Utility of the C-Peptide/Insulin Molar Ratio for Distinguishing Type A Insulin Resistance Syndrome From Type 2 Diabetes

Seiji Nishikage, Yushi Hirota, Tomofumi Takayoshi, Kai Yoshimura, Takehito Takeuchi, Tetsushi Hamaguchi, Mariko Ueda, Akane Yamamoto, Kazuhiko Sakaguchi, Wataru Ogawa
The Journal of Clinical Endocrinology & Metabolism, Volume 110, Issue 10, October 2025, Pages e3383–e3390
https://doi.org/10.1210/clinem/dgaf043

Abstract

Objective

Type A insulin resistance syndrome (IRS), characterized by impaired insulin receptor function due to variants of the insulin receptor gene, manifests as severe insulin-resistant diabetes. Differentiation of type A IRS from type 2 diabetes on the basis of hyperinsulinemia can be challenging. Given the association between insulin receptor dysfunction and reduced insulin clearance, we evaluated the potential of the circulating C-peptide reactivity (CPR)/immunoreactive insulin (IRI) molar ratio, a marker of insulin clearance, for distinguishing type A IRS from type 2 diabetes.

Methods

We retrospectively analyzed CPR and IRI levels measured during a 75-g oral glucose tolerance test (OGTT) in 18 individuals with type A IRS and 126 with type 2 diabetes. Receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic performance of the CPR/IRI molar ratio and IRI levels.

Results

IRI levels were significantly higher and the CPR/IRI molar ratio significantly lower in individuals with type A IRS compared with those with type 2 diabetes. The area under the ROC curve for the CPR/IRI molar ratio at baseline, 1 hour, and 2 hours after OGTT initiation was 0.997 (sensitivity 100%, specificity 99.2%), 0.999 (sensitivity 100%, specificity 97.6%), and 0.997 (sensitivity 100%, specificity 95.1%), respectively. The CPR/IRI molar ratio demonstrated robust diagnostic performance regardless of body mass index or hyperinsulinemia severity.

Conclusion

The CPR/IRI molar ratio, both at baseline and during OGTT, exhibited higher sensitivity and specificity than IRI levels alone for distinguishing type A IRS from type 2 diabetes. This ratio may serve as a reliable clinical marker for early and accurate diagnosis of type A IRS.

You may also like...