Involvement of α2-adrenoceptor subtypes A and C in glucose homeostasis and adrenaline-induced hyperglycaemia.
OBJECTIVE
Insulin secretion is controlled by pancreatic α(2A)-adrenoceptors. Mice lacking α(2A)-adrenoceptors (α(2A)AR(-/-) mice) show hyperinsulinaemia, reduced blood glucose levels and improved glucose tolerance.


METHODS
In the present study, we used α(2AC)AR(-/-), α(2C)AR(-/-) and α(2A)AR(-/-) 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(2C)AR(-/-) mice.


RESULTS
α(2AC)AR(-/-) mice had a similar glucose and insulin phenotype as α(2A)AR(-/-) 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(2AC)AR(-/-) mice were more sensitive to the glucose-lowering effect of insulin than WT mice. This was not observed in α(2A)AR(-/-) mice. The α(2C)AR(-/-) mice showed impaired glucose tolerance that was reversed by pretreatment with (±)-propranolol. No difference in insulin secretion was observed in α(2C)AR(-/-) mice compared with WT animals.


CONCLUSIONS
The results underline that depletion of postsynaptic pancreatic α(2A)-adrenoceptors has major effects on the regulation of glucose homeostasis in α(2AC)AR(-/-) and α(2A)AR(-/-) mice. Deletion of the α(2C) subtype leads to increased adrenaline secretion and has the potential to increase blood glucose levels via enhanced glycogenolysis.
Department of Pharmacology, Drug Development and Therapeutics and Turku Center for Disease Modeling, University of Turku, Finland. suvi.ruohonen@utu.fi
Suvi T
ST
Ruohonen
Saku
S
Ruohonen
Ralf
R
Gilsbach
Eriika
E
Savontaus
Mika
M
Scheinin
Lutz
L
Hein
D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002395:Catecholamines / Q000097:blood; D004837:Epinephrine / Q000097:blood; D005215:Fasting; D006706:Homeostasis / Q000187:drug effects; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009638:Norepinephrine / Q000097:blood; D011433:Propranolol / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000172:deficiency / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D058647:Adrenergic alpha-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D001786:Blood Glucose; D002395:Catecholamines; D007328:Insulin; D018341:Receptors, Adrenergic, alpha-2; D011943:Receptors, Adrenergic, beta; D011433:Propranolol; D009638:Norepinephrine; D004837:Epinephrine