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1 Metabolic Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Scotland, UK Email: mark.strachan{at}luht.scot.nhs.uk
The human brain has enormous metabolic requirements that are almost completely provided by the oxidation of glucose. However, because it is unable to synthesize or store glucose, the brain is reliant on the cerebral circulation to provide a constant supply of its primary source of energy. Acute hypoglycaemia quickly causes energy failure in cerebral neurons and this is manifest by the onset of neuroglycopaenic symptoms, such as poor concentration, drowsiness and reduced co-ordination. As blood glucose concentrations fall further, cognitive impairment and confusion develop and ultimately seizures, coma and permanent neurological deficit occur.
Because of the dependence of the central nervous system on glucose, multiple mechanisms have evolved to maintain glucose homeostasis (Fig. 1). A fall in blood glucose is detected by glucose sensors within the brain, located mainly in the ventromedial nuclei of the hypothalamus, and the hepatic portal system. Activation of these glucose sensors instigates a cascade of responses to raise blood glucose (King & Macdonald, 1999). These responses include the following.
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The haemodynamic changes include increased heart rate, cardiac output and systolic blood pressure. There are also significant increases in regional blood flow, not only to the brain, but also to other organs (notably the liver and muscle) that can increase substrate delivery to the brain.
It is well established that the carotid bodies activate the autonomic nervous system and increase ventilation in response to falling oxygen or rising carbon dioxide tensions. There are also in vivo data from dogs that suggest that the carotid bodies play a role in the sensing of hypoglycaemia and in the initiation of the subsequent counterregulatory response (Koyama et al. 2000). In vitro, several studies have demonstrated that carotid bodies are responsive to low glucose concentrations and that ventilatory responses are additive to those obtained during hypoxia or hypercapnia (Zhang et al. 2007). In one study in rats, hypoglycaemia increased spontaneous ventilation and this effect was abolished if the carotid sinus nerves were sectioned; however, in vitro chemoreceptor discharge frequency was not altered by low glucose concentrations leading the authors to conclude that glucose was being sensed indirectly by the carotid bodies (Bin-Jaliah et al. 2004).
The study by Ward et al. (2007) reported in this issue of the The Journal of Physiology examined the effects of acute hypo- and hyperglycaemia on the hypoxic ventilatory response in humans. When blood glucose concentration was dropped to 2.8 mmol l–1, using a hyperinsulinaemic glucose clamp technique, in 11 healthy volunteers, there was a 54% increase in isocapnic ventilation and a 108% increase in the hypoxic ventilatory response. There was a predictable elevation in counterregulatory hormones. Clearly there are several plausible mechanisms to explain this response. In keeping with the animal and in vitro studies described above, there could be direct (or indirect) sensing of hypoglycaemia by the carotid bodies. Alternatively, there could be direct stimulation of the central nervous system respiratory centre by counterregulatory hormones or via direct projections from glucose-sensing neurons in the hypothalamus or even in the tractus solitarius itself. Whatever the underlying mechanism, the physiological response makes biological ‘sense’ in that there is an attempt by the body to ensure that oxygen tensions in tissues are optimized at a time when the concentrations of glucose are suboptimal. This ensures that whatever glucose is available for metabolism is oxidized, to release its maximum potential energy yield, rather than undergoing anaerobic metabolism.
Intriguingly, Ward et al. (2007) observed that acute hyperglycaemia (blood glucose concentration of 11.2 mmol l–1) was also associated with a mild increase in the hypoxic ventilatory response. This was not in keeping with in vitro data. However, it must be remembered that hypoglycaemia and hyperglycaemia are not simple opposites. Hypoglycaemia poses a direct threat to the viability of physiological systems, whereas transient hyperglycaemia does not. Therefore, we should not always expect to see mirror image physiological responses to the two conditions. The physiological mechanism and value of the ventilatory response to hyperglycaemia await elucidation.
Acute hypoglycaemia is rare in healthy humans, but continues to blight the lives of people with insulin-treated diabetes more than 80 years since the discovery of insulin. Studies like those of Ward et al. (2007) will not suddenly transform the lives of people with diabetes, but they add to our incremental knowledge of the physiology of hypoglycaemia. Studies of hypoglycaemia are also of relevance in understanding the physiology of exercise and so further investigations in this area are certainly warranted.
References
Bin-Jaliah I, Maskell PD & Kumar P (2004). Indirect sensing of insulin-induced hypoglycaemia by the carotid body in the rat. J Physiol 556, 225–266.
Heller SR (2003). In Textbook of Diabetes, 3rd edn, ed. Pickup JC & Williams G. Blackwell Science, Oxford. p. 33.1–33.19.
King P & Macdonald IA (1999). In Frier BM & Fisher BM, ed. Hypoglycaemia in Clinical Diabetes. John Wiley & Sons, Chichester. p. 1–27.
Koyama Y, Coker RH, Stone EE, Lacy DB, Jabbour K, Williams PE & Wasserman DH (2000). Diabetes 49, 1342–1442.
Ward DS, Voter WA & Karan S (2007). J Physiol 582, 859–869.
Zhang M, Buttigieg J & Nurse CA (2007). J Physiol 578, 735–750.
Related Article
J. Physiol. 2007 582: 859-869.
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