What are the normal fasting C‑peptide levels and how can they be used to differentiate type 1 diabetes from type 2 diabetes?

Fasting C-Peptide Levels: Normal Values and Diabetes Classification

Normal Reference Range

Normal fasting C-peptide levels range from approximately 0.5–2.0 ng/mL (approximately 200–600 pmol/L), though the precise cutoffs vary slightly by assay. 1

Diagnostic Thresholds for Diabetes Classification

C-peptide values <200 pmol/L (<0.6 ng/mL) are consistent with type 1 diabetes and indicate substantial β-cell loss requiring insulin therapy. 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
• These patients have lost the majority of their pancreatic β-cell mass and require insulin for survival. 1

C-peptide values between 200–600 pmol/L (0.6–1.8 ng/mL) represent an intermediate zone that may indicate type 1 diabetes, maturity-onset diabetes of the young (MODY), or long-standing insulin-treated type 2 diabetes. 1

• In this gray zone, additional testing with islet autoantibodies (GAD, IA-2, ZnT8) or genetic testing may be needed for definitive classification. 1
• The clinical context—including age at onset, body habitus, family history, and presence of ketoacidosis—helps guide interpretation. 1

C-peptide values >600 pmol/L (>1.8 ng/mL) strongly suggest type 2 diabetes with preserved β-cell function. 1, 2

• These patients retain substantial endogenous insulin production and are candidates for oral antihyperglycemic agents rather than immediate insulin therapy. 1, 2
• High C-peptide reflects insulin resistance as the primary pathophysiologic defect, not absolute insulin deficiency. 2

Optimal Testing Methodology

A random C-peptide sample obtained within 5 hours of eating can replace formal stimulation testing for diabetes classification purposes. 1

• This practical approach eliminates the need for fasting or glucagon stimulation in most clinical scenarios. 1
• The American Diabetes Association endorses this simplified testing strategy for routine classification. 1

For insurance documentation of insulin pump eligibility, measure fasting C-peptide when the simultaneous fasting plasma glucose is ≤220 mg/dL (≤12.5 mmol/L). 1

• This specific requirement applies only to payer-mandated documentation, not routine clinical classification. 1

When formal stimulation is required for challenging cases, glucagon-stimulated C-peptide testing offers the best balance of sensitivity and practicality. 1, 3

Critical Testing Caveats

Do not measure C-peptide within 2 weeks of a hyperglycemic emergency (diabetic ketoacidosis or hyperosmolar hyperglycemic state). 1

• Acute metabolic decompensation temporarily suppresses β-cell function, yielding falsely low results that do not reflect baseline secretory capacity. 1

If concurrent glucose is <70 mg/dL (<4 mmol/L) when C-peptide is measured, consider repeating the test. 1

• Hypoglycemia physiologically suppresses insulin and C-peptide secretion, potentially leading to misclassification. 1
• Very low results (<80 pmol/L) do not require repetition regardless of glucose level, as they are unequivocally diagnostic. 1

In insulin-treated patients, C-peptide must be measured prior to insulin discontinuation to exclude severe insulin deficiency. 1

• Stopping insulin in a patient with absolute deficiency risks life-threatening ketoacidosis. 1

Clinical Algorithm for Diabetes Classification

Step 1: Measure islet autoantibodies first in patients with ambiguous presentation (e.g., type 2 phenotype with ketoacidosis). 1

• Check GAD, IA-2, and ZnT8 antibodies as the initial diagnostic step. 1

Step 2: If antibody-negative and classification remains uncertain, proceed to C-peptide testing. 1

• This is particularly important in patients under 35 years without clear clinical features of type 2 or monogenic diabetes. 1
• For antibody-negative patients over 35 years, C-peptide assists with treatment decisions. 1

Step 3: After at least 3 years of diabetes duration in antibody-negative patients, C-peptide testing can confirm classification. 1, 4

• Persistence of substantial C-peptide after several years strongly suggests type 2 or monogenic diabetes rather than type 1. 4
• Absent C-peptide at any time confirms absolute insulin requirement regardless of apparent etiology. 4

Treatment Implications Based on C-Peptide Results

For low C-peptide (<200 pmol/L): Initiate or continue intensive insulin therapy with type 1 diabetes management strategies. 1

• These patients require basal-bolus insulin regimens or insulin pump therapy. 1
• They are at risk for diabetic ketoacidosis and require close monitoring. 1

For high C-peptide (>600 pmol/L): Start metformin as first-line pharmacotherapy combined with intensive lifestyle modification. 2

• Target at least 60 minutes daily of moderate-to-vigorous exercise to enhance insulin sensitivity. 2
• Insulin-sensitizing agents such as thiazolidinediones can be considered given robust endogenous secretion. 2
• Monitor HbA1c every 3 months and intensify treatment if the target of <7.0% is not achieved. 2

Additional Clinical Applications

C-peptide is essential for investigating nondiabetic hypoglycemia to exclude surreptitious insulin administration. 1, 5

• Exogenous insulin suppresses endogenous production, yielding low C-peptide despite elevated insulin levels. 5
• In contrast, insulinoma produces elevated C-peptide alongside inappropriately high insulin during hypoglycemia. 5

An elevated proinsulin-to-insulin ratio during hypoglycemia strongly suggests an islet cell tumor (insulinoma). 5

• This pattern reflects abnormal prohormone processing characteristic of neuroendocrine tumors. 5

Common Pitfalls to Avoid

Do not use C-peptide routinely in the general diabetic population or for screening individuals at risk for diabetes. 1

• Its primary role is to resolve diagnostic uncertainty in specific clinical scenarios, not for population-wide assessment. 1

Do not rely solely on C-peptide to predict future insulin requirement in established type 2 diabetes. 6

• While low C-peptide suggests advanced β-cell failure, the relationship between C-peptide levels and timing of insulin initiation is complex and influenced by multiple factors. 6

Recognize that fasting C-peptide concentrations between 0.13–0.36 nmol/L (approximately 0.4–1.1 ng/mL) do not reliably discriminate between diabetes types. 6

• In this intermediate range, clinical context and additional testing are essential for accurate classification. 6