In a patient with type 2 diabetes, when is C‑peptide testing indicated and how should the results be interpreted to guide therapy decisions?

C-Peptide Testing in Type 2 Diabetes

Primary Clinical Indication

In type 2 diabetes, C-peptide testing is indicated primarily when the patient is insulin-treated and the diabetes classification is uncertain—particularly when clinical features suggest type 2 diabetes but the patient presented with ketoacidosis or lacks typical phenotypic markers. 1 C-peptide measurement is not routinely indicated in the general type 2 diabetic population for everyday management decisions. 1

When to Order C-Peptide Testing

Insulin-Treated Patients with Diagnostic Uncertainty

• Order C-peptide when an insulin-treated adult has ambiguous diabetes type, especially if they are antibody-negative for islet autoantibodies (GAD, IA-2, ZnT8) and you need to determine whether they have absolute insulin deficiency or retained β-cell function. 1, 2
• Test after at least 3 years of diabetes duration in antibody-negative patients, as this timing provides the greatest clinical utility for confirming classification—persistence of substantial C-peptide suggests type 2 or monogenic diabetes rather than type 1. 1, 3
• Measure C-peptide in patients initially diagnosed with type 2 diabetes who present with ketoacidosis, as this distinguishes ketosis-prone type 2 diabetes (which maintains higher C-peptide) from misdiagnosed type 1 diabetes. 1, 2

Insurance Documentation

• Obtain fasting C-peptide when insurance requires documentation for insulin pump coverage, ensuring the concurrent fasting plasma glucose is ≤220 mg/dL (≤12.5 mmol/L) at the time of sampling. 1, 4

When NOT to Order C-Peptide

• Do not use C-peptide routinely in non-insulin-treated type 2 diabetics, as clinical features (BMI, metabolic syndrome markers, absence of weight loss) and autoantibodies should guide diagnosis in this population. 1, 2
• Avoid testing within 2 weeks of a hyperglycemic emergency (DKA or HHS), as results will be unreliable during acute metabolic decompensation. 1, 4
• Do not order C-peptide for assessment of insulin resistance or polycystic ovary syndrome, as it provides no advantage over standard clinical markers like BMI and acanthosis nigricans. 1

Testing Methodology

Practical Sampling Approaches

• A random (non-fasting) C-peptide sample drawn within 5 hours of eating is acceptable for diabetes classification and can replace formal stimulation tests in routine practice. 1, 5 This approach allows testing when the patient is seen in clinic without requiring fasting or meal challenges. 5
• For insurance documentation requiring fasting levels, obtain the sample when fasting glucose is ≤220 mg/dL to meet payer requirements. 1, 4
• If a formal stimulation test is needed for challenging cases, intravenous glucagon-stimulated C-peptide offers the best balance of sensitivity and practicality. 1

Important Sampling Caveats

• If concurrent glucose is <70 mg/dL (<4 mmol/L) at the time of C-peptide sampling, consider repeating the test, as hypoglycemia may suppress C-peptide secretion and yield falsely low results. 1
• Very low C-peptide levels (<80 pmol/L or <0.24 ng/mL) do not require repeat testing, as they definitively indicate severe insulin deficiency regardless of glucose level. 1, 2

Interpretation of Results in Type 2 Diabetes

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

• C-peptide >600 pmol/L strongly indicates type 2 diabetes with preserved β-cell function, reflecting substantial residual insulin secretory capacity despite hyperglycemia. 1, 4, 2 This finding confirms that insulin resistance—not absolute insulin deficiency—is the primary pathophysiologic defect. 4
• Look for supporting clinical features: BMI ≥25 kg/m², absence of significant weight loss, absence of ketoacidosis at presentation, and features of metabolic syndrome (hypertension, dyslipidemia, central adiposity). 2
• In insulin-treated patients with high C-peptide, retained endogenous insulin production indicates they may not have absolute insulin requirement, potentially allowing treatment modification away from insulin toward oral agents or GLP-1 agonists. 4

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

• C-peptide in the intermediate range may indicate type 1 diabetes, MODY, or long-duration insulin-treated type 2 diabetes. 1, 2 Further testing with islet autoantibodies or genetic testing may be needed for definitive diagnosis. 1
• Consider MODY if the patient is <35 years old, has HbA1c <7.5% at diagnosis, and has one parent with diabetes, as MODY typically presents with intermediate C-peptide levels. 2
• In established type 2 diabetes treated with insulin for many years, progressive β-cell failure can result in intermediate C-peptide levels. 2

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

• C-peptide <200 pmol/L is consistent with type 1 diabetes and indicates substantial β-cell loss, prompting initiation or continuation of insulin therapy as the patient has absolute insulin deficiency. 1, 2
• Approximately 5–10% of adults with type 1 diabetes are antibody-negative, making C-peptide measurement essential in this subset to avoid misdiagnosis as type 2 diabetes—a misclassification that occurs in 40% of adults with new-onset type 1 diabetes. 2
• Very low levels (<80 pmol/L or <0.24 ng/mL) definitively indicate severe insulin deficiency and confirm absolute insulin requirement regardless of apparent etiology. 1, 3

Therapeutic Decisions Based on C-Peptide

For High C-Peptide (Type 2 Diabetes Phenotype)

• Initiate metformin as first-line pharmacotherapy, as preserved β-cell function makes the patient an ideal candidate for insulin-sensitizing agents. 4
• Implement intensive lifestyle modification including nutrition counseling aimed at weight reduction, since excess adiposity drives insulin resistance in this population. 4
• Target at least 60 minutes daily of moderate-to-vigorous exercise to enhance insulin sensitivity. 4
• Consider thiazolidinediones or other insulin-sensitizing agents for patients with robust C-peptide levels, as they enhance cellular responsiveness to insulin and improve hepatic insulin sensitivity. 4
• Monitor HbA1c every 3 months and intensify treatment if goals are not met, targeting HbA1c <7.0% in most patients to reduce microvascular disease risk. 4

For Low C-Peptide (Absolute Insulin Deficiency)

• Continue or initiate insulin therapy, as low C-peptide confirms absolute insulin requirement and the appropriateness of type 1 diabetes management strategies. 3
• Employ intensive insulin regimens (basal-bolus or pump therapy) with carbohydrate counting and frequent glucose monitoring. 1

Key Clinical Pitfalls

• Misdiagnosis is common: 40% of adults with new type 1 diabetes are initially misclassified as type 2 diabetes, leading to delayed appropriate insulin therapy. 2
• Do not rely solely on age or BMI: younger patients with obesity increasingly present with type 2 diabetes, while lean adults can have type 1 diabetes. 4
• C-peptide reflects relative—not absolute—insulin sufficiency in type 2 diabetes: high C-peptide in the setting of severe hyperglycemia (e.g., HbA1c ≈13%) represents relative insulin deficiency, as marked cellular insulin resistance limits glucose uptake despite substantial insulin secretion. 4
• Timing matters: C-peptide measured during concurrent hypoglycemia (<70 mg/dL) may be falsely low and should be repeated. 1
• C-peptide utility is greatest after 3–5 years from diagnosis, when persistence of substantial insulin secretion strongly suggests type 2 or monogenic diabetes rather than type 1. 3