What does a C‑peptide level indicate about endogenous insulin secretion and the type of diabetes?

What C-Peptide Levels Tell You

C-peptide is the definitive marker of endogenous insulin secretion because it is produced in equimolar amounts to insulin but has minimal hepatic extraction, making it far superior to measuring insulin itself for assessing pancreatic β-cell function. 1, 2

Physiologic Basis

• C-peptide is cleaved from proinsulin in pancreatic β-cells and secreted in equal amounts to insulin, but unlike insulin, it undergoes minimal first-pass hepatic clearance and has a longer half-life, making it a stable and reliable marker of endogenous insulin production. 3, 4
• Exogenous insulin administration does not affect C-peptide levels, so measurement remains accurate even in insulin-treated patients. 5
• A small, constant proportion is excreted in urine, allowing for both serum and urinary measurement. 4

Interpretation for Diabetes Classification

Low C-Peptide (<200 pmol/L or <0.6 ng/mL)

• C-peptide values <200 pmol/L are consistent with type 1 diabetes and indicate substantial β-cell loss requiring insulin therapy for survival. 1
• Very low levels (<80 pmol/L or <0.24 ng/mL) strongly suggest absolute insulin deficiency and are diagnostic of type 1 diabetes. 1
• In research contexts, C-peptide <0.2 nmol/L is specifically associated with a diagnosis of type 1 diabetes mellitus. 6
• Low C-peptide at any time confirms absolute insulin requirement and the appropriateness of type 1 diabetes management strategies regardless of apparent etiology. 2

Intermediate C-Peptide (200–600 pmol/L or 0.6–1.8 ng/mL)

• C-peptide values between 200–600 pmol/L may indicate type 1 diabetes, maturity-onset diabetes of the young (MODY), or insulin-treated type 2 diabetes with long duration. 1
• Further testing with islet autoantibodies (GAD, IA-2, ZnT8) or genetic testing may be needed for definitive diagnosis in this range. 1
• Persistence of C-peptide is an important clinical feature of MODY, helping distinguish it from type 1 diabetes where patients are commonly misdiagnosed and unnecessarily treated with insulin. 7

High C-Peptide (>600 pmol/L or >1.8 ng/mL)

• C-peptide values >600 pmol/L strongly suggest type 2 diabetes rather than type 1 diabetes, reflecting substantial residual insulin secretory capacity and insulin resistance as the primary pathophysiologic defect. 8
• High uncorrected fasting C-peptide in the presence of hyperglycemia suggests insulin resistance, where absolute insulin production is normal or increased but disproportionately low for the degree of insulin sensitivity. 7, 8
• Preserved β-cell function (high C-peptide) makes patients ideal candidates for metformin and other insulin-sensitizing agents rather than insulin. 8

Clinical Applications Beyond Diabetes Classification

Distinguishing Endogenous vs. Exogenous Hyperinsulinism

• Simultaneous elevation of serum insulin and C-peptide during hypoglycemia suggests an insulinoma or other cause of endogenous hyperinsulinism, requiring evaluation to exclude a pancreatic neuroendocrine tumor. 3
• The diagnostic criteria for insulinoma include insulin level >3 µIU/mL (often >6 µIU/mL) when glucose <40–45 mg/dL, insulin-to-glucose ratio ≥0.3, and elevated C-peptide ≥0.6 ng/mL (≈200 pmol/L) during hypoglycemia. 8, 3
• A supervised 48–72 hour fast with simultaneous measurement of plasma glucose, insulin, C-peptide, and proinsulin when glucose falls below 55 mg/dL is the standard approach to confirm endogenous hyperinsulinemic hypoglycemia. 3
• Urine sulfonylurea testing must be performed to rule out factitious hypoglycemia in patients with elevated C-peptide and low glucose. 8, 3

Predicting Clinical Course and Treatment Response

• C-peptide level may be a good predictor of clinical partial remission during the first year of type 1 diabetes. 7
• C-peptide levels correlate with microvascular and macrovascular complications, future use of insulin therapy, and likely response to individual therapies. 6
• Residual β-cell function as measured by C-peptide in those with type 1 diabetes has repeatedly been demonstrated to be clinically important, though the Eisenbarth model suggests most people with longstanding T1D show little to no residual C-peptide secretion. 5

Latent Autoimmune Diabetes in Adults (LADA)

• LADA is clinically similar to type 2 diabetes but with positivity for pancreatic autoantibodies and lower C-peptide levels than typical type 2 diabetes. 7
• The natural course shows that C-peptide will decrease with time in LADA patients in parallel with the curve for C-peptide in classical type 1 diabetic patients. 7

Testing Methodology and Timing

When to Order C-Peptide

• Use C-peptide testing in insulin-treated adults when the diabetes type is unclear—especially if they present with ketoacidosis but exhibit a phenotype typical of type 2 diabetes or are antibody-negative. 1
• For antibody-negative patients, C-peptide testing after at least 3 years of diabetes duration can help confirm classification, as utility is greatest after 3–5 years from diagnosis when persistence of substantial insulin secretion suggests type 2 or monogenic diabetes. 1, 2
• Measure fasting C-peptide to satisfy insurance documentation requirements for insulin-pump coverage when simultaneous fasting plasma glucose is ≤220 mg/dL. 1
• Employ C-peptide measurement when evaluating unexplained (nondiabetic) hypoglycemia to exclude surreptitious insulin administration. 1

Testing Approach

• A random C-peptide sample within 5 hours of eating can replace a formal C-peptide stimulation test for diabetes classification purposes. 1
• When a formal stimulation test is required, an intravenous glucagon-stimulated C-peptide assay offers the best balance of sensitivity and practicality for differentiating type 1 from type 2 diabetes in challenging cases. 1, 6
• If the C-peptide result is <600 pmol/L and concurrent glucose is <4 mmol/L (<70 mg/dL), consider repeating the test; results showing very low levels (e.g., <80 pmol/L) do not need to be repeated. 1

Critical Caveats

• Do not test C-peptide within 2 weeks of a hyperglycemic emergency, as results will be unreliable. 1, 8
• For insulin-treated patients, C-peptide must be measured prior to insulin discontinuation to exclude severe insulin deficiency. 1
• Do not use C-peptide routinely in the general diabetic population or in individuals at risk for diabetes; its primary role is research-oriented rather than for everyday clinical management. 1
• Avoid C-peptide testing for assessment of polycystic ovary syndrome, as it provides no advantage over standard clinical markers of insulin resistance (e.g., BMI, acanthosis nigricans). 1
• Major sources of assay error include standard, tracer, antiserum specificity and reactivity with proinsulin, and degradation of C-peptide. 4