GPR39 receptors and actions of trace metals on pancreatic beta cell function and glucose homoeostasis

G-protein-coupled receptor 39 (GPR39) has been implicated in glucose homoeostasis, appetite control and gastrointestinal tract function. This study used clonal BRIN-BD11 cells and mouse pancreatic islets to assess the insulin-releasing actions of trace metals believed to act via GPR39, and the second messenger pathways involved in mediating their effects. Micromolar concentrations of Zn2+, Cu2+, Ni2+ and Co2+ were examined under normoglycaemic and hyperglycaemic conditions. Mechanistic studies investigated changes of intracellular Ca2+, cAMP generation and assessment of cytotoxicity by LDH release. Cellular localisation of GPR39 was determined by double immunohistochemical staining. All trace metals (7.8-500 A mu mol/l) stimulated insulin release with Cu2+ being the most potent in isolated islets, with an EC50 value of 87 mu mol/l. Zn2+ was the most selective with an EC50 value of 125 mu mol/l. Enhancement of insulin secretion was also observed with Ni2+ (179 mu mol/l) and Co2+ (190 mu mol/l). These insulin-releasing effects were confirmed using clonal BRIN-BD11 cells which exhibited enhanced intracellular Ca2+ (p < 0.05-p < 0.001) and cAMP generation (p < 0.05-p < 0.001) in response to trace metals. Oral administration of Zn2+, Ni2+ and Cu2+ (50 A mu mol/kg together with 18 mmol/kg glucose) decreased the glycaemic excursion (p < 0.05-p < 0.01) and augmented insulin secretion (p < 0.05-p < 0.01) in NIH Swiss mice. This study has demonstrated the presence of GPR39 and the insulinotropic actions of trace metals on BRIN-BD11 cells and pancreatic beta cells, together with their antihyperglycaemic actions in vivo. These data suggest that development of agonists capable of specifically activating GPR39 may be a useful new therapeutic approach for diabetes management.