Activation of Hindbrain Neurons Is Mediated by Portal-Mesenteric Vein Glucosensors During Slow-Onset Hypoglycemia

Abstract

Hypoglycemic detection at the portal-mesenteric vein (PMV) appears mediated by spinal afferents and is critical for the counter-regulatory response (CRR) to slow-onset, but not rapid-onset, hypoglycemia. Since rapid-onset hypoglycemia induces Fos protein expression in discrete brain regions, we hypothesized that denervation of the PMV or lesioning spinal afferents would suppress Fos expression in the dorsal medulla during slow-onset hypoglycemia, revealing a central nervous system reliance on PMV glucosensors. Rats undergoing PMV deafferentation via capsaicin, celiac-superior mesenteric ganglionectomy (CSMG), or total subdiaphragmatic vagotomy (TSV) were exposed to hyperinsulinemic–hypoglycemic clamps where glycemia was lowered slowly over 60–75 min. In response to hypoglycemia, control animals demonstrated a robust CRR along with marked Fos expression in the area postrema, nucleus of the solitary tract, and dorsal motor nucleus of the vagus. Fos expression was suppressed by 65–92% in capsaicin-treated animals, as was epinephrine (74%), norepinephrine (33%), and glucagon (47%). CSMG also suppressed Fos expression and CRR during slow-onset hypoglycemia, whereas TSV failed to impact either. In contrast, CSMG failed to impact upon Fos expression or the CRR during rapid-onset hypoglycemia. Peripheral glucosensory input from the PMV is therefore required for activation of hindbrain neurons and the full CRR during slow-onset hypoglycemia.

Circuit organization of sugar reinforcement

“…In fact, small infusions of intra-portal, but not intra-jugular, D-glucose produced robust dopamine release in dorsal striatum [29]. This is consistent with the notion that glucose, upon duodenal transport, activates metabolic sensors residing within the portal-mesenteric system [37, 38]. In flies, recent accounts identified novel sugar-sensing candidates residing in the Drosophila brain.…”

Hepatic glycogen can regulate hypoglycemic counterregulation via a liver-brain axis

“…Of note, altered neural feedback from the hepatoportal region to the brain has been previously shown to alter counterregulatory hormone secretion in the setting of hypoglycemia, albeit under very different experimental conditions. Elegant studies by Donovan and colleagues (24)(25)(26)(27) showed that denervation of the mesenteric region in the rat can alter the counterregulatory responses to insulin-induced hypoglycemia. This effect was only observed, however, when the fall in plasma glucose was slow (i.e., ~0.5 mg/dl/min), whereas disruption of neural input was of no consequence when the fall of the plasma glucose level was rapid (~1.3 mg/dl/min).…”

Peripheral and Central Glucose Sensing In Hypoglycemic Detection

“…However, when peripheral portal-mesenteric vein glucose sensors are eliminated, the counterregulatory response to slow onset hypoglycemia, i.e., Յ1 mg·dl Ϫ1 ·min Ϫ1 , is severely diminished (FIGURE 2) (97). Concomitant with the suppression in the CRR is a failure for hindbrain neuronal activation, as denoted by Fos expression under these conditions (10). Interestingly, lesioning catecholaminergic afferents projecting from the hindbrain to the hypothalamus results in a similar impaired response to slow-onset hypoglycemia (48).…”

“…Of the sensory CVOs, only the area postrema (AP) and subfornical organ (SFO) have been shown to contain glucose-sensing neurons (39,63). Although little is known regarding the potential contribution of the SFO in hypoglycemic detection, neurons in the AP do demonstrate robust Fos expression in response to systemic hypoglycemia and 2-deoxyglucose (10,80,100). There has been some suggestion that neurons of the arcuate nucleus may also be exposed to higher glucose concentrations, given their proximity to the median eminence (60).…”