Non-obese genetic type 2 diabetes causes brain and behavioral hallmarks of chronic stress

The comorbidity of obesity, type 2 diabetes (T2D), and psychiatric disorders— particularly anxiety and depression—is well documented. However, it remains unclear whether T2D, independently of obesity, contributes to the development of emotional dysfunctions. Furthermore, alterations in the hypothalamic-pituitary-adrenal (HPA) stress axis are commonly associated with both T2D and depression, but the role of stress in emotional disorders linked to T2D has been poorly explored. This study aimed to investigate the impact of T2D, independent of obesity, on the neuroendocrine stress axis, as well as molecular, cellular, and behavioral indicators of emotional dysfunction. Using the non-obese Goto-Kakizaki (GK) rat model of T2D, we assessed the effects of diabetes on hormonal and neuronal stress responses, molecular and structural markers of stress in the brain, and anxiety- and depressive-like behaviors. We also evaluated the impact of adrenalectomy in GK rats to determine the contribution of glucocorticoids to their behavioral impairments. Our findings reveal that non-obese diabetes leads to heightened endocrine and brain responses to stress, along with upregulation of stress-related molecular markers and structural features indicative of chronic stress, particularly in the medial prefrontal cortex. Additionally, GK rats exhibited pronounced anxiety- and depressive-like behaviors. Importantly, lowering glucocorticoid levels in GK rats helped alleviate some of the metabolic and emotional disturbances. This study suggests that T2D, independent of obesity, induces stress-related brain and behavioral changes, partly mediated by glucocorticoids.