The effects of hypo- and hyperglycaemia on the hypoxic ventilatory response in humans

Abstract

Animal and tissue studies have indicated that the carotid bodies are sensitive to glucose concentrations within the physiological range. This glucose sensitivity may modulate the ventilatory response to hypoxia, with hyperglycaemia suppressing the hypoxic response and hypoglycaemia stimulating it. This study was designed to determine whether hypo- and hyperglycaemia modulate the hypoxic ventilatory response in humans. In 11 normal research participants, glucose levels were clamped at 2.8 and 11.2 mmol l(-1) for 30 min. At the start and end of each clamp, blood was drawn for hormone measurement and the isocapnic hypoxic ventilatory response was measured. Because generation of reactive oxygen species may be a common pathway for the interaction between glucose and oxygen levels, the experiments were repeated with and without pretreatment for 1 week with vitamins C and E. Hypoglycaemia caused an increase in the counter-regulatory hormones, a 54% increase in isocapnic ventilation, and a 108% increase in the hypoxic ventilatory response. By contrast, hyperglycaemia resulted in small but significant increases in both ventilation and the hypoxic ventilatory response. Antioxidant vitamin pretreatment altered neither response. In conclusion, the stimulant effect of hypoglycaemia on the hypoxic ventilatory response is consistent with a direct effect on the carotid body, but an indirect effect through the activation of the counter-regulatory response cannot be excluded. The mechanisms behind the mild stimulating effect of hyperglycaemia remain to be elucidated.

Figure 1. Glucose and insulin measurements for both the hypoglycaemic and the hyperglycaemic clamps

No statistical difference was found between the placebo and vitamin treatments and the averages are given for both treatments combined. Statistical testing (see Methods) within the hypoglycaemic and hyperglycaemic clamps: *significantly different from Pre-Clamp value; +significantly different from Post-Clamp value; #significantly different from Start-Clamp value.

Figure 2. Example of hypoxic ventilatory response during hypoglycaemia

The left panel shows the instantaneous measurement of airway gases and tidal volume. The end-tidal and are controlled by manipulation of the inspired gas concentration. The right panel shows the ventilation versus saturation for each of the seven defined time intervals (see text) and the linear regression line.

Figure 3. Hypoxic ventilatory response for both the hypoglycaemic and hyperglycaemic clamps

No statistical difference was found between the placebo and vitamin treatments and the averages are given for both treatments combined. Statistical testing (see Methods) within the hypoglycaemic and hyperglycaemic clamps: *significantly different from Pre-Clamp value; +significantly different from Post-Clamp value.

Figure 4. Ventilation, tidal volume and breathing frequency averaged over the last 2 min of the normoxic period prior to the hypoxic periods for the four time periods in both the hypoglycaemic and hyperglycaemic clamps

Ventilation showed a significant increase during the clamp periods for both hypoglycaemia and hyperglycaemia but the frequency was increased for hypoglycaemia and tidal volume was increased for hyperglycemia. Statistical testing (see Methods): *significantly different from Pre-Clamp value; +significantly different from Post-Clamp value.

Figure 5. Hormonal response to hypoglycaemic and hyperglycaemic clamps

Except for noradrenaline level during the hyperglycaemic clamp, there was no difference between the placebo and antioxidant treatments and the responses for the two treatments are shown averaged together. For noradrenaline, there was no effect of the clamp time period, but the values following vitamin treatment were significantly (P < 0.01) higher than for placebo (see Results). Statistical testing (see Methods): *significantly different from Pre-Clamp value; +significantly different from Post-Clamp value; #significantly different from Start-Clamp value.

Figure 6. Neuroglycopenic and autonomic symptoms scores Average of the symptom score

shown as the symptoms related to an increase in autonomic activity and those related to neuroglycopenia (Mitrakou et al. 1991) for the hypoglycaemic clamp. Statistical testing (see Methods): *significantly different from Pre-Clamp value; +significantly different from Post-Clamp value.