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Test ID: CPR    
C-Peptide, Serum

Useful For Suggests clinical disorders or settings where the test may be helpful

Diagnostic workup of hypoglycemia:

-Diagnosis of factitious hypoglycemia due to surreptitious administration of insulin

-Evaluation of possible insulinoma

-Surrogate measure for the absence or presence of physiological suppressibility of endogenous insulin secretion during diagnostic insulin-induced hypoglycemia (C-peptide suppression test)

 

Assessing insulin secretory reserve in selected diabetic patients (as listed below) who either have insulin autoantibodies or who are receiving insulin therapy:

-Assessing residual endogenous insulin secretory reserve

-Monitoring pancreatic and islet cell transplant function

-Monitoring immunomodulatory therapy aimed at slowing progression of preclinical, or very early stage type 1 diabetes mellitus

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

C-peptide (connecting peptide), a 31-amino-acid polypeptide, represents the midportion of the proinsulin molecule. Proinsulin resembles a hairpin structure, with the 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 it 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 <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 < or =1). Both serum C-peptide and serum insulin levels are elevated in renal 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 in 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.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

1.1-4.4 ng/mL

Reference intervals have not been formally verified in-house for pediatric patients. The published literature indicates that reference intervals for adult and pediatric patients are comparable.

Interpretation Provides information to assist in interpretation of the test results

To compare insulin and C-peptide concentrations (ie, insulin to C-peptide ratio):

-Convert insulin to pmol/L: insulin concentration in mcIU/mL x 6.945 = insulin concentration in pmol/L.

-Convert C-peptide to pmol/L: C-peptide concentration in ng/mL x 331 = C-peptide concentration in pmol/L.

 

Factitious hypoglycemia due to surreptitious insulin administration results in elevated serum insulin levels and low or undetectable C-peptide levels, with a clear reversal of the physiological molar insulin to C-peptide ratio (< or =1) to an insulin to C-peptide ratio of >1. By contrast, insulin and C-peptide levels are both elevated in insulinoma and the insulin to C-peptide molar ratio is < or =1. Sulfonylurea ingestion also is associated with preservation of the insulin to C-peptide molar ratio of < or =1.

 

In patients with insulin autoantibodies, the insulin to C-peptide ratio may be reversed to >1, because of the prolonged half-life of autoantibody-bound insulin.

 

Dynamic testing may be necessary in the workup of hypoglycemia; the C-peptide suppression test is most commonly employed. C-peptide levels are measured following induction of hypoglycemia through exogenous insulin administration. The test relies on the demonstration of the lack of suppression of serum C-peptide levels within 2 hours following insulin-induced hypoglycemia in patients with insulinoma.

 

Reference intervals have not been formally verified in-house for pediatric patients. The published literature indicates that reference intervals for adult and pediatric patients are comparable.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Significant hemolysis will result in artifactually lower C-peptide levels and such specimens are usually rejected. However, even mild hemolysis can lead to modest decrements in C-peptide values.

 

There is significant (>20%) cross-reactivity between C-peptide and proinsulin. There is no significant cross-reactivity with other pancreatic islet cell peptides or neuroendocrine peptides.

 

Very high C-peptide levels (>180 ng/mL) may result in artifactually low measurements (hook effect). Such levels are very unlikely to occur in patients, but if individuals are suspected of having serum levels >180 ng/mL, the laboratory should be alerted in order to allow dilution of the specimen prior to testing.

 

This assay uses 2 mouse-derived monoclonal antibodies and may, therefore, be prone to interference by heterophile antimouse antibodies (HAMA). The lab should be alerted to suspected or known HAMA-positive specimens in order to allow the use of heterophile antibody blocking tubes for such specimens.

 

In the assessment of hypoglycemia, neither C-peptide nor insulin measurements are useful, or indicated, if serum blood glucose levels exceed 60 mg/dL.

 

In the diagnosis and management of diabetes mellitus, measurement of serum insulin levels usually provides superior information to that of serum C-peptide.

 

Patients with a body mass index (BMI) >25 may have elevated fasting C-peptide levels.

 

In patients receiving therapy with high biotin doses (ie, >5 mg/day), no specimen should be taken until at least 8 hours after the last biotin administration.

 

In rare cases, interference due to extremely high titers of antibodies to ruthenium or streptavidin can occur.

Clinical Reference Provides recommendations for further in-depth reading of a clinical nature

1. Service FJ, O'Brien PC, Kao PC, Young WF Jr: C-peptide suppression test: effects of gender, age, and body mass index; implications for the diagnosis of insulinoma. J Clin Endocrinol Metab 1992;74:204-210

2. Lebowitz MR, Blumenthal SA: The molar ratio of insulin to C-peptide. An aid to the diagnosis of hypoglycemia due to surreptitious (or inadvertent) insulin administration. Arch Int Med 1993 Mar 8;153(5):650-655

3. Service FJ: Hypoglycemic disorders. N Engl J Med 1995 Apr 27;332(17):1144-1152

4. Wahren J, Ekberg K, Johansson J, et al: Role of C-peptide in human physiology. Am J Physiol Endocrinol Metab 2000 May;278(5):E759-E768

5. Young DS, Huth EJ, et al: SI Units for Clinical Measurement. First edition. BMJ Publishing Group, Philadelphia, PA, 1998; 90