Hyperoxia blunts counterregulation during hypoglycaemia in humans: possible role for the carotid bodies?

Abstract

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.

Figure 1. Experimental time-line

A detailed explanation for hypoglycaemic clamp is given in Methods. Arrows indicate blood draws.

Figure 2. Arterial oxygen tension is significantly elevated and arterial carbon dioxide tension are maintained during the hypoglycaemic clamp

A, arterial oxygen time course; B, arterial carbon dioxide time course. Black symbols: normoxia, grey symbols: hyperoxia. Values are means ± s.e.m., n = 7.

Figure 3. High dose insulin infusion reduced plasma glucose and C-peptide during normoxia and hyperoxia

Plasma glucose (A), insulin (B) and C-peptide (C) during hypoglycaemic clamp with concurrent normoxia or hyperoxia. Normoxia: black symbols, hyperoxia: grey symbols. Points are means ± s.e.m., n = 7.

Figure 4. Glucose infusion rate is significantly higher under hyperoxic conditions

A, time course for glucose infusion rate under normoxia and hyperoxia. Normoxia: black symbols, hyperoxia: grey symbols. Values are means ± s.e.m. Significance denoted as *P < 0.05. B, glucose infusion rate at steady state during normoxia and hyperoxia for each subject. Mean values are indicated with a horizontal line. n = 7.

Figure 5. Counterregulatory hormone response to hypoglycaemia was blunted under hyperoxic conditions

Time courses for counterregulatory hormones are shown. A, noradrenaline; B, adrenaline; C, dopamine; D, cortisol; E, growth hormone; and F, glucagon. Normoxia: black symbols, hyperoxia: grey symbols. Significance denoted as *P < 0.05 for differences between normoxia and hyperoxia. G area under the curve for counterregulatory hormones was calculated. Normoxia was normalized to 100% and hyperoxia is shown as a percentage of normoxia. Dopamine was not included in area under the curve calculations since there was no significant difference between normoxia and hyperoxia. Normoxia: black symbols, hyperoxia: grey symbols. Significance denoted as *P < 0.05 for differences between normoxia and hyperoxia. n = 7.