Metabolic disturbances, hemoglobin A1c, and social cognition impairment in Schizophrenia spectrum disorders

Abstract

Social cognitive impairments are core features of schizophrenia spectrum disorders (SSD) and are associated with greater functional impairment and decreased quality of life. Metabolic disturbances have been related to greater impairment in general neurocognition, but their relationship to social cognition has not been previously reported. In this study, metabolic measures and social cognition were assessed in 245 participants with SSD and 165 healthy comparison subjects (HC), excluding those with hemoglobin A1c (HbA1c) > 6.5%. Tasks assessed emotion processing, theory of mind, and social perception. Functional connectivity within and between social cognitive networks was measured during a naturalistic social task. Among SSD, a significant inverse relationship was found between social cognition and cumulative metabolic burden (β = -0.38, p < 0.001) and HbA1c (β = -0.37, p < 0.001). The relationship between social cognition and HbA1c was robust across domains and measures of social cognition and after accounting for age, sex, race, non-social neurocognition, hospitalization, and treatment with different antipsychotic medications. Negative connectivity between affect sharing and motor resonance networks was a partial mediator of this relationship across SSD and HC groups (β = -0.05, p = 0.008). There was a group x HbA1c effect indicating that SSD participants were more adversely affected by increasing HbA1c. Thus, we provide the first report of a robust relationship in SSD between social cognition and abnormal glucose metabolism. If replicated and found to be causal, insulin sensitivity and blood glucose may present as promising targets for improving social cognition, functional outcomes, and quality of life in SSD.

Fig. 1. Social Cognition and Metabolic Risk in SSD.

A Cumulative metabolic burden included the following: obesity, high waist circumference, prediabetic HbA1c, diagnosis or medication for DM, diagnosis or medication for hypertension, and diagnosis or medication for hyperlipidemia; on a linear regression, there was a significant relationship between higher number of metabolic risk factors and greater impairment in social cognition (β = −0.38, p < 0.001, Adj R² = 0.14). B There was a significant negative relationship between overall social cognition and HbA1c (β = −0.37, p < 0.001, Adj R² = 0.14). There was no significant relationship between social cognition and (C) Body Mass Index (β = −0.05, p = 0.49) or (D) Obesity (Cohen’s d = 0.09, p = 0.34). E High waist circumference was significantly correlated with greater impairment in social cognition (Cohen’s d = 0.49, p = 0.002). However, only HbA1c remains significantly correlated with social cognition after covarying for age, sex, race, ethnicity, and non-social neurocognition (β = −0.16, p = 0.005, Adj R² = 0.53). Standardized β coefficients are reported.

Fig. 2. Hemoglobin A1c and Social Cognition in SSD.

Among participants with schizophrenia spectrum disorders (SSD), there was a significant inverse relationship between hemoglobin A1c and each domain of social cognition: (A) Emotion Processing (β = −0.36, p < 0.001), B Theory of Mind (β = −0.31, p < 0.001), and (C) Social Perception (β = −0.27, p < 0.001). D Age was also related to greater impairment in aggregate social cognition (β = −0.40, p < 0.001), but elevated HbA1c in the top third of the SSD group (≥5.7%) was related to still greater impairment (β = −0.25, p = 0.001). E There was no significant effect of sex on the relationship between HbA1c and aggregate social cognition (β = 0.01, p = 0.93). Standardized β coefficients are reported.

Fig. 3. SSD Group by Hemoglobin A1c Effect on Social Cognition.

A Overall Social Cognition, HbA1c (β = −0.35, p < 0.001), HC group (β = −1.0, p = 0.10), and HC group x HbA1c (β = 1.5, p = 0.01). B Emotion Processing Domain, HbA1c (β = −0.35, p < 0.001), HC group (β = −1.2, p = 0.07), and HC group x HbA1c (β = 1.6, p = 0.01). C Theory of Mind Domain, HbA1c (β = −0.30, p < 0.001), HC group (β = −0.45, p = 0.47), and HC group x HbA1c (β = 0.90, p = 0.15). D Social Perception Domain, HbA1c (β = −0.24, p < 0.001), HC group (β = −0.99, p = 0.12), and HC group x HbA1c (β = 1.45, p = 0.02). Standardized β coefficients are reported.

Fig. 4. Functional Connectivity Mediation of Hemoglobin A1c and Social Cognition Across SSD and HC Groups.

The association between hemoglobin A1c and overall social cognition was partially mediated by negative connectivity between the affect sharing and motor resonance networks (n = 253).