Reduced blood glucose levels, increased insulin levels and improved glucose tolerance in α2A-adrenoceptor knockout mice

alpha(2)-Adrenoceptors regulate insulin secretion and sympathetic output. In the present study, alpha(2A)-adrenoceptor knockout (alpha(2A)-KO) mice and their C57BL/6J wild-type (WT) controls were used to assess the glucoregulatory role of the alpha(2A)-adrenoceptor subtype in vivo. Fasting and glucose-stimulated blood glucose and plasma insulin levels were determined with or without (+/-)-propranolol (5 mg/kg) or atropine (10 mg/kg)pre-treatment. Intraperitoneal glucose (1 g/kg) and insulin (0.5 and 1.0IU/kg)tolerance tests were performed. Fasting plasma glucagon and corticosterone levels were measured. Blood glucose levels (mean +/- S.E.M.) were lower in alpha(2A)-KO males (7.2 +/- 0.6 mM) and females (7.2 +/- 0.2 mM) than in WT males (9.8 0.3 MM) and females (9.1 +/- 0.3 mM). Plasma insulin levels were higher in alpha(2A)-KO males (2.2 +/- 0.5 mu g/l) and females (1.7 +/- 0.3 mu g/l) than in WT males (0.7 +/- 0.1 mu g/l) and females (0.8 +/- 0.2 mu g/l). These differences remained after pharmacological beta-adrenoceptor and muscarinic acetylcholine receptor inhibition. In spite of a tendency for slightly decreased insulin sensitivity in alpha(2A)-KO mice, glucose tolerance in alpha(2A)-KO mice was significantly better than in WT mice. However, glucose-stimulated insulin secretion was not increased in alpha(2A)-KO mice compared to WT controls. Plasma glucagon levels, but not corticosterone levels, were elevated in alpha(2A)-KO mice. These results suggest that lack of inhibitory pancreatic beta-cell alpha(2A)-adrenoceptor function results in hyperinsulinaemia, reduced blood glucose levels and improved glucose tolerance in alpha(2A)-KO mice, and demonstrate a key role for the alpha(2A)-adrenoceptor in adrenergic regulation of blood glucose and insulin homeostasis. (c) 2007 Elsevier B.V. All rights reserved.