C-Peptide: What it is, What it Does, Why You Test For It, What it Means
Proinsulin C-peptide (connecting peptide) is a 31-amino-acid polypeptide that represents the mid-portion of the proinsulin molecule. Proinsulin resembles a hairpin structure, with 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 it is enzymatically sliced off and co-secreted 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).
What C-Peptide Does
C-peptide was first described in 1967 in connection with the discovery of the insulin biosynthesis. It 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.
C-peptide has been shown to bind to the surface of a number of cell types such as neuronal, endothelial, fibroblast and renal tubular. People with type I diabetes typically have very little C-peptide secretion because as the disease progresses most of their beta cells are either been destroyed or inactivated. This has 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 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. C-peptide also has been reported to have anti-inflammatory effects as well as aid repair of smooth muscle cells.
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. 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).
Why Test For C-Peptide
Newly diagnosed diabetes patients often get their C-peptide levels measured as a means of distinguishing between type 1 diabetes, Maturity Onset Diabetes of the Young (MODY), Latent Autoimmune Diabetes of Adults (LADA) and type 2 diabetes.
- The pancreas of a person with type 1 diabetes is unable to produce adequate insulin, and, therefore, they will usually have a decreased level of C-peptide.
- 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.
A C-peptide lab test can also help find the cause of low blood sugar (hypoglycemia), such as excessive use of medicine to treat diabetes or a noncancerous growth (tumor) in the pancreas (insulinoma). Because man-made (synthetic) insulin does not have C-peptide, a person with a low blood sugar level from taking too much insulin will have a low C-peptide level. An insulinoma causes the pancreas to release too much insulin, which causes blood sugar levels to drop (hypoglycemia). A person with an insulinoma will have a high level of C-peptide in the blood.
The C-Peptide Test and What it Means
A C-peptide test measures the level of this peptide in the blood. C-peptide is found in amounts equal to endogenously secreted insulin because insulin and C-peptide are linked when first made by the pancreas. The level of C-peptide in the blood can show how much insulin is being made by the pancreas. C-peptide itself does not affect the blood sugar level in the body.
The normal values listed here-called a reference range-are just a guide. These ranges vary from lab to lab, so your lab may have a different range for what’s normal. Your lab report should contain the range your lab uses. Also, your doctor will evaluate your results based on your health and other factors. This means that a value that falls outside the normal values listed here may still be normal for you or your lab.
The level of C-peptide in the blood must be read with the results of a blood glucose test. Both these tests will be done at the same time.
C-peptide – Fasting: 0.51-2.72 nanograms per milliliter (ng/mL) or 0.17-0.90 nanomoles per liter (nmol/L)
- High levels of both C-peptide and blood glucose are found in people with type 2 diabetes or insulin resistance (such as from Cushing’s syndrome).
- A high level of C-peptide with a low blood glucose level may mean that an insulin-producing tumor of the pancreas (insulinoma) is present or that the use of certain medicines such as sulfonylureas (for example, glyburide) is causing the high level.
- If C-peptide levels are high after an insulinoma is taken out, it may mean that the tumor has returned or that the tumor has spread to other parts of the body (metastasized).
- A low level of C-peptide with a high blood glucose level is found in people with type 1 diabetes.
- Persons with LADA typically have low, although sometimes moderate, levels of C-peptide as the disease progresses and high blood glucose levels.
- The most common MODY syndrome may also have normal fasting C-peptide results because the flaw in this case is in the secretion of insulin in response to rising glucose and fasting secretion is still near normal. Their postprandial C-peptide however is below normal with elevated blood glucose.
- Low levels of both C-peptide and blood glucose are found in liver disease, a severe infection, Addison’s disease, or insulin therapy.
What to Think About
- A C-peptide test must be done at the same time as a blood glucose test. In order to have a full picture of what is happening, knowing fasting blood glucose and fasting C-peptide, and post prandial blood glucose and C-peptide is most helpful.
- A person with new type 2 diabetes often has a normal or high level of C-peptide in the blood. Over time, a person with type 2 diabetes may develop a low level of C-peptide.
- People with type 1 diabetes, typically have very low or undetectable levels of C-peptide coupled with elevated blood glucose levels. C-peptide can still be secreted during the honeymoon and beyond, indicating that beta cell destruction or deactivation is not complete.
- To help tell the difference between type 1 and type 2 diabetes and to help guide treatment, most doctors look at a person’s age, weight, and how long symptoms have been present.
- In some cases, a C-peptide stimulation test may be done to help tell the difference between the two types of diabetes. During a C-peptide stimulation test, a blood sample is taken to measure C-peptide. Then a shot of a hormone to increase blood sugar (glucagon) is given into a vein in the arm. Another blood sample is taken. In people with type 1 diabetes, C-peptide levels will be low because the pancreas cannot make sufficient or any insulin in response to the glucagon. In people with type 2 diabetes, C-peptide levels will be higher than the first blood test because the pancreas is making more insulin in response to the glucagon.