β2-Adrenergic receptor agonist administration promotes counter-regulatory responses and recovery from hypoglycaemia in rats

Abstract

Aims/hypothesis We have previously reported that local activation of β2-adrenergic receptors (B2ARs) in the ventromedial hypothalamus (VMH) enhances hypoglycaemic counter-regulation. This study examines whether peripheral delivery of a selective B2AR agonist could also promote counter-regulatory responses and thereby has potential therapeutic value to limit hypoglycaemia risk. Methods Conscious male Sprague–Dawley rats received an intra-arterial injection of the B2AR specific agonist, formoterol, or a control solution either before a hyperinsulinaemic–hypoglycaemic clamp study or immediately before recovery from insulin-induced hypoglycaemia. In addition, the capacity of a VMH-targeted microinjection of a B2AR antagonist to limit the anti-insulin effect of the B2AR agonist was assessed. Results Systemic delivery of B2AR agonist markedly reduced the exogenous glucose infusion rate (GIR) required during the hypoglycaemic clamp study. This effect was mediated by blockade of insulin’s inhibitory effect on endogenous glucose production. Local blockade of B2ARs within the VMH using a specific antagonist partially diminished the effect of systemic activation of B2ARs during hypoglycaemia at least in part by diminishing the adrenaline (epinephrine) response to hypoglycaemia. Peripheral B2AR agonist injection also enhanced glucose recovery from insulin-induced hypoglycaemia. Conclusions/interpretation Systemic B2AR agonist administration acts to limit insulin-induced hypoglycaemia by offsetting insulin’s inhibitory effect on hepatic glucose production. This effect appears to be predominately mediated via a direct effect on liver B2ARs, but a small stimulatory effect on B2ARs within the VMH cannot be excluded. Our data suggest that formoterol may have therapeutic value to limit the risk of hypoglycaemia in patients with diabetes.

Inhaled Formoterol Diminishes Insulin-Induced Hypoglycemia in Type 1 Diabetes

“…In the current study, inhaled formoterol significantly decreased the amount of glucose required to keep circulating glucose at a standardized hypoglycemic level during a hyperinsulinemic clamp study in healthy control subjects and in subjects with type 1 diabetes. These findings are consistent with the established insulin antagonistic effects of formoterol in humans ( 25 ) as well as rodent data showing that peripheral administration of formoterol mainly acts to directly increase hepatic glucose production with no significant effect on counterregulatory hormones ( 22 ). These results imply that the metabolic effects of inhaled formoterol are most likely due to a direct effect of formoterol on β-2 receptors in the peripheral tissues (i.e., hepatic glucose production and/or insulin-stimulated peripheral glucose uptake).…”

“…In summary, our results from this pilot study suggest that specific β-2 agonists delivered via inhalation may prove useful during intensive insulin therapy in patients with type 1 diabetes who have hypoglycemia-associated autonomic failure and thus are at high risk for hypoglycemia. Its effects occur rapidly and appear to be a direct effect of formoterol on peripheral glucose metabolism, particularly in the liver ( 22 ), because counterregulatory hormone responses were not significantly altered in subjects with and without diabetes. Although, as our data suggest, formoterol acts to directly offset the effects of insulin and most likely can cause mild hyperglycemia (similar to the studies using terbutaline for hypoglycemia [ 18 ]), we believe that due to the limited options for prevention of hypoglycemia, a more specific β-agonist might benefit a particular group of patients unable to generate a counterregulatory hormone response, resulting in a history of severe and frequent hypoglycemia.…”

“…Among these drugs, terbutaline, a specific β-2 agonist, has been reported to prevent nocturnal hypoglycemia ( 21 ), although the nighttime dose of terbutaline required was associated with hyperglycemia the following morning ( 18 ). The more specific long-acting β-2 agonist, formoterol, has been shown in rodent studies to limit insulin-induced hypoglycemia by diminishing the inhibitory effect of insulin on glucose production ( 22 ). Formoterol’s effect appears to be mediated in large part via a direct effect on the liver, although activation of β-2 receptors in the ventral medial hypothalamus might contribute as well ( 23 ).…”

Possible association of arrestin domain-containing protein 3 and progression of non-alcoholic fatty liver disease

“…Knockdown of β-arrestin-2 also prevented the cAMP-binding protein Epac1-induced histone deacetylase 4 (HDAC4) nuclear export [11]. β2-adrenergic receptor agonists may possibly exert multiple effects including a direct-effect on liver β2-adrenergic receptors and could promote recovery from insulin-induced hypoglycemia [12].…”

Dipyrone in association with atropine inhibits the effect on gastric emptying induced by hypoglycemia in rats

“…The sympathetic-adrenal system is rapidly activated in order to increase blood glucose levels in hypoglycemia and the α 2A- receptor is an important regulator of glycemia which, when activated, inhibits the release of insulin by pancreatic β cells ( 25 ). It has been recently suggested that activation of peripheral β 2 -adrenoceptors (possibly in the liver) and of the ventromedial region of the hypothalamus also occurs in rats with insulin-induced hypoglycemia as a counter-regulatory response for the recovery of glycemic levels ( 26 , 27 ).…”