Does elevated C-peptide during marked hyperglycemia indicate endogenous insulin production and insulin resistance?

C-peptide is a useful marker of pancreatic beta-cell insulin secretion, but its meaning depends on the glucose and clinical context in which it was obtained.

Clinical interpretation

• C-peptide and insulin arise from proinsulin processing and are secreted in approximately equimolar amounts. Because pharmaceutical insulin contains no C-peptide, a measurable or elevated C-peptide indicates endogenous—not injected—insulin production.
• During marked hyperglycemia, a high C-peptide strongly supports preserved, substantial endogenous insulin secretion. A random sample with glucose >8 mmol/L (144 mg/dL) is effectively a stimulated measurement.
• Persistent hyperglycemia despite substantial secretion is consistent with compensatory hyperinsulinemia and therefore supports insulin resistance as a clinical inference. However, C-peptide measures secretion, not insulin sensitivity; it cannot quantify insulin resistance or establish its severity from a universal cutoff.

Mechanistic and analytical considerations

• Peripheral C-peptide is generally a more stable marker of endogenous secretion than insulin because insulin undergoes variable first-pass hepatic extraction, whereas C-peptide has negligible hepatic extraction and a longer half-life.
• Sampling conditions matter: food intake and glucose stimulate secretion, while fasting hypoglycemia can suppress it. Fasting, random, and stimulated samples should not be judged by one threshold.
• Units and assay method are essential: 1 ng/mL ≈333 pmol/L (0.333 nmol/L), and laboratory reference intervals and decision limits vary by platform and protocol.
• Kidney function is a major confounder. C-peptide is predominantly cleared by the kidneys; reduced eGFR can elevate circulating values independent of increased beta-cell secretion.

Bottom line

• The claim is well supported overall: elevated C-peptide during marked hyperglycemia indicates ongoing endogenous insulin production and can reflect compensation for insulin resistance, but interpretation requires concurrent glucose, fasting/stimulated status, assay-specific units and ranges, medication context, and creatinine/eGFR—especially in moderate-to-severe CKD.