Reduced blood glucose levels, increased insulin levels and improved glucose tolerance in α 2A-adrenoceptor knockout mice

Abstract

α 2-Adrenoceptors regulate insulin secretion and sympathetic output. In the present study, α 2A-adrenoceptor knockout (α 2A-KO) mice and their C57BL/6J wild-type (WT) controls were used to assess the glucoregulatory role of the α 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 1.0 IU/kg) tolerance tests were performed. Fasting plasma glucagon and corticosterone levels were measured. Blood glucose levels (mean ± S.E.M.) were lower in α 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 α 2A-KO males (2.2 ± 0.5 μg/l) and females (1.7 ± 0.3 μg/l) than in WT males (0.7 ± 0.1 μg/l) and females (0.8 ± 0.2 μg/l). These differences remained after pharmacological β-adrenoceptor and muscarinic acetylcholine receptor inhibition. In spite of a tendency for slightly decreased insulin sensitivity in α 2A-KO mice, glucose tolerance in α 2A-KO mice was significantly better than in WT mice. However, glucose-stimulated insulin secretion was not increased in α 2A-KO mice compared to WT controls. Plasma glucagon levels, but not corticosterone levels, were elevated in α 2A-KO mice. These results suggest that lack of inhibitory pancreatic β-cell α 2A-adrenoceptor function results in hyperinsulinaemia, reduced blood glucose levels and improved glucose tolerance in α 2A-KO mice, and demonstrate a key role for the α 2A-adrenoceptor in adrenergic regulation of blood glucose and insulin homeostasis.