Modulation of monoaminergic neural circuits: potential for the treatment of type 2 diabetes mellitus

A plethora of data from experimental animals provide strong support for the concept that reduced dopaminergic neuronal activity and enhanced noradrenergic tone in specific hypothalamic nuclei are involved in the pathogenesis of the metabolic syndrome. The available information on these neurotransmitter systems in insulin-resistant humans with obesity is in keeping with the postulate that analogous mechanisms may underlie their adverse metabolic profile. Treatment with bromocriptine, which has dopaminergic (D2 receptor agonist) and sympatholytic (alpha2-adrenoceptor agonistic and an alpha1-adrenoceptor antagonistic) actions, can reverse the metabolic anomalies in a variety of obese mammalian species. Combined D1/D2 receptor activation appears to exert even more powerful effects on fuel metabolism in various animal models of the metabolic syndrome. The currently available data on the metabolic effects of bromocriptine in humans with obesity and type 2 diabetes mellitus point in the same direction. Bromocriptine favorably affects glucose metabolism and various other components of the metabolic syndrome simultaneously to ameliorate the risk of damage to eyes, neural tissue, kidneys and the cardiovascular system in patients with type 2 diabetes mellitus. Moreover, a substantial number of studies indicate that bromocriptine lowers blood pressure in animals and humans with hypertension via its sympatholytic capacities. However, the effects of bromocriptine alone are relatively modest, the metabolic mechanism of action in humans remains uncertain, and the long-term efficacy and safety profiles of this compound are unknown. It seems important to seek for ways to boost the action of bromocriptine, by combining dopaminergic D2 and D1 receptor activation, for example. Notably, there is no antidiabetic drug that acts through central (dopaminergic) mechanisms. This novel approach may, therefore, result in synergistic actions with other available agents to favorably impact the risk of tissue damage in patients with type 2 diabetes mellitus.