooth muscle cells. ii
Clinical uses of C-peptide testingEdit
- Patients with diabetes may have their C-peptide levels measured as a means of distinguishing type 1 diabetes from type 2 diabetes or Maturity onset diabetes of the young (MODY). Measuring C-peptide can help to determine how much of their own natural insulin a person is producing as C-peptide is secreted in equimolar amounts to insulin. C-peptide levels are measured instead of insulin levels because C-peptide can assess a person's own insulin secretion even if they receive insulin injections, and because the liver metabolizes a large and variable amount of insulin secreted into the portal vein but does not metabolise C-peptide, meaning blood C-peptide may be a better measure of portal insulin secretion than insulin itself. A very low C-peptide confirms Type 1 diabetes and insulin dependence and is associated with high glucose variability, hyperglycaemia and increased complications. The test may be less helpful close to diagnosis, particularly where a patient is overweight and insulin resistant, as levels close to diagnosis in Type 1 diabetes may be high and overlap with those seen in type 2 diabetes.
- Differential diagnosis of hypoglycemia. The test may be used to help determine the cause of hypoglycaemia (low glucose), values will be low if a person has taken an overdose of insulin but not suppressed if hypoglycaemia is due to an insulinoma or sulphonylureas.
- Factitious (or factitial) hypoglycemia may occur secondary to the surreptitious use of insulin. Measuring C-peptide levels will help differentiate a healthy patient from a diabetic one.
- C-peptide may be 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 may be checked in women with Polycystic Ovarian Syndrome (PCOS) to help determine degree of insulin resistance.
Therapeutic use of C-peptide has been explored in small clinical trials in diabetic kidney disease. Creative Peptides, Eli Lilly, and Cebix all had drug development programs for a C-peptide product. Cebix had the only ongoing program until it completed a Phase IIb trial in December 2014 that showed no difference between C-peptide and placebo, and it terminated its program and went out of business.
- C-Peptide - Compound Summary, PubChem.
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