Glucose and the vagus: sensory cells savour sweet substances

While glucose is the ubiquitous fuel for all types of cells, including mammalian neurons, some neurons possess the additional ability to sense fluctuations in glucose levels and use these variations as a means to alter their activity. Within the central nervous system, for example, nucleus tractus solitarii (NTS) neurons within the brainstem can respond to glucose with either a decrease in activity (glucose-sensitive or glucose-inhibited neurons) or an increase in activity (glucose-responsive or glucose-excited neurons). NTS neurons appear different, however, from other central nuclei such as the lateral, ventromedial and arcuate hypothalamic nuclei where generally only one population of neurons (glucose excited or glucose inhibited), but not both, are present (Routh, 2002). Blood glucose levels fluctuate throughout the day and increase dramatically following ingestion of a meal. Adaptive sensory and motor responses of the autonomic nervous system to these ongoing alterations in glucose levels are necessary to stabilize these oscillations and maintain homeostasis. Effective and appropriate homeostasis requires the integration of a wide range of different visceral signals with neuronal, hormonal and metabolic signals to maintain a suitable effector response. In this regard, altering gastric emptying is a critical mechanism by which the rate of absorption, and hence blood glucose levels, can be controlled. An increase in gastric motility (as seen following hypoglycaemia) can accelerate fuel absorption and re-establish plasma glucose levels whereas a hyperglycaemia-mediated decrease in gastric motility reduces further glucose absorption and prevents potentially dangerous episodes of prolonged elevated glucose levels (Rayner et al. 2001). Vagally mediated reflex pathways are clearly important in the homeostatic regulation of gastrointestinal functions. The cell bodies of vagal sensory neurons lie within the paired nodose ganglia and serve the classic afferent functions, including sensory transduction, somatic processing and neurotransmitter release. They also contribute to body homeostasis by relaying to the CNS the changing conditions of the internal milieu, including changes in blood glucose levels. Both human and animal studies have provided evidence for the presence of a portal glucose ‘sensor’ and the firing rate of glucose-sensitive hepatic vagal afferents is decreased by glucose in the portal vein (Niijima, 1982). In contrast, glucose within the intestinal tract induces an excitation of vagal sensory nerve fibres (Mei, 1978). Less recognized, until recently perhaps, is the observation that intravenous glucose is also able to modulate the response of vagal afferent nerve fibres to intraluminal glucose. This would suggest that circulating glucose may directly modulate the activity and sensitivity of vagal sensory neurons to intraluminal glucose (Mei, 1978). In a recent issue of The Journal of Physiology, Grabauskas et al. (2010) have confirmed and elaborated on this early observation by demonstrating, for the first time, that the activity of vagal afferent sensory neurons is sensitive to blood glucose levels. Specifically, vagal afferent sensory neurons display either glucose-excited or glucose-inhibited properties. Furthermore, these attributes appear differentially distributed with respect to the afferent neurons’ target organ; neurons innervating the stomach, for example, are more likely to display excitatory responses to glucose while neurons innervating the portal vein have a higher incidence of inhibitory responses to glucose. These authors concluded that the glucose-induced excitation of vagal sensory neurons most likely involves the closure of an ATP-sensitive potassium channel in a manner similar to the canonical model in pancreatic β-cells. In contrast, the glucose-induced inhibition of vagal sensory neurons appears to involve an ATP-insensitive potassium channel although the precise nature of the current(s) involved remains to be elucidated. At face value, this suggests simply that the activity of gastric or hepatic vagal sensory neurons is open to modulation by circulating blood glucose levels. At a more integrative level, however, it could be interpreted to imply that gastrointestinal sensation, or indeed, visceral sensory ‘perception’ in general, is regulated in an ongoing and flexible manner by, for example, feeding status, stress level, glycaemic condition or, indeed, any other circumstance during which blood glucose levels may be altered. It seems likely, therefore, that glucose activates (or modulates) vagal sensory signalling via actions at multiple sites. This certainly may result in amplification of the sensory signal, but it also may serve to prolong the signal. Several lines of evidence have demonstrated that intraluminal glucose excites gastrointestinal vagal sensory nerve terminals indirectly, via activation of 5-HT3 receptors subsequent to glucose-induced release of 5-HT from enteroendocrine cells (Raybould et al. 2003). One may reasonably expect this to be the site of initial vagal afferent activation by glucose. The recent article by Grabauskas et al. suggests that glucose is also capable of activating gastrointestinal vagal sensory neurons directly. This presumably occurs over a longer time course, secondary to glucose absorption and an elevation in circulating blood glucose levels. Extending such observations further, one may also consider that the central terminals of vagal afferents may be a yet later site of activation, assuming CNS assimilation of alterations in peripheral glucose levels (Wan & Browning, 2008). From the point of view of vagally mediated homeostatic reflex control, this would ensure a rapid but also sustained efferent vagal GI response following glucose ingestion, inducing gastric relaxation and delaying gastric emptying. This may also go some way towards explaining the profound gastrointestinal disturbances observed frequently during diabetes or glycaemic dysregulation and provide additional information critical to the management of patients with gastrointestinal complications.