This report was presented at a Physiological Society Themed Meeting on Orchestration of metabolism in health and disease, which took place at the University of Oxford, UK, 9–11 September 2008.
Dissociation between sensing and metabolism of glucose in sugar sensing neurones
Article first published online: 2 JAN 2009
© 2009 The Authors. Journal compilation © 2009 The Physiological Society
The Journal of Physiology
Volume 587, Issue 1, pages 41–48, January 2009
How to Cite
Gonzàlez, J. A., Reimann, F. and Burdakov, D. (2009), Dissociation between sensing and metabolism of glucose in sugar sensing neurones. The Journal of Physiology, 587: 41–48. doi: 10.1113/jphysiol.2008.163410
- Issue published online: 2 JAN 2009
- Article first published online: 2 JAN 2009
- (Received 16 September 2008; accepted after revision 22 October 2008; first published online 27 October 2008)
Some of the neurones controlling sleep, appetite and hormone release act as specialized detectors of ambient glucose. Their sugar sensing is conventionally thought to involve glucokinase-dependent metabolism of glucose to ATP, which then alters membrane excitability by modulating ATP-dependent channels or transporters, such as ATP-inhibited K+ channels (KATP). However, recent studies also provide examples of both glucose-excited (GE) and glucose-inhibited (GI) neurones that sense glucose independently of such metabolic pathways. Two-thirds of hypothalamic GE neurones in primary cultures are also excited by the non-metabolizable glucose analogue α-methylglucopyranoside (α-MDG), which acts as a substrate for electrogenic (depolarizing) sodium–glucose cotransporter (SGLT). The excitatory responses to both glucose and α-MDG are abolished by arresting SGLT activity by sodium removal or the SGLT inhibitor phloridzin. Direct depolarization and excitation by glucose-triggered SGLT activity may ensure that GE neurones continue to sense glucose in ‘high-energy’ states, when KATP channels are closed. A major class of hypothalamic GI neurones, the orexin/hypocretin cells, also appear to use a non-metabolic sensing strategy. In these cells, glucose-induced hyperpolarization and inhibition are unaffected by glucokinase inhibitors such as alloxan, d-glucosamine, and N-acetyl-d-glucosamine, and mimicked by the non-metabolizable glucose analogue 2-deoxyglucose, but not by stimulating intracellular ATP production with lactate. The dissociation between sensing and metabolism of sugar may allow the brain to predict and prevent adverse changes in extracellular glucose levels with minimal impact on the flow of intracellular fuel.