The most plausible explanation for MDD-T2D CRHR1-mediated comorbidity lies in the central limbic noradrenergic response to CRH, which triggers central NE [65], stimulating adrenal cortisol secretion [66, 67] and—by a positive feedback—hypothalamic and limbic CRH secretion, driving and maintaining the central HPA hyperactivation [68, 69]. Here, CRHR1 is linked to major depressive disorder.