4593
J Physiol 588.22 (2010) pp 4593–4601
Hyperoxia blunts counterregulation during hypoglycaemia in humans: possible role for the carotid bodies? Erica A. Wehrwein1 , Rita Basu2 , Ananda Basu2 , Timothy B. Curry1 , Robert A. Rizza2 and Michael J. Joyner1 1 2
Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA Endocrine Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic College of Medicine, Rochester, MN, USA
Chemoreceptors in the carotid bodies sense arterial oxygen tension and regulate respiration. Isolated carotid body glomus cells also sense glucose, and animal studies have shown the carotid bodies play a role in the counterregulatory response to hypoglycaemia. Thus, we hypothesized that glucose infusion rate would be augmented and neuro-hormonal counterregulation blunted during hypoglycaemia when the carotid bodies were desensitized by hyperoxia. Seven healthy adults (four male, three female) underwent two 180 min hyperinsulinaemic (2 mU (kg fat-free mass (FFM))−1 min−1 ), hypoglycaemic (3.33 mmol l−1 ) clamps 1 week apart, randomized to either normoxia (arterial P O2 (P aO2 ) 111 ± 6.3 mmHg) or hyperoxia (P aO2 345 ± 80.6 mmHg) (P < 0.05). Plasma glucose concentrations were similar during normoxia and hyperoxia at baseline (5.52 ± 0.15 vs. 5.55 ± 0.13 μmol ml−1 ) and during the clamp (3.4 ± 0.05 vs. 3.3 ± 0.05 μmol ml−1 ). The glucose infusion rate was 44.2 ± 3.5% higher (P < 0.01) during hyperoxia than normoxia at steady state during the clamp (28.2 ± 0.15 vs. 42.7 ± 0.65 μmol (kg FFM)−1 min−1 ; P < 0.01). Area under the curve values (expressed as percentage normoxia response) for counterregulatory hormones during hypoglycaemia were significantly suppressed by hyperoxia (noradrenaline 50.7 ± 5.2%, adrenaline 62.6 ± 3.3%, cortisol 63.2 ± 2.1%, growth hormone 53.1 ± 2.7%, glucagon 48.6 ± 2.1%, all P < 0.05 vs. normoxia). These data support the idea that the carotid bodies respond to glucose and play a role in the counterregulatory response to hypoglycaemia in humans. (Received 6 August 2010; accepted after revision 29 September 2010; first published online 11 October 2010) Corresponding author M. J. Joyner: Department of Anesthesiology, 200 1st St SW, SMH Joseph 4-184, Rochester, MN 55905, USA. Email:
[email protected] Abbreviations COPD, chronic obstructive pulmonary disease; DEXA, dual energy x-ray absorptiometry; FFM, fat-free mass; T, protocol time.
Introduction The carotid body includes Type I glomus cells that secrete neurotransmitters and activate sensory afferents in response to reduced partial pressure of oxygen in arterial blood (P aO2 ). This secretory response also occurs during exposure to low glucose concentrations in vitro (Pardal & Lopez-Barneo, 2002). Additionally, the cellular response to low glucose is influenced by the local P aO2 such that secretory response is augmented when P aO2 is lower (Pardal & Lopez-Barneo, 2002). These observations raise the possibility that the carotid bodies play a role in sensing hypoglycaemia in vivo. Along these lines, carotid body resection in dogs drastically impairs the systemic counterregulatory responses to hypoglycaemia (Koyama et al. 2000). C 2010 The Authors. Journal compilation C 2010 The Physiological Society
One approach to study this topic in humans is to use hyperoxia to acutely desensitize the carotid bodies. In humans hyperoxia can depress minute ventilation (Downes & Lambertsen, 1966), and inhalation of 100% oxygen is thought to dramatically reduce peripheral chemoreceptor activity (Lahiri & DeLaney, 1975). Hyperoxia also suppresses afferent nerve traffic from the carotid bodies in animals (Fitzgerald & Lahiri, 1986). With this information as a background, we sought to test the role of the carotid bodies in the systemic counterregulatory response to hypoglycaemia in humans by using hyperoxia to acutely desensitize the carotid bodies. On separate days we performed paired hyperinsulinaemic hypoglycaemic clamps in healthy humans exposed to normoxia or hyperoxia. We hypothesized that the glucose infusion rate would be augmented and neuro-hormonal
DOI: 10.1113/jphysiol.2010.197491
4594
E. A. Wehrwein and others
counterregulation blunted during hypoglycaemia when the carotid bodies were desensitized by hyperoxia. Methods
J Physiol 588.22
anaesthesia. Two intravenous catheters were placed in the arm opposite the brachial arterial catheter for infusions. For patient safety, heart rate was monitored with a five-lead electrocardiogram, respirations via a pneumobelt, and arterial oxygen saturation by a pulse oximeter.
Ethical approval
All experiments and procedures were approved by the Institutional Review Board at Mayo Clinic. Informed consent was obtained in writing from all subjects prior to study enrollment and testing. The studies conformed to the Declaration of Helsinki. Subjects
Subjects were healthy non-obese (BMI 5.5 mmol l−1 , hypertension (
