Major depressive disorder (MDD) and type 2 diabetes (T2D) are complex disorders whose comorbidity can be due to hypercortisolism and may be explained by dysfunction of the corticotropin-releasing hormone receptor 1 (CRHR1) and cortisol feedback within the hypothalamic–pituitary–adrenal axis (HPA axis). The gene discussed is CRHR1; the disease is major depressive disorder.