Sex modifies the association between insulin resistance and psychiatric comorbidities among individuals with type 2 diabetes

Introduction The co-occurrence of neuropsychiatric disorders and type 2 diabetes (T2D) is well-documented. Insulin resistance (IR) has emerged as a potential biological mechanism associated with psychiatric disorders. However, the influence of sex on this relationship remains underexplored. This study aimed to determine whether sex modifies the association between insulin resistance, assessed using the METS-IR Index, and psychiatric comorbidities in patients with type 2 diabetes. Methods Comparative cross-sectional study of 4,699 individuals (2689 females, 2010 males) with T2D (duration < 10 years) who attended a multidisciplinary care center in Mexico City. IR was estimated using the METS-IR index (cutoff ≥ 50). Psychiatric comorbidities, including affective, anxiety, and eating disorders, were evaluated using standardized clinical assessments. Multiple logistic regression models were constructed to evaluate the association between the sex-insulin resistance interaction and four distinct psychopathological outcomes. Results Females exhibited a significantly higher prevalence of all psychiatric comorbidities compared to males: affective (27.8% vs. 13.5%), anxiety (25.9% vs. 17.5%), and eating disorders (28.9% vs. 20.1%) (all p < 0.001). In females, high IR (METS-IR ≥ 50) was significantly associated with a higher frequency of affective disorders (30.5% vs. 26.0%, p = 0.011), anxiety disorders (28.0% vs. 24.5%, p = 0.040), and eating disorders (38.3% vs. 22.7%, p < 0.001). Conversely, in males, high METS-IR was only associated with eating disorders (27.0% vs. 14.4%, p < 0.001), showing no significant impact on affective or anxiety symptoms. Females with METS-IR ≥ 50 were two-fold more likely to have any psychiatric disorder (OR = 2.40; IC95%:1.85–3.11). Conclusion Higher METS-IR was associated with psychiatric comorbidities in a sex-specific manner. These findings suggest that the relationship between insulin resistance and psychiatric disorders differs between females and males. While IR broadly increases the risk for multiple psychiatric domains in females, its impact in males is primarily restricted to eating behaviors. These findings underscore the critical need for sex-stratified metabolic monitoring to improve mental health screening and integrated care in T2D.