Preliminary evidence for obesity and elevations in fasting insulin mediating associations between cortisol awakening response and hippocampal volumes and frontal atrophy

Recent studies have demonstrated alterations in the cortisol awakening response (CAR) and brain abnormalities in adults with obesity and type 2 diabetes mellitus (T2DM). While adolescents with T2DM exhibit similar brain abnormalities, less is known about whether brain impairments and hypothalamic-pituitary-adrenal (HPA) axis abnormalities are already present in adolescents with pre-diabetic conditions such as insulin resistance (IR). This study included 33 adolescents with IR and 20 without IR. Adolescents with IR had a blunted CAR, smaller hippocampal volumes, and greater frontal lobe atrophy compared to controls. Mediation analyses indicated pathways whereby a smaller CAR was associated with higher BMI which was in turn associated with fasting insulin levels, which in turn was related to smaller hippocampal volume and greater frontal lobe atrophy. While we had hypothesized that HPA dysregulation may result from brain abnormalities, our findings suggest that HPA dysregulation may also impact brain structures through associations with metabolic abnormalities.