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Hypoglycemia on the brain
HOUSTON—For individuals with type 1 or type 2 diabetes, tracking and managing their blood glucose levels is a fact of life. As it turns out, they have backup in this endeavor—certain neurons in the brain are also constantly monitoring blood sugar levels. A multi-institution research group led by Dr. Yong Xu, associate professor of pediatrics-nutrition and of molecular and cellular biology at Baylor College of Medicine, reported on these neurons in a paper published in Nature Communications under the title “Estrogen receptor-α expressing neurons in the ventrolateral VMH regulate glucose balance.”
According to the authors, glucose-sensing neurons are located in multiple areas throughout the brain, including the “ventromedial hypothalamic nucleus (VMH, also known as VMN), the arcuate nucleus (ARH), the paraventricular nucleus of the hypothalamus (PVH), the nucleus of solitary tract (NTS), and the medial amygdala.” The research team examined those found in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH). Among other biological factors, the VMH is associated with issues such as thermoregulation and registering hunger or satiety.
“Glucose-sensing neurons sense fluctuations in blood sugar levels and respond by rapidly decreasing or increasing their firing activities. This response can trigger changes in behavior to increase glucose levels. For instance, the animals may begin eating,” Xu explained. “Glucose-sensing neurons also can affect the production of hormones such as glucagon that can directly regulate glucose production or uptake by peripheral tissues. It’s a feedback system that keeps the balance of blood glucose.”
The researchers found that in the vlVMH of the mice they studied, all estrogen receptor-alpha neurons were glucose-sensing. Glucose-sensing neurons in the VMH are either triggered to greater activity when they sense high glucose levels (glucose-excited) or to decreased activity (glucose-inhibited). To get a clearer picture of how exactly these neurons sense glucose and how they respond, Xu and colleagues “used fiber photometry, optogenetics, and CRISPR-Cas9 approaches to identify the ionic and circuitry mechanisms by which these neurons sense glucose fluctuations and regulate blood glucose levels,” as noted in the Nature Communications paper.
According to a Baylor press release by Homa Shalchi, this led the team to a closer look at the ion channels each type of neuron utilizes. Glucose-excited neurons were found to use a KATP ion channel, while glucose-inhibited neurons used the Ano4 ion channel. Xu remarked that “The KATP ion channel is well known in our field, but the role of Ano4 ion channel in glucose sensing has never been reported. We have identified a new ion channel that is important for glucose-inhibited neurons.”
The differences between these two types of glucose-sensing neurons don't end at their response to glucose or their preferred ion channel, however. The team reported that glucose-excited and glucose-inhibited neurons use different circuits, projecting neuronal connection to different brain regions when they react to low blood sugar levels, as noted in Shalchi's article. Though the neurons utilized different circuits in the face of low glucose levels—glucose-inhibited neurons activated one circuit, while glucose-excited neurons inhibited a different circuit—the end result in both cases was an increase in blood glucose.
“This forms a perfect feedback system to regulate blood glucose levels,” Xu remarked.
As for where this research might lead in the future, the authors hope to explore whether or not estrogen or gender impact the glucose-sensing process, given the fact that all the neurons examined in this work express estrogen receptor-alpha.
Other institutions involved in this work included the University of Cincinnati, the University of Texas Health Science Center at San Antonio and the University of Texas Health Science Center at Houston.