Is There Cross Talk Between Portal and Hypothalamic Glucose-Sensing Circuits?

The detection of hypoglycemia stems from sensors located in both the periphery and within the central nervous system and likely involves a complex circuit that incorporates information from both peripheral and central components. Glucose sensors located in each of these regions play a unique role in hypoglycemia detection that appears to be at least in part dependent on the rate of fall of blood glucose levels. Sensors that are located within the brain, particularly those located within the ventromedial hypothalamus (VMH), appear to dominate when glucose levels fall rapidly (1–3). While still speculative, it has been proposed that this may serve as a protective fail-safe mechanism that is put in place to prevent a sudden and potentially catastrophic depletion of fuel supply to the brain. On the other hand, glucose sensors located in the portal-mesenteric vein (PMV) have been proposed to be more important for detecting a gradual decline in blood glucose levels (4–6). Interestingly, it has recently been suggested that central and peripheral sensors appear to operate independently from one another as lesions that are made to PMV sensors do not influence the ability of central sensors to detect rapid-onset hypoglycemia but did prevent the detection of slow-onset hypoglycemia (7). This implies that these two sets of hypoglycemia sensors may exert differential roles in glucose sensation and glucose counterregulation and that they are not merely redundant mechanisms. Hypoglycemic signals from PMV glucose sensors that are transmitted to the central nervous system appear to use central pathways that are independent from those used by hypothalamic centers. Although much of our current understanding of glucosesensing mechanisms stems from work that was conducted in the VMH of the brain (8), the existence of a relay circuit between PMV sensors, the brain, and the sympathoadrenal system has been postulated for some time (9–11). Moreover, the reliance of PMV sensors on central nervous system networks to relay their message to peripheral targets has not been explored to date. This brings into question which brain regions are crucial for integrating and transmitting glucoprivic signals derived from PMV glucose sensors to regulate sympathoadrenal responses during slow-onset hypoglycemia and whether these systems overlap with neural circuits generated in the VMH that regulate the sympathoadrenal responses during rapid-onset hypoglycemia. In this issue, there are two articles presented by the research groups of Donovan and Watts at the University of Southern California that explore the PMV circuit in more detail (12,13). The first article by Bohland et al. (12) identified the crucial PMV sensor-brain arm of the circuit using some elegant denervation studies. Here, the authors either used capsaicin to denervate PMV sensors or they eliminated spinal afferents from the portal and superior mesenteric veins using celiac-superior mesenteric ganglionectomy (CSMG) or they removed vagal afferents from the PMV using a total subdiaphragmatic vagotomy. These three different forms of lesions helped to identify the role of PMV glucose sensors and establish whether hypoglycemic signals from the PMV are carried to the hindbrain via spinal or vagal afferents, respectively. They then subjected the animals to either a slowor rapid-onset hypoglycemic clamp to identify the effect of these manipulations on the counterregulatory hormone responses. They demonstrated that PMV denervation blunts the counterregulatory responses to slow-onset hypoglycemia, and this was associated with a substantial reduction in Fos-labeled nuclei within hindbrain centers, including the area postrema, the nucleus of the solitary tract, and the dorsal motor vagal complex, that receive PMV projections. Lesioning of the spinal afferents with CSMG reduced counterregulatory hormone responses to slow-onset hypoglycemia, and this was associated with a reduction in