How Valuable Is Measurement of C-Peptide and Insulin Levels in Type 2 Diabetes?

Q:What is the rationale behind checking C-peptide and insulin levels?

A:When insulin secretion by the pancreatic ß-cell is not sufficient to maintain normal blood glucose levels, diabetes develops. Although the exact cause of defective insulin secretion is not well-defined in type 2 diabetes, it is generally accepted that there is progressive ß-cell failure. The ß-cell produces proinsulin, which is then processed into C-peptide and insulin. C-peptide and insulin are released in equal concentrations in the blood. Therefore, C-peptide and insulin levels should be a marker for ß-cell function.

Q:What are the pitfalls to testing C-peptide and insulin levels?

A:C-peptide and insulin are produced at the same rate, but they are processed and eliminated by the body in different ways. After insulin is released from the pancreas, it undergoes significant first-pass clearance by the liver. Therefore, measuring peripheral levels of insulin is not a reliable indicator of insulin secretion by the pancreas. Also, either proinsulin or insulin antibodies can interfere with insulin assays. C-peptide is a more reliable indicator of insulin secretion because it is not cleared by the liver, it has a longer half-life than insulin (30 minutes compared to 4 minutes for insulin), and the pharmacokinetics of C-peptide have been well established in research studies.¹

High glucose levels and renal failure can also affect blood levels of C-peptide and insulin. High glucose levels can cause glucose toxicity to the ß-cell and impair both
C-peptide and insulin release.² Renal failure, with a creatinine clearance of less than 50 mL/min, has been shown to increase fasting insulin levels by approximately 20% and fasting C-peptide levels increase by 100%.³

Q:Are there indications for the routine measurement of C-peptide and insulin levels in type 2 diabetes?

A:The general consensus is that there is not a role for the routine measurement of C-peptide and insulin levels in patients with type 2 diabetes. Measuring C-peptide and insulin levels rarely affects the overall clinical management of a patient with type 2 diabetes. Studies have shown that insulin secretion decreases eventually in a group of patients with type 2 diabetes as expected, but the rate of decline is variable between individuals and also within the same individual. It was observed that C-peptide concentrations could have a trend of decreasing but then returning to baseline, or even increasing to higher levels, in the same person.⁴ Thus, the predictive value of measuring C-peptide in particular is limited.

Furthermore, C-peptide and insulin levels are a function of plasma glucose levels, which will vary from visit to visit. Since type 2 diabetes is also characterized by insulin resistance, insulin and C-peptide levels may be high early in the course of the disease as a compensatory response, making it difficult to interpret results. There is not a consensus as to which therapies may be more effective at any given C-peptide and insulin level.

Patients who are on insulin pump therapy for type 2 diabetes may be required to have C-peptide levels checked to meet the insurance criteria for “insulinopenia.” For example, Medicare requires that the fasting glucose level is less than or equal to 225 mg/dL when the fasting C-peptide level is checked, because high glucose levels can affect
C-peptide levels. Medicare defines insulinopenia as a fasting C-peptide level that is less than or equal to 110% of the lower limit of normal of the laboratory’s measurement method. For patients with a creatinine clearance of 50 mL/min or lower, insulinopenia is defined as a fasting C-peptide level that is less than or equal to 200% of the lower limit of normal of the laboratory’s measurement method.⁵ n