An Association Between Stress-Induced Disruption of the Hypothalamic-Pituitary-Adrenal Axis and Disordered Glucose Metabolism in an Animal Model of Post-Traumatic Stress Disorder

Retrospective clinical reports suggesting that traumatic stress populations display an increased propensity for glucose metabolism disorders were examined in a controlled prospective animal model. Stress-induced behavioural and hypothalamic-pituitary-adrenal (HPA) axis response patterns were correlated to central and peripheral parameters of glucose metabolism and signalling, and to body measurements in Sprague-Dawley rats exposed to predator scent stress. Forty days post-exposure, fasting blood glucose and insulin levels, oral glucose tolerance test, body weight and white adipose tissue mass, systemic corticosterone levels and brain expression of insulin receptor (IR) and insulin-sensitive glucose transporter 4 (GLUT4) protein levels were evaluated. In a second experiment inbred strains with hyper- (Fischer) and hypo- (Lewis) reactive HPA axes were employed to assess the association of metabolic data with behavioural phenomenology versus HPA axis response profile. For data analysis, animals were classified according to their individual behavioural response patterns (assessed at day 7) into extreme, partial and minimal response groups. The exposed Sprague-Dawley rats fulfilling criteria for extreme behavioural response (EBR) (20.55%) also exhibited significant increases in body weight, abdominal circumference and abdominal white adipose tissue mass; a hyperglycaemic oral glucose tolerance test; and fasting hyperglycaemia, hyperinsulinaemia and hypercorticosteronemia, whereas minimal responders (MBR) and control animals displayed no such disturbances. Hippocampal and hypothalamic expression of IR and GLUT4 protein were significantly lower in EBR than in MBR and control rats. The inbred strains showed no metabolic differences at baseline. Exposed Fischer rats displayed hyperglycaemia and hyperinsulinaemia, whereas Lewis rats did not. A significant protracted disorder of glucose metabolism was induced by exposure to a stress paradigm. This metabolic response was associated with the characteristic pattern of HPA axis (corticosterone) response, which underlies the behavioural response to stress.