Insulin resistance and type 2 diabetes mellitus: its relationship with the beta 3-adrenergic receptor

The beta 3 subtype of adrenaline and noradrenaline receptors has been extensively characterized at structural and functional levels. Ligand binding and adenyl cyclase activation studies have helped to define their unique beta-adrenergic profile. Humans, other larger mammals, and rodents share most of the characteristic beta 3-adrenergic receptor properties, although obvious species-specific differences have been identified. Most studies in animal models have shown a distinct beta 3-adrenergic receptor activity that results in an increase in energy expenditure, decrease of fat mass (especially of intra-abdominal fat), and increased glucose disposal efficiency. It is of interest that mild weight increase was shown to develop in female but not male mice, in whom the beta 3-adrenergic receptor gene was disrupted. Recently, the incidence of a naturally occurring variant of the human beta 3-adrenergic receptor was shown to correlate with hereditary obesity in Pima Indians and Japanese individuals. In Western obese patients, this phenotype increased the capacity to gain weight and develop type 2 diabetes mellitus. Studies of humans with the Trp64Arg variant have shown controversial results. Many studies have failed to show any effect in heterozygous male subjects, and only modest effects in homozygous male subjects. In women, several studies have shown modest-to-significant effects regarding weight gain, intra-abdominal fat, and decreased insulin sensitivity in heterozygous and homozygous women. Other studies have failed to show any effect in heterozygous females. Disruptions in the activity of the beta 3-adrenergic receptor in the homozygous male and the heterozygous or homozygous female appear to have a profound effect in animal models, but a limited consequence in human physiology. Association with obesity or diabetes in humans is still controversial. This difference between animal and human models may be explained by the different quantity and distribution of metabolically active brown adipose tissue in the two.