CNSPulse

IS BRAIN INSULIN ACTION IMPLICATED IN THE BIOLOGY OF DEPRESSION? A PILOT NEUROIMAGING STUDY IN ADOLESCENTS

Kateryna Maksyutynska — Nicolette Stogios2, Vittal Korran2, Laurie Hamel1, Daphne Korczak3, Benjamin Goldstein2, Gary Remington2, Marcos Sanches1, Margaret Hahn2, Ariel Graff-Guerrero2, Sri Mahavir Agarwal2 1Centre for Addiction and Mental Health, 2Centre for Addiction and Mental Health, University of Toronto,3The Hospital for Sick Children, University of Toronto Kateryna Maksyutynska, Centre for Addiction and Mental Health

2026 ASCP Annual Meeting

Depression is associated with metabolic dysfunction including insulin resistance, while insulin resistance is associated with greater depression severity and worse cognition. This bidirectional relationship has encouraged a reconceptualization of depression as a metabolic disorder, with brain insulin action implicated as a unifying mechanism. This has not been studied directly in humans. The aim of this study was to examine if brain insulin action is implicated in the biology of depression in adolescents.

Methods

Twelve patients with depression, 14-18 years of age, and twelve age-, sex-, and BMI-matched healthy controls were recruited for this single-blinded crossover pilot study. To quantify insulin action in the brain, resting state function MRI (rs-fMRI) scans were performed twice: the first following intranasal placebo (INP) and the second following intranasal insulin (INI) challenge (80 IU). This protocol leverages the property of INI to induce changes in resting-state functional connectivity (rsFC) in the brain. The difference in changes induced by INI compared to that with INP were used as an index of insulin action, since any difference observed between treatments during this controlled manipulation is likely to be due to INI. Absence or reduction in the magnitude of change was interpreted as impaired brain insulin action. Cognitive function and depression severity were also assessed. For cases, clinical assessments were repeated after six months to study the short-term effects of brain insulin action. Two-way repeated measures ANOVA was conducted to assess the main effect of treatment (INI vs. INP) as within-subject factor, the participant group (Cases vs. Controls) as between-subject factor, and their interaction on whole-brain ROI-to-ROI connectivity. Statistically significant connections were identified using a whole-brain false discovery rate (FDR) corrected p-value < 0.05, controlling for multiple comparisons. Post hoc pairwise comparisons were performed. Correlations between insulin-induced changes in rsFC with depression severity and cognition were assessed using multiple regressions. Age, sex, and BMI were controlled for in analyses.

Results

A significant Group × Condition interaction effect was identified for INI > INP, Controls > Cases contrast. Only controls, and not cases, exhibited a significant increase in rsFC in response to INI vs. INP between the following brain regions: 1) the left Hippocampus left and Occipital Fusiform Gyrus (OFusG-l); 2) right Parahippocampal Gyrus, anterior division (aPaHc-r) and left Temporal Pole (F = 19.3, p < 0.001); and 3) aPaHC-r and right Temporal Fusiform Cortex, anterior division (aTFusCr) (F = 17.5, p < 0.001). At baseline, subjective cognitive performance was positively associated with changes in connectivity between the aPaHC-r and TP-l (β = 0.571, p = 0.004); and aPaHC-r and aTFusC-r (β = 0.453, p = 0.026). In longitudinal analyses, cases with less increase in rsFC between the TP-l and aPaHc-r in response to INI vs. INP at baseline exhibited greater depression severity after 6 months (β = -0.62, p = 0.031).

Conclusions

Demonstrating disrupted brain insulin action can provide novel insights into poorly understood mechanisms underlying the relationship between depression and metabolic dysfunction. Evidence of impaired brain insulin action early in the course of illness may provide us with a modifiable risk factor that can be targeted using insulin sensitizers as an early intervention.

Learning Objective 1: Insulin action in the brain may be disrupted in individuals with depressive disorders.

Learning Objective 2: Insulin action in the brain may predict long-term clinical outcomes, such as depression severity.

References

  1. Kullmann S, Heni M, Hallschmid M, Fritsche A, Preissl H, Häring HU. Brain Insulin Resistance at the Crossroads of Metabolic and Cognitive Disorders in Humans. Physiol Rev. 2016 Oct;96(4):1169-209. 2) Kullmann S, Heni M, Veit R, Scheffler K, Machann J, Häring HU, Fritsche A, Preissl H. Intranasal insulin enhances brain functional connectivity mediating the relationship between adiposity and subjective feeling of hunger. Sci Rep. 2017 May 9;7(1):1627.