Mechanism of action of bromocriptine and prolactin antagonists in the treatment of Diabetes and Obesity

Abstract

The type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by dysfunctions in the metabolism of glucose, amino acids and free fat acids. Although most therapies to treat diabetes have peripheral effects, a growing number of studies show that the brain plays a critical role in the control of glucose homeostasis. The quick release bromocriptine mesylate (Cycloset®) was the first FDA approved drug to treat T2DM that has its primary actions on central nervous system. Several studies have shown beneficial effects of bromocriptine, a dopaminergic agonist, to reduce hyperglycemia and hyperlipidemia in obese animals. Therefore, a possible mechanism of action of this drug can be by blocking prolactin secretion. High serum prolactin levels in patients with prolactinomas or during the usage of antipsychotics cause abnormalities in the metabolism of carbohydrates and lipids, resembling the features of the metabolic syndrome. At the present study, we hypothesized that at least part of the beneficial effects of bromocriptine is mediated by inhibiting prolactin secretion. In this context, we believe that administration of prolactin antagonist (anti-PrlR) may be a promising approach for the treatment of diabetes and obesity. Based on this hypothesis, we will carry out experiments in four groups of genetically obese and diabetic mice (ob/ob): 1) control group, 2) group treated with prolactin, 3) group treated with bromocriptine, and 4) group treated with bromocriptine and prolactin. Another group of animals will receive Anti-PrlR and their results will be compared with those observed in control animals and in a group that will be treated with bromocriptine. We will assess whether Anti-PrlR improve the diabetes and obesity phenotype of ob/ob mice. Thus, if we confirm our hypothesis, the anti-PrlR may become a new class of drugs for the treatment of metabolic diseases such as obesity and T2DM.