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.

Mechanisms of antihyperglycaemic action of efaroxan in mice: time for reappraisal of α2A-adrenergic antagonism in the treatment of type 2 diabetes?

“…Although further investigations are needed to extend this conclusion to other imidazolines, our results evidently challenge the broadly accepted paradigm that α 2 -antagonism has minor relevance to their glucose lowering action. While most of our experiments used compounds lacking subtype specificity beyond α 2 , the observed activity of an α 2A -specific antagonist supports extensive previous evidence that α 2A is the responsible subtype for glucose lowering [5,31,37,38]. Considering the recent identification of patient subpopulations in which a congenitally higher level of α 2A -adrenergic activation of beta cells seems to contribute to the development and pathophysiology of type 2 diabetes, it is time to critically reappraise the potential utility of specifically interacting drugs in the emerging personalised medicine that is dedicated to optimal treatment selection by means of pharmacogenomics.…”

“…Again, similar effects of yohimbine back our conclusion that this indicates an α 2 -antagonistic mode of action. While efaroxan and yohimbine lack specificity for a particular α 2 -adrenoceptor subtype, the observed antihyperglycaemic activity of the specific antagonist BRL44408 confirms earlier reports pointing at α 2A as the receptor subtype that mediates enhanced insulin secretion and decreased blood glucose [5,31,37,38].…”

Increased Energy Expenditure, Lipolysis and Hyperinsulinemia Confer Resistance to Central Obesity and Type 2 Diabetes in Mice Lacking Alpha2α-Adrenoceptors

“…Physical activity had very little effects on serum levels of hormones reflecting glucose homeostasis, but genotype differences in insulin and resistin levels were evident. Resistin, which is a marker of insulin insensitivity [64], was decreased in α 2A -/-mice, which fits with their improved glucose metabolism [31,32], and also provides additional support for the suggested improved insulin sensitivity of the model on HFD in this study. Leptin is associated with increased adiposity, and the activity-induced weight loss suppressed leptin levels in active, regular chow-fed animals and WD-fed WT mice as expected.…”

“…Mice lacking α 2A -ARs (α 2A -/-mice) display increased sympathoadrenal tone [30,31], hyperinsulinemia and improved glucose tolerance [31,32], but differences in body weight have not been reported between α 2A -/-and WT control mice under standard diet conditions and without stressors. However, mice are generally resistant to weight gain on standard rodent chow, and the effects of reduced α 2A -AR signalling on obesogenic insults have not been comprehensively addressed.…”

Blood glucose, acid–base and electrolyte changes during loading doses of alpha2-adrenergic agonists followed by constant rate infusions in horses

“…Postsynaptic alpha 2 -adrenergic receptors of the pancreatic b-cells are involved in insulin regulation (Ruohonen et al, 2012) and probably play an important role in the hyperglycaemic effect of alpha 2 -adrenergic agonists. However, other authors have suggested that the effects of alpha 2 -adrenergic agonist on glycaemic response are not only due to actions mediated by alpha 2 -adrenergic receptors (Ambrisko and Hikasa, 2002;Kanda and Hikasa, 2008).…”