Transgenic mice overexpressing alpha(2A)-adrenoceptors in pancreatic beta-cells show altered regulation of glucose homeostasis

Aims/hypothesis. To study the role of the human alpha(2A)-adrenoceptor in t he regulation of insulin secretion and the maintenance of glucose homeostas is in transgenic mice overexpressing this receptor in pancreatic beta cells . Methods. A human insulin promoter/human alpha(2)C10-adrenoceptor chimeric g ene was microinjected into mouse embryos and transgenic mice were obtained. Results. Analysis by RT-PCR showed that the expression of the transgene was restricted to pancreatic islets. Study of the binding of the alpha(2)-anta gonist [H-3]RX821 002 to membrane preparations showed that islets from tran sgenic mice had ninefold higher alpha(2)-adrenoceptor density than those fr om controls. Immunohistological analysis showed, however, no change in the number or size of islets between control and transgenic mice. Transgenic an imals had normal glycaemia and insulinaemia in basal conditions but greater hyperglycaemic and hypoinsulinaemic responses after injection of the alpha (2)-agonist, UK14303. The lower blood insulin concentration detected in tra nsgenic mice was a reflection of a stronger inhibitory effect of the alpha( 2)-agonist on glucose-stimulated insulin secretion in transgenic islets tha n in controls. Furthermore, transgenic mice did not have lower glycaemia to basal values after an intraperitoneal glucose tolerance test. This defect was abolished by treatment with the alpha(2)-adrenoceptor antagonist, RX821 002. Conclusion/interpretation. These results provide evidence in vivo that over expression of alpha(2)-adrenoceptors in beta cells can lead to impaired ins ulin secretion and glucose intolerance.