Insulin resistance and type 2 diabetes mellitus: Its relationship with thebeta(3)-adrenergic receptor

The beta(3) subtype of adrenaline and noradrenaline receptors has been exte nsively characterized at structural and functional levels. Ligand binding a nd adenyl cyclase activation studies have helped to define their unique bet a-adrenergic profile. Humans, other larger mammals, and rodents share most of the: characteristic beta(3)-adrenergic receptor properties, although obv ious species-specific differences have been identified. Most studies in ani mal models have shown a distinct beta(3)-adrenergic receptor activity that results in an increase in energy expenditure, decrease of fat mass (especia lly 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 P ima Indians and Japanese individuals. In Western obese patients, this pheno type increased the capacity to gain weight and develop type 2 diabetes mell itus. Studies of humans with the Trp(64)Arg variant have shown controversia l results. Many studies have failed to show any effect in heterozygous male subjects, and only modest effects in homozygous male subjects. In women, s everal studies have shown modest-to-significant effects regarding weight ga in, intra-abdominal fat, and decreased insulin sensitivity in heterozygous and homozygous women. Other studies have failed to show any effect in heter ozygous females. Disruptions in the activity of the beta(3)-adrenergic receptor in the homoz ygous male and the heterozygous or homozygous female appear to have a profo und effect in animal models, but a limited consequence in human physiology. Association with obesity or diabetes in humans is still controversial. Thi s difference between animal and human models may be explained by the differ ent quantity and distribution of metabolically active brown adipose tissue in the two. (C) 2000 IMSS. Published by Elsevier Science Inc.