Utility of C-peptide: how, when, and where?

Abstract

C-peptide is a key biomarker for assessing pancreatic beta-cell function and reserve. Because it is secreted in equimolar amounts with insulin, undergoes no significant hepatic first-pass metabolism, and has a longer half-life (three to seven times that of insulin), it provides an accurate estimate of endogenous insulin secretion without cross-reacting with exogenous insulin. How is it measured? C-peptide levels can be determined in blood (serum or plasma) or urine, often using the urinary C-peptide/creatinine ratio (UCPCR).

Testing strategies include fasting samples, random (non-fasting) samples, and formal stimulation tests. Although stimulation tests—such as the mixed-meal tolerance test (MMT) and the glucagon stimulation test (GST)—are considered the gold standard due to their excellent sensitivity in detecting residual secretion, random non-fasting measurement is the most practical approach in routine clinical practice for accurately classifying severe insulin deficiency. It is important to note that there is significant variability among different commercial assays and automated immunoassays; therefore, the standardization of these tests remains an urgent clinical need. Furthermore, a recent innovation involves the development of portable devices based on microneedle arrays for the continuous, minimally invasive monitoring of C-peptide in interstitial fluid (ISF).

When should it be measured? Key clinical applications for its measurement include:

• Diabetes classification. It is crucial for distinguishing between type 1 diabetes (T1DM), T2DM, and monogenic forms, especially when symptoms overlap. Measuring it is considered a highly cost-effective intervention in patients diagnosed more than three years prior. Random values ​​<200 pmol/L confirm T1DM or severe insulin deficiency, whereas levels >600 pmol/L suggest T2DM.

• Hypoglycemia assessment. It is used to investigate hypoglycemic episodes and predict glycemic variability; low C-peptide levels are associated with an increased risk of hypoglycemia during insulin therapy.

• Prediction of therapeutic response. It is useful for predicting diabetes remission following bariatric surgery, assessing the efficacy of GLP-1 analog treatments, and guiding the safe discontinuation of insulin therapy. In conclusion, selecting the appropriate strategy and timing for C-peptide measurement greatly facilitates the classification, prognosis, and personalized management of patients with diabetes.