Acanthosis nigricans as a cutaneous marker of compensatory hyperinsulinemia with preserved glycemia: a cross-sectional study

Abstract Purpose Acanthosis nigricans is associated with insulin resistance and hyperinsulinemia; however, its distribution across predefined metabolic stages remains poorly characterized. This study examined the association between acanthosis nigricans and a five-stage metabolic stratification spanning normoglycemia to diabetes. Methods In this cross-sectional study, 1,158 adults undergoing acanthosis nigricans screening at the Endocrinology Clinic of Shanghai Tenth People’s Hospital (2010–2021) were classified into five mutually exclusive metabolic stages: Normal, Isolated Insulin Resistance, Hyperinsulinemia, Prediabetes with Insulin Resistance, and Diabetes with Insulin Resistance. The association between acanthosis nigricans and metabolic stage was examined using multinomial logistic regression with sequential covariate adjustment for demographic and metabolic factors. Subgroup analyses assessed effect modification by age, sex, and body mass index. Receiver operating characteristic analysis was used to evaluate the incremental discriminative value of acanthosis nigricans for hyperinsulinemia, and mediation analysis was performed to estimate the contributions of waist circumference, uric acid, and alanine aminotransferase to the acanthosis nigricans–hyperinsulinemia association. Results Acanthosis nigricans prevalence differed across metabolic stages in a non-monotonic pattern: it was highest in the Hyperinsulinemia stage (71.3%) and lower in the Prediabetes with Insulin Resistance (51.7%) and Diabetes with Insulin Resistance (44.6%) stages ( P < 0.001). Acanthosis nigricans–positive participants were younger, had higher body mass index, and showed higher fasting insulin and C-peptide levels than acanthosis nigricans–negative participants (all P < 0.001). The Hyperinsulinemia stage showed the strongest association with acanthosis nigricans in both unadjusted and fully adjusted models (fully adjusted odds ratio = 4.69, 95% confidence interval: 1.58–13.95), whereas the associations for Prediabetes with Insulin Resistance and Diabetes with Insulin Resistance were attenuated after full adjustment. Adding acanthosis nigricans modestly improved discrimination for hyperinsulinemia (area under the curve 0.776 vs. 0.730, P < 0.001). In exploratory mediation analysis, waist circumference, uric acid, and alanine aminotransferase together accounted for a substantial proportion of the acanthosis nigricans–hyperinsulinemia association. Conclusion In this clinic-based cohort of adults with obesity, acanthosis nigricans was most strongly associated with the compensatory hyperinsulinemia stage. These findings support acanthosis nigricans as an adjunctive clinical sign—rather than a standalone screening tool—to prompt metabolic evaluation in high-risk individuals.