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

J. C. Devedjian, A. Pujol, C. Cayla, M. George, A. Casellas, H. Paris, F. Bosch

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52 Citations (Scopus)

Abstract

Aims/hypothesis. To study the role of the human α(2A)adrenoceptor in the regulation of insulin secretion and the maintenance of glucose homeostasis in transgenic mice overexpressing this receptor in pancreatic beta cells. Methods. A human insulin promoter/human α2C10-adrenoceptor chimeric gene 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 α2-antagonist [3H]RX821002 to membrane preparations showed that islets from transgenic mice had ninefold higher α2-adrenoceptor density than those from controls. Immunohistological analysis showed, however, no change in the number or size of islets between control and transgenic mice. Transgenic animals had normal glycaemia and insulinaemia in basal conditions but greater hyperglycaemic and hypoinsulinaemic responses after injection of the α2- agonist, UK14304. The lower blood insulin concentration detected in transgenic mice was a reflection of a stronger inhibitory effect of the α2- agonist on glucose-stimulated insulin secretion in transgenic islets than 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 α2-adrenoceptor antagonist, RX821002. Conclusion/interpretation. These results provide evidence in vivo that overexpression of α2-adrenoceptors in beta cells can lead to impaired insulin secretion and glucose intolerance.
Original languageEnglish
Pages (from-to)899-906
JournalDiabetologia
Volume43
Issue number7
DOIs
Publication statusPublished - 1 Jan 2000

Keywords

  • Adrenoceptor
  • Catecholamines
  • Diabetes
  • Insulin
  • Islets
  • Transgenic mice
  • α - agonist 2

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