In a patient receiving exogenous insulin, does the therapy alter C‑peptide levels and reflect residual β‑cell function?

Does Exogenous Insulin Therapy Affect C-Peptide Levels?

Exogenous insulin administration does not directly suppress C-peptide secretion; instead, the reduction in C-peptide levels observed during insulin therapy is primarily due to the improvement in glycemic control rather than a direct inhibitory effect of the administered insulin itself. 1

Understanding C-Peptide as a Marker of Endogenous Insulin Production

C-peptide is produced in equimolar amounts with endogenous insulin when proinsulin is cleaved in pancreatic β-cells, making it the most reliable marker of residual β-cell function. 2, 3

Key physiological principles:

• C-peptide and insulin are secreted together into the portal circulation, but only minimal C-peptide is extracted by the liver (unlike insulin, which undergoes significant first-pass hepatic metabolism). 3
• The kidney is the primary site of C-peptide removal, with a small constant proportion excreted in urine. 3
• Critically, exogenous insulin does not contain C-peptide, so measuring C-peptide allows differentiation between endogenous β-cell secretion and administered insulin. 2, 3

The Effect of Exogenous Insulin on C-Peptide Levels

Blood Glucose Reduction is the Primary Mechanism

A controlled study in 21 patients with type 2 diabetes examined C-peptide levels under three conditions: untreated hyperglycemia, after IV insulin infusion (withdrawn 1 hour prior to testing), and with bedtime NPH insulin. 1

The findings demonstrate:

• Both fasting and glucagon-stimulated C-peptide levels were highest during untreated hyperglycemia and lower when glucose was controlled with insulin. 1
• When comparing the percentage of C-peptide increment or the C-peptide-to-glucose ratio across all three conditions, no significant differences emerged, indicating that glucose normalization—not exogenous insulin per se—accounts for the C-peptide reduction. 1
• This confirms that improved glycemic control reduces the stimulus for endogenous insulin secretion, thereby lowering C-peptide levels. 1

Exogenous Insulin May Enhance β-Cell Response in Critical Illness

In critically ill patients with type 2 diabetes managed with permissive hyperglycemia (target 10-14 mmol/L), a prospective study of 45 patients revealed a paradoxical finding. 4

Key observations:

• Patients requiring insulin had higher baseline HbA1c, more premorbid insulin-dependent diabetes, greater blood glucose levels, but lower admission C-peptide levels. 4
• Increases in C-peptide correlated positively with increases in blood glucose in both insulin-treated and non-insulin-treated patients (r = 0.54 and r = 0.56, respectively). 4
• Insulin administration was independently associated with a greater increase in C-peptide (P = 0.04), suggesting that in the context of critical illness and hyperglycemia, exogenous insulin may actually enhance rather than suppress β-cell responsiveness. 4

This finding likely reflects improved β-cell function when glucose toxicity is reduced, rather than a direct stimulatory effect of exogenous insulin. 4

Clinical Implications for Interpreting C-Peptide in Insulin-Treated Patients

C-Peptide Remains Valid for Assessing Residual β-Cell Function

The primary clinical utility of C-peptide measurement is to differentiate between endogenous and exogenous hyperinsulinism and to establish the need for insulin therapy. 3

• In insulin-treated patients, C-peptide measurement is most useful 3-5 years after diagnosis, when persistence of substantial C-peptide suggests type 2 or monogenic diabetes rather than type 1 diabetes. 2
• Absent C-peptide at any time confirms absolute insulin requirement and the appropriateness of type 1 diabetes management strategies, regardless of apparent etiology. 2
• C-peptide can be measured reliably on spot urine samples (urine C-peptide:creatinine ratio), facilitating measurement in routine clinical practice. 2

Factors That Influence C-Peptide Levels

When interpreting C-peptide in patients receiving exogenous insulin, consider these confounding factors:

• Renal function: Greater plasma creatinine is independently associated with higher C-peptide levels because the kidney is the primary site of C-peptide clearance. 4 In advanced chronic kidney disease, reduced insulin clearance by the damaged kidney can lead to decreased insulin requirements despite ongoing C-peptide production. 5
• Glycemic state: C-peptide levels respond to and are influenced by ambient glycemia; higher glucose levels stimulate greater endogenous insulin and C-peptide secretion. 1, 4
• Timing of measurement: C-peptide should be measured when exogenous insulin levels are low (e.g., fasting state or after withdrawal of short-acting insulin) to minimize confounding from acute glucose fluctuations caused by administered insulin. 1

Common Pitfalls and How to Avoid Them

Pitfall 1: Assuming exogenous insulin directly suppresses C-peptide secretion

• The evidence clearly shows that glucose normalization, not exogenous insulin itself, reduces C-peptide levels. 1
• When interpreting low C-peptide in an insulin-treated patient, consider whether this reflects true β-cell failure or simply improved glycemic control reducing the stimulus for endogenous secretion. 1

Pitfall 2: Failing to account for renal function

• In patients with chronic kidney disease, C-peptide levels may be elevated due to reduced renal clearance, even when β-cell function is declining. 5, 4
• Always interpret C-peptide in the context of estimated glomerular filtration rate. 4

Pitfall 3: Measuring C-peptide at inappropriate times

• Avoid measuring C-peptide immediately after insulin administration when exogenous insulin is causing rapid glucose fluctuations. 1
• Fasting C-peptide or stimulated C-peptide (e.g., after glucagon administration) provides more reliable assessment of residual β-cell function. 2, 3

Algorithmic Approach to Using C-Peptide in Insulin-Treated Patients

Step 1: Determine the clinical question

• Are you trying to classify diabetes type (type 1 vs. type 2 vs. monogenic)?
• Are you assessing whether a patient can discontinue insulin therapy?
• Are you evaluating for insulinoma or factitious hypoglycemia?

Step 2: Optimize timing of measurement

• Measure fasting C-peptide when short-acting insulin has been withheld for at least 4-6 hours. 1
• Alternatively, perform glucagon stimulation test (1 mg IV) and measure C-peptide at baseline and 6 minutes post-injection. 3

Step 3: Interpret results in context

• Absent or very low C-peptide (<0.2 nmol/L): Confirms absolute insulin deficiency; patient requires insulin for survival. 2
• Detectable C-peptide (>0.2 nmol/L) after 3-5 years of diabetes: Suggests type 2 or monogenic diabetes; consider non-insulin therapies or insulin dose reduction. 2
• Elevated C-peptide with hypoglycemia: Consider insulinoma or sulfonylurea use; exogenous insulin would cause low C-peptide. 5

Step 4: Account for confounders

• Adjust interpretation for renal function (elevated creatinine raises C-peptide). 4
• Consider recent glycemic control (recent hyperglycemia may transiently elevate C-peptide). 1, 4