title: Reduced blood glucose levels, increased insulin levels and improved glucose tolerance in alpha2A-adrenoceptor knockout mice.
abstract: 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 1.0 IU/kg) tolerance tests were performed. Fasting plasma glucagon and corticosterone levels were measured. Blood glucose levels (mean+/-S.E.M.) were lower in 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 microg/l) and females (1.7+/-0.3 microg/l) than in WT males (0.7+/-0.1 microg/l) and females (0.8+/-0.2 microg/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.
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Clinical Pharmacology, TYKSLAB, Hospital District of Southwest Finland, Itäinen Pitkäkatu 4B, FI-20520 Turku, Finland. eriika.savontaus@utu.fi
authors.forename: Eriika
authors.initials: E
authors.lastname: Savontaus
authors.forename: Veronica
authors.initials: V
authors.lastname: Fagerholm
authors.forename: Olli
authors.initials: O
authors.lastname: Rahkonen
authors.forename: Mika
authors.initials: M
authors.lastname: Scheinin
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D005215:Fasting / Q000378:metabolism; D005260:Female; D005934:Glucagon / Q000097:blood; D018149:Glucose Intolerance / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018727:Muscarinic Antagonists / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: C547769:Adra2a protein, mouse; D000319:Adrenergic beta-Antagonists; D001786:Blood Glucose; D007328:Insulin; D018727:Muscarinic Antagonists; D018341:Receptors, Adrenergic, alpha-2; D001285:Atropine; D005934:Glucagon; D011433:Propranolol; D003345:Corticosterone