In patients with diabetes mellitus (DM), which insulin test should be ordered first?

Insulin Testing in Diabetes Mellitus Patients

Routine insulin testing is not recommended for most patients with diabetes mellitus, as these assays are primarily useful for research purposes rather than clinical management. 1

When NOT to Order Insulin Tests

The American Diabetes Association explicitly states that in most people with diabetes or at risk for diabetes or cardiovascular disease, routine testing for insulin or proinsulin is not recommended. 1 These assays lack clinical utility for:

• Routine diabetes management 1
• Monitoring glycemic control 1
• Adjusting treatment regimens 1

Additionally, there is no published evidence supporting the use of insulin antibody testing for routine care of people with diabetes. 1

When C-Peptide Testing IS Indicated

Instead of insulin testing, C-peptide measurement is the appropriate test when assessing endogenous insulin secretion is clinically necessary. 1 C-peptide is produced in equimolar amounts to insulin but provides a more accurate measure of pancreatic beta cell function. 2, 3

Specific Clinical Scenarios for C-Peptide Testing:

Ambiguous diabetes classification: C-peptide measurements help distinguish type 1 from type 2 diabetes in unclear cases, such as individuals with a type 2 phenotype who present in ketoacidosis. 1

Insurance requirements: If required by the payer for coverage of insulin pump therapy, measure fasting C-peptide level when simultaneous fasting plasma glucose is <12.5 mmol/L (<220 mg/dL). 1

Timing considerations: C-peptide testing is most useful after 3-5 years from diagnosis, when persistence of substantial insulin secretion suggests type 2 or monogenic diabetes rather than type 1. 2

Interpretation Guidelines from ADA Classification Algorithm:

The 2024 American Diabetes Association provides specific C-peptide thresholds for classification: 1

• <200 pmol/L (<0.6 ng/mL): Consistent with type 1 diabetes
• 200-600 pmol/L (0.6-1.8 ng/mL): Indeterminate, usually consistent with type 1 diabetes or maturity-onset diabetes of the young (MODY)
• >600 pmol/L (>1.8 ng/mL): Suggests type 2 diabetes

Important caveat: A random C-peptide sample (with concurrent glucose) within 5 hours of eating can replace a formal stimulation test. If the result is >600 pmol/L, the circumstances of testing do not matter. If <600 pmol/L and concurrent glucose is <4 mmol/L (<70 mg/dL) or the person may have been fasting, consider repeating the test. 1

What to Order Instead for Routine Diabetes Management

For standard diabetes care and monitoring, the following tests are appropriate: 1, 4

• A1C testing: At least twice yearly for stable patients, quarterly for those not meeting goals 1
• Fasting plasma glucose: For diagnosis and monitoring 4
• Self-monitoring of blood glucose (SMBG): Particularly for insulin-treated patients 1
• Continuous glucose monitoring (CGM): For selected patients on intensive insulin regimens 1

Key Pitfalls to Avoid

Do not order insulin levels to differentiate diabetes types - this is ineffective and not evidence-based. 1 C-peptide is the correct test for assessing endogenous insulin production. 2, 3

Do not test C-peptide within 2 weeks of a hyperglycemic emergency - results will be unreliable. 1

Do not use C-peptide to predict insulin requirement in type 2 diabetes - while it helps with classification, it has low predictive value for determining which type 2 patients will need insulin therapy. 5