Involvement of α2-Adrenoceptor Subtypes A and C in Glucose Homeostasis and Adrenaline-Induced Hyperglycaemia

Abstract

Background and Aims: Insulin secretion is controlled by pancreatic α_2A-adrenoceptors. Mice lacking α_2A-adrenoceptors (α_2AAR^–/– mice) show hyperinsulinaemia, reduced blood glucose levels and improved glucose tolerance. Methods: In the present study, we used α_2ACAR^–/–, α_2CAR^–/– and α_2AAR^–/– mice and a mouse line with adrenergic cell-specific expression of α_2A-adrenoceptors (lacking these receptors in non-adrenergic cells), and their wild-type (WT) controls, to assess the glucoregulatory role of the α_2C-adrenoceptor subtype in vivo. Glucose and insulin tolerance tests were performed and blood glucose and serum insulin levels were determined after fasting and glucose stimulation. Plasma catecholamines were also measured. In addition, the effect of pretreatment with (±)-propranolol was determined in α_2CAR^–/– mice. Results: α_2ACAR^–/– mice had a similar glucose and insulin phenotype as α_2AAR^–/– mice and mice with restored α_2A-autoreceptors, suggesting that only deletion of postsynaptic α_2A-adrenoceptors has major effects on glucose disposition. However, α_2ACAR^–/– mice were more sensitive to the glucose-lowering effect of insulin than WT mice. This was not observed in α_2AAR^–/– mice. The α_2CAR^–/– mice showed impaired glucose tolerance that was reversed by pretreatment with (±)-propranolol. No difference in insulin secretion was observed in α_2CAR^–/– mice compared with WT animals. Conclusion: The results underline that depletion of postsynaptic pancreatic α_2A-adrenoceptors has major effects on the regulation of glucose homeostasis in α_2ACAR^–/– and α_2AAR^–/– mice. Deletion of the α_2C subtype leads to increased adrenaline secretion and has the potential to increase blood glucose levels via enhanced glycogenolysis.