What is the use of C-peptide (Connecting peptide) in diabetes management?

C-Peptide: Clinical Applications in Diabetes Management

C-peptide measurement is primarily used to distinguish between type 1 and type 2 diabetes in ambiguous cases and to assess residual pancreatic beta cell function, which directly guides treatment decisions including insulin pump coverage and therapy selection. 1, 2

Primary Clinical Indications

C-peptide testing serves several critical roles in diabetes care:

• Diabetes classification in ambiguous presentations - When patients present with features that don't clearly fit type 1 or type 2 diabetes (such as a type 2 phenotype with ketoacidosis), C-peptide helps differentiate between diabetes types 1, 2
• Insurance authorization - Payers often require fasting C-peptide measurement for insulin pump therapy coverage, measured when simultaneous fasting plasma glucose is ≤220 mg/dL (≤12.5 mmol/L) 1, 2
• Hypoglycemia investigation - C-peptide is essential for investigating nondiabetic hypoglycemia to rule out surreptitious insulin administration, as exogenous insulin suppresses C-peptide while endogenous hyperinsulinemia maintains elevated C-peptide 1, 3

Optimal Testing Approach

When to Test

• Timing relative to diagnosis - C-peptide utility is greatest after 3-5 years from diabetes diagnosis when persistence of substantial insulin secretion suggests type 2 or monogenic diabetes rather than type 1 4
• Avoid testing within 2 weeks of hyperglycemic emergencies (DKA, HHS) as results will be unreliable 2, 5
• For insulin-treated patients, measure C-peptide prior to insulin discontinuation to exclude severe insulin deficiency 1, 2

Testing Method Selection

• Random (non-fasting) C-peptide within 5 hours of eating can replace formal stimulation testing for diabetes classification purposes 2, 5
• Fasting C-peptide is required when testing for insurance coverage of insulin pump therapy, with simultaneous glucose ≤220 mg/dL 1, 2
• Glucagon stimulation testing provides the best balance of sensitivity and practicality when more definitive assessment is needed 6

Interpretation Algorithm

C-Peptide Values and Diabetes Type

Very Low (<200 pmol/L or <0.6 ng/mL):

• Consistent with type 1 diabetes 1, 2
• Indicates absolute insulin deficiency requiring insulin therapy for survival 2
• Values <80 pmol/L (<0.24 ng/mL) strongly confirm type 1 diabetes and do not need repeat testing 2

Intermediate (200-600 pmol/L or 0.6-1.8 ng/mL):

• May indicate type 1 diabetes, MODY (maturity-onset diabetes of the young), or long-duration insulin-treated type 2 diabetes 1, 2
• Further testing with autoantibodies (GAD, IA-2, ZnT8) or genetic testing may be needed for definitive diagnosis 2

High (>600 pmol/L or >1.8 ng/mL):

• Suggests type 2 diabetes 1, 2
• Indicates preserved beta cell function and potential responsiveness to oral agents 2

Important Testing Caveats

• If concurrent glucose is <70 mg/dL (<4 mmol/L) when C-peptide is measured, consider repeating the test as hypoglycemia suppresses C-peptide secretion 2
• Very low C-peptide levels (<80 pmol/L) do not require repeat testing regardless of glucose level 2
• For antibody-negative patients under 35 years with suspected type 1 diabetes but no clinical features of type 2 or monogenic diabetes, C-peptide testing should be ordered after checking autoantibodies first 2

Clinical Decision-Making Based on C-Peptide

Treatment Selection

• Absent or very low C-peptide confirms absolute insulin requirement and appropriateness of type 1 diabetes management strategies regardless of apparent etiology 4
• Robust C-peptide levels suggest patients may respond to oral agents rather than requiring insulin therapy 2
• Normal C-peptide in insulin-treated patients indicates retained endogenous insulin production and potential for treatment modification 2

Risk Stratification

• Low C-peptide in non-diabetic individuals may indicate pre-clinical type 1 diabetes with ongoing autoimmune beta cell destruction, warranting close monitoring for hyperglycemia and DKA 2
• C-peptide levels correlate with microvascular and macrovascular complications and future insulin requirements in type 2 diabetes 6

Common Pitfalls to Avoid

• Do not routinely test insulin or proinsulin in most people with diabetes - these assays are primarily for research purposes 1
• Do not use insulin antibody testing for routine diabetes care as there is no published evidence supporting this practice 1
• Do not rely on C-peptide alone to predict insulin requirement in established type 2 diabetes, as it performs poorly for this purpose 7
• Relating C-peptide to glucose ratios (C-peptide/glucose or HOMA-β) does not improve diagnostic accuracy over C-peptide alone for diabetes classification 7