ADRB2 and major depressive disorder: Possible biological support for this observed latent effect is given by findings regarding the activation of the hypothalamic–pituitary adrenal axis, which has been postulated to have a major role in the T2DM and depression comorbidity.25 A preliminary study reported sex difference between hypothalamic–pituitary adrenal axis activity and adrenergic polymorphisms in 189 patients with depression.26 Increased hypothalamic–pituitary adrenal axis activity was associated with the ADRA2A genotype in males and ADRB2 genotype in females.