High C-Peptide with Persistent Hyperglycemia: Evidence for Impaired Insulin Bioactivity Beyond Insulin Resistance

Abstract

Objective:

Elevated C‑peptide levels in the setting of hyperglycemia are usually taken as a marker of insulin resistance. We suggest that this view is incomplete and that reduced insulin bioactivity may also play a key role.

Research Design and Methods:

We conducted a focused narrative review that brings together physiological, biochemical, and clinical data on insulin secretion, processing, and action, with particular attention to proinsulin handling, pulsatile insulin release, and hepatic insulin signaling.

Results:
Several mechanisms may explain why robust endogenous insulin secretion can coexist with poor glycemic control: increased secretion of proinsulin and partially processed insulin with lower metabolic potency; disruption of pulsatile insulin release, leading to impaired hepatic signaling; hepatic insulin resistance, which limits suppression of gluconeogenesis; and structural or post‑translational changes in insulin that reduce receptor activation. Clinically, many patients with high C‑peptide and marked hyperglycemia experience substantial glycemic improvement with relatively small doses of exogenous insulin, pointing to preserved insulin sensitivity but diminished effectiveness of endogenous insulin.

Conclusions:

Hyperglycemia with high C‑peptide should not automatically be attributed only to insulin resistance. A framework centered on impaired insulin bioactivity, or “low‑quality insulin,” may better capture this phenotype and has important diagnostic and therapeutic implications. Integrating proinsulin‑based measures and earlier β‑cell–directed interventions could improve patient classification and clinical outcomes.