Joyner, Michael J.

New Findings What is the central question of this study? Hyperoxia blunts hypoglycaemia counterregulation in healthy adults. We hypothesized that this effect is mediated by the carotid bodies and that: (i) hyperoxia would have no effect on hypoglycaemia counterregulation in carotid body‐resected patients; and (ii) carotid body‐resected patients would exhibit an impaired counterregulatory response to hypoglycaemia. What is the main finding and its importance? Our data indicate that the effect of hyperoxia on hypoglycaemic counterregulation is mediated by the carotid bodies. However, a relatively normal counterregulatory response to hypoglycaemia in carotid body‐resected patients highlights: (i) the potential for long‐term adaptations after carotid body resection; and (ii) the importance of redundant mechanisms in mediating hypoglycaemia counterregulation. Hyperoxia reduces hypoglycaemia counterregulation in healthy adults. We hypothesized that this effect is mediated by the carotid bodies and that: (i) hyperoxia would have no effect on hypoglycaemia counterregulation in patients with bilateral carotid body resection; and (ii) carotid body‐resected patients would exhibit an impaired counterregulatory response to hypoglycaemia. Five patients (three male and two female) with bilateral carotid body resection for glomus tumours underwent two 180 min hyperinsulinaemic, hypoglycaemic (∼3.3 mmol l−1) clamps separated by a minimum of 1 week and randomized to either normoxia (21% fractional inspired O2) or hyperoxia (100% fractional inspired O2). Ten healthy adults (seven male and three female) served as control subjects. Hypoglycaemia counterregulation in carotid body‐resected patients was not significantly altered by hyperoxia (area under the curve expressed as a percentage of the normoxic response: glucose infusion rate, 111 ± 10%; cortisol, 94 ± 6%; glucagon, 107 ± 7%; growth hormone, 92 ± 10%; adrenaline, 89 ± 26%; noradrenaline, 79 ± 15%; main effect of condition, P > 0.05). This is in contrast to previously published results from healthy adults. However, the counterregulatory responses to hypoglycaemia during normoxia were not impaired in carotid body‐resected patients when compared with control subjects (main effect of group, P > 0.05). Our data provide further corroborative evidence that the effect of hyperoxia on hypoglycaemic counterregulation is mediated by the carotid bodies. However, relatively normal counterregulatory responses to hypoglycaemia in carotid body‐resected patients highlight the importance of redundant mechanisms in mediating hypoglycaemia counterregulation.

Key pointsCommon single nucleotide polymorphisms in the beta‐2 adrenoceptor (ADRB2) gene influence cardiovascular function, but they exist in combinations (haplotypes), so it is crucial to characterize the haplotypes to improve the functional predictive power of ADRB2 gene variation.Dietary sodium affects ADRB2 function.In a large randomized cross‐over phenotyping trial that administered low, normal and high dietary sodium, we determined the interactions between ADRB2 haplotype, receptor density on lymphocytes, cardiovascular haemodynamics during stress manoeuvres, forearm blood flow vasodilator responsiveness and dietary sodium.Healthy young adults were recruited based on the homozygous haplotypes of the ADRB2 gene: Arg16+Gln27, the rare Gly16+Gln27 and Gly16+Glu27.Independent of dietary sodium, the Gly16+Glu27 haplotype had the greatest ADRB2 density and Arg16+Gln27 had the least, suggesting that ADRB2 haplotype influences ADRB2 protein expression, yet the haemodynamic consequences appear modest in healthy humans, necessitating larger trials that explore variation in multiple candidate genes.AbstractDietary sodium affects function of the beta‐2 adrenoceptor (ADRB2). We tested the hypothesis that haplotype variation in the ADRB2 gene would influence the cardiovascular and regional vasodilator responses to sympathoexcitatory manoeuvres following low, normal and high sodium diets, and ADRB2‐mediated forearm vasodilation in the high sodium condition. Seventy‐one healthy young adults were grouped by double homozygous haplotypes: Arg16+Gln27 (n = 31), the rare Gly16+Gln27 (n = 10) and Gly16+Glu27 (n = 30). Using a randomized cross‐over design, subjects were studied following 5 days of controlled low, normal and high sodium with 1 month or longer between diets (and low hormone phase of the menstrual cycle). All three visits utilized ECG and finger plethysmography for haemodynamic measures, and the high sodium visit included a brachial arterial catheter for forearm vasodilator responses to isoprenaline with plethysmography. Lymphocytes were sampled forex vivoanalysis of ADRB2 density and binding conformation. We found a main effect of haplotype on ADRB2 density (P = 0.03) with the Gly16+Glu27 haplotype having the greatest density (low, normal, high sodium: 12.9 ± 0.9, 13.5 ± 0.9 and 13.6 ± 0.8 fmol mg−1protein, respectively) and Arg16+Gln27 having the least (9.3 ± 0.6, 10.1 ± 0.5 and 10.3 ± 0.6 fmol mg−1protein, respectively), but there were no sodium or haplotype effects on receptor binding conformation. In the mental stress trial, there was a main effect of haplotype on cardiac output (P = 0.04), as Arg16+Gln27 had the lowest responses. Handgrip and forearm vasodilation yielded no haplotype differences, and no correlations were present for ADRB2 density and haemodynamics. Our findings support cell‐based evidence that ADRB2 haplotype influences ADRB2 protein expression independent of dietary sodium, yet the haemodynamic consequences appear modest in healthy humans.

Hyperoxia can cause substantial reductions in peripheral and coronary blood flow at rest and during exercise, which may be caused by reactive oxygen species (ROS) generated during hyperoxia. The aim of this study was to investigate the role of ROS in hyperoxia-induced reductions in skeletal muscle blood flow during forearm exercise. We hypothesized that infusion of vitamin C would abolish the effects of hyperoxia on the forearm blood flow (FBF) responses to exercise. Twelve young healthy adults performed rhythmic forearm handgrip exercise (10% of maximum voluntary contraction for 5 min) during normoxia and hyperoxia. For each condition, two trials were conducted with intra-arterial administration of saline or vitamin C. FBF was measured using Doppler ultrasound. During hyperoxia with saline, FBF and forearm vascular conductance (FVC) were 86.3 ± 5.1 and 86.8 ± 5.2%, respectively, of the normoxic values (100%) ( P < 0.05). During vitamin C, hyperoxic FBF and FVC responses were 90.9 ± 4.2 and 90.9 ± 4.1%, respectively, of the normoxic values ( P = 0.57 and 0.59). Subjects were then divided into three subgroups based on their percent decrease in FBF (>20, 10–20, and <10%) during hyperoxia. In the subgroup that demonstrated the greatest hyperoxia-induced changes (>20%), FBF and FVC during hyperoxia were 67.1 ± 4.0 and 66.8 ± 3.6%, respectively, of the normoxic values. Vitamin C abolished these effects on FBF and FVC with values that were 102.0 ± 5.2 and 100.8 ± 6.1%, respectively. However, vitamin C had no effect in the other two subgroups. This analysis is consistent with the idea that ROS generation blunts the FBF responses to exercise in the subjects most affected by hyperoxia.

This single-centre, 12-week, double-blind, placebo-controlled trial assessed how the human glucagon-like-peptide 1 analogue liraglutide impacted endothelial function in adult patients (n = 49) with type 2 diabetes and no overt cardiovascular disease. Patients were randomized to liraglutide, placebo or glimepiride. At baseline and Week 12, venous occlusion plethysmography was used to measure forearm blood flow (FBF) in response to acetylcholine (ACh) and sodium nitroprusside (SNP) before and after l-N G -monomethyl arginine (L-NMMA) infusion. At Week 12, ACh-mediated FBF increased with liraglutide and decreased with placebo; however, the between-treatment difference was not significant ( p = 0.055). Inhibition of ACh-mediated FBF after L-NMMA infusion increased with liraglutide and decreased with placebo; this between-treatment difference was also not significant ( p = 0.149). No change in FBF was observed with SNP. Liraglutide did not significantly impact endothelium-dependent vasodilation after 12 weeks; however, additional investigations looking at the effect of liraglutide on endothelial function in alternative vasculature and during the postprandial period are warranted.