Inheritance of the Arg64 Polymorphic Variants of the β3-Adrenergic Receptor is Linked to Impaired Insulin Secretion

The Arg64 β3-adrenergic receptor (β3AR) variant is associated with an earlier age of onset of diabetes mellitus. The aims of this study were: i) to characterize the insulin secretory activity of human subjects carrying the Arg64 allele; ii) to investigate whether β3AR is expressed by islet cells; iii) to study whether cell transfection of islet-derived β-cells with the β3AR Arg64 variant was capable of altering the insulin secretory activity of cells. We observed a lower level of insulin secretion in response to an i.v. glucose tolERαnce test in individuals carrying the Arg64 polymorphism compared to wild-type controls. Western blotting of human pancreas demonstrated that the β3AR gene is transcribed and translated in the human pancreas; and immuno-staining showed that it is expressed by the islets of Langerhans. Transfection of cultured rat β-cells with the wild-type human β3AR produced a ligand-dependent insulin secretion. Cell transfection with the Arg64 variant induced a down-regulation of insulin secretion, both spontaneously and after exposure to a human β3AR agonist. Furthermore, while transfection with the wild-type β3AR preserved the glucose-dependent secretion of insulin, expression of the variant receptor rendered the host cells significantly less responsive to glucose.