Modulation of gastrointestinal vagal neurocircuits by hyperglycemia

Abstract

Glucose sensing within autonomic neurocircuits is critical for the effective integration and regulation of a variety of physiological homeostatic functions including the co-ordination of vagally-mediated reflexes regulating gastrointestinal (GI) functions. Glucose regulates GI functions via actions at multiple sites of action, from modulating the activity of enteric neurons, endocrine cells, and glucose transporters within the intestine, to regulating the activity and responsiveness of the peripheral terminals, cell bodies and central terminals of vagal sensory neurons, to modifying both the activity and synaptic responsiveness of central brainstem neurons. Unsurprisingly, significant impairment in GI functions occurs in pathophysiological states where glucose levels are dysregulated, such as diabetes. A substantial obstacle to the development of new therapies to modify the disease, rather than treat the symptoms, are the gaps in our understanding of the mechanisms by which glucose modulates GI functions, particularly vagally-mediated responses and a more complete understanding of disease-related plasticity within these neurocircuits may open new avenues and targets for research.

Molecular and functional changes in glucokinase expression in the brainstem dorsal vagal complex in a murine model of type 1 diabetes

“…Despite this hypothalamic focus, abundant evidence indicates that brainstem dorsal vagal complex (DVC) plays a primary and critical role in glucose-sensitive modulation of plasma glucose and insulin levels, feeding and energy balance Zsombok and Smith 2009). Subsets of DVC neurons and synaptic terminals are glucose-sensitive (Balfour et al 2006;Boychuk et al 2015a;Browning 2013;Lamy et al 2014;Wan et al 2008), consistent with longstanding evidence that glucose-sensing neurons in this region regulates both feeding and blood glucose concentrations . Injection of a glucoprivic glucose analogue into the vagal complex, but not hypothalamic areas, increases both feeding and hyperglycemia in rats .…”

“…These effects persisted for hours (at least) after glucose was standardized to control levels in vitro. In addition to insulin-dependent receptor trafficking (Zsombok et al 2011), postsynaptic and action potential responses to glucose of specific sets of vagal complex neurons are suppressed in this model after several days of hyperglycemia (Browning 2013). Thus, chronic glycemic dysregulation in diabetes is accompanied by altered neuronal function in the DVC.…”

“…Vagal motor activity is tightly regulated by synaptic inputs arising from GABA and glutamate neurons of the adjacent nucleus NTS (Davis et al 2004;Travagli et al 1991), and NTS neurons also project to other central autonomic regulatory centers. As a unit, primary viscerosensory afferents, second-order sensory neurons in the NTS, and preganglionic parasympathetic vagal motor neurons in the DMV mediate vago-vagal reflexes-includes cardiovascular and gastrointestinal reflexes (Browning 2013;Travagli et al 2006). These reflexes can often be modulated by synaptic input from other brain areas and, at least for the NTS, by substances in the blood (e.g., glucose).…”

“…Neurons in the NTS normally respond to elevated or reduced glucose concentration with either increases or decreases in excitability (Balfour et al 2006;Boychuk et al 2015a;Browning 2013;Lamy et al 2014;Wan et al 2008), which are often GCK-dependent.…”

“…The NTS consists of a heterogeneous population of cells, which incorporate mechanical and chemical stimuli from periphera l organs with centrally derived neuronal information as well as signals mediated by circulating hormones and metabolites. The NTS integrates this information and transmits to other autonomic centers, including the dorsal motor nucleus of the vagus nerve (DMV) (Browning 2013;Travagli et al 2006). The DMV contains preganglionic motor neurons that project to all thoracic and most subdiaphragmatic peripheral organs.…”