What is the appropriate management for a patient with a C-peptide (Connecting Peptide) level of 0.6 and Hyperglycemia?

Management of C-peptide 0.6 ng/mL with Blood Glucose 191 mg/dL

This patient requires immediate initiation of insulin therapy, as the C-peptide level of 0.6 ng/mL (approximately 200 pmol/L) with concurrent hyperglycemia indicates significant insulin deficiency consistent with type 1 diabetes, LADA, or checkpoint inhibitor-associated diabetes mellitus (CIADM). 1, 2

Immediate Diagnostic Workup

Measure islet autoantibodies (GAD, IA-2, ZnT8) immediately to determine if this is autoimmune diabetes—if antibody-positive, the diagnosis is type 1 diabetes regardless of clinical presentation. 1, 2

Additional urgent testing includes:

• Capillary ketones to assess for diabetic ketoacidosis risk, as patients with C-peptide in this range are at high risk for DKA. 3
• Serum bicarbonate and electrolytes—if bicarbonate <16 mmol/L or ketones >2 mmol/L, refer immediately to hospital for DKA workup. 3
• Serum lipase to evaluate for pancreatic pathology that could indicate type 3c diabetes. 3, 2
• HbA1c to assess chronic glycemic control. 2

Interpretation of C-peptide Result

The C-peptide of 0.6 ng/mL (approximately 200 pmol/L) falls into a critical diagnostic zone:

• C-peptide 200-600 pmol/L usually indicates type 1 diabetes, LADA, or MODY, but may occur in long-standing insulin-treated type 2 diabetes. 1
• This level represents borderline absolute insulin deficiency and mandates insulin therapy initiation. 3, 2
• Values <400 pmol/L require management similar to type 1 diabetes with insulin as the primary therapy. 3

Important caveat: If the concurrent glucose was <70 mg/dL when C-peptide was drawn, consider repeating the test, as hypoglycemia suppresses C-peptide secretion. 1, 2 However, with glucose of 191 mg/dL, this result is valid and does not require repeat testing. 1

Insulin Initiation Protocol

Start basal-bolus insulin regimen immediately:

• Long-acting basal insulin (insulin glargine or degludec): 0.2-0.3 units/kg/day, typically higher doses with higher body weight. 3
• Rapid-acting prandial insulin (insulin aspart or lispro): 0.05-0.1 units/kg/meal, given three times daily with meals. 3

Do not delay insulin therapy while awaiting autoantibody results—persistent hyperglycemia with C-peptide in this range represents high-risk diabetes requiring urgent treatment. 2

Risk Stratification Based on Autoantibody Results

If Autoantibody-Positive (Type 1 Diabetes/LADA):

• Lifelong insulin therapy is required with no expectation of oral agent efficacy. 3, 4
• Refer to endocrinology for diabetes education, insulin pump evaluation, and continuous glucose monitoring. 3
• Provide sick day management education including hypoglycemia management, stress dosing, ketone monitoring, and DKA prevention. 3

If Autoantibody-Negative:

• Consider genetic testing for MODY if family history suggests monogenic diabetes, as MODY patients retain C-peptide and may respond to oral agents. 1, 5
• Evaluate for type 3c diabetes if lipase is elevated or imaging shows pancreatic pathology—these patients may have variable insulin requirements. 3
• If on checkpoint inhibitor therapy, diagnose as CIADM, which requires lifelong insulin with high risk of glycemic variability. 3

Glucose Targets and Monitoring

Target glucose range: 5-10 mmol/L (90-180 mg/dL) for most patients, with more flexible targets if elderly, palliative, or experiencing frequent hypoglycemia. 3

Implement daily self-monitoring of blood glucose with capability to test ketones at home, as patients with C-peptide in this range are at ongoing DKA risk. 3

Common Pitfalls to Avoid

• Do not assume type 2 diabetes based on age or BMI alone—approximately 40% of adults with new type 1 diabetes are initially misdiagnosed as type 2 diabetes. 2
• Do not attempt oral agent monotherapy in patients with C-peptide <600 pmol/L and persistent hyperglycemia, as this indicates inadequate endogenous insulin production. 3, 1
• Do not attribute poor control to non-adherence without first confirming insulin secretory capacity. 2
• Do not test C-peptide within 2 weeks of a hyperglycemic emergency, as results will be unreliable. 1, 6

Long-term Management Considerations

Even low-level C-peptide secretion (200-600 pmol/L) may provide some protection against severe hypoglycemia and ketoacidosis compared to complete insulin deficiency. 7

Monitor for progressive beta cell loss with repeat C-peptide testing after 3-5 years, particularly in antibody-positive patients, as the natural course shows C-peptide will decrease over time. 5, 4

Consider pancreatic exocrine insufficiency screening (fecal elastase) if patient develops symptoms of malabsorption, as this is under-recognized in patients with low C-peptide. 3