Researchers discovered how the vagus nerve relays signals from the periphery to the brain to help regulate glucose


Theodoros Zanos, Ph.D., head of the Neural & Data Science Lab & assistant professor at the Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, and his collaborators, discovered how the vagus nerve relays signals from the periphery to the brain to help regulate glucose, potentially uncovering a new way to measure blood glucose levels.

This finding progresses research into future bioelectronic medicine treatments and diagnostics for metabolic syndrome and diabetes.

The findings were published today in the Springer Nature journal, Bioelectronic Medicine.

In humans, glucose is the primary sugar for high energy demanding cells in brain, muscle and peripheral neurons.

Any deviation of normal blood glucose levels for an extended period of time can be dangerous or even fatal, so regulation of blood glucose levels is a biological imperative.

Prior research showed that the vagus nerve, which connects to many major organs in the body and communicates changes in the body to the brainstem, plays a role in regulating metabolism.

Because the specifics of how this was accomplished were largely unknown, Dr. Zanos and his colleagues’ sought to identify the specific signals relayed from the periphery to the brain that responded to changes in glucose levels.

By deciphering these signals, they can better understand when and how to stimulate the vagus nerve to regulate metabolism.

“One of our goals is to understand the neural code of the vagus nerve as it related to different conditions, because we believe by listening to and stimulating this nerve, we can open new possibilities to diagnose and treat various diseases,” said Dr. Zanos.

“The vagus nerve is one of the major information conduits of the body with an average of 100,000 nerve fibers, making this code difficult to pick up and decipher, so we have a lot to learn.

We’re excited to demonstrate in this most recent study that the vagus nerve of a mouse transports important signals from the periphery to the central nervous system related to glucose homeostasis – this discovery gets us closer to new technologies that will have the potential of helping many patients living with various metabolic diseases.”

Dr. Zanos collaborated on this study with Feinstein Institutes researchers Emily Battinelli Masi, Ph.D., Todd Levy, MS, Tea Tsaava, MD, Chad E. Bouton, MS, and Sangeeta S. Chavan, Ph.D. Also co-authoring the article, titled “Identification of hypoglycemia-specific neural signals by decoding murine vagus nerve activity,” was Feinstein Institutes President and CEO Kevin J. Tracey, MD.

“This discovery by Dr. Zanos and our bioelectronic medicine researchers give us new understanding of the body’s neural signaling and offers hope for diabetes management,” said Dr. Tracey.

Bioelectronic medicine is a new approach to treating and diagnosing disease and injury that has emerged from the Feinstein Institutes’ labs.

It represents a convergence of molecular medicine, neuroscience and bioengineering. Bioelectronic medicine uses device technology to read and modulate the electrical activity within the body’s nervous system, opening new doors to real-time diagnostics and treatment options for patients.

Last year, Dr. Zanos and his collaborators were the first to decode specific signals the nervous system uses to communicate immune status and inflammation to the brain.

Identifying these neural signals and what they’re communicating about the body’s health was a step forward for bioelectronic medicine as provided insight into diagnostic and therapeutic targets, and device development.

Those findings were published in Proceedings of the National Academy of Sciences (PNAS).

  • Vagal afferent nerve terminals innervate layers of the gastrointestinal wall to sense nutrient-related hormonal and/or mechanical signals and trigger neuronal transmission to the central nervous system to affect metabolic homeostasis.
  • Nutrient-dependent hormonal and mechanical stimulation in the stomach and the intestine regulate feeding through the vagal afferent network.
  • Nutrient-dependent hormonal stimulation in the intestine regulates glucose homeostasis through the vagal afferent network.
  • Manipulating gut nutrient-dependent and vagal-dependent afferent firing represents a potential novel therapeutic strategy for obesity and diabetes.

Vagal nerve stimulation (VNS) has been considered a potential treatment option for patients with a variety of diseases including obesity (Masi et al. 2018), heart failure (De Ferrari et al. 2011; Premchand et al. 2014; Zannad et al. 2015; Gold et al. 2016), chronic pain (Chakravarthy et al. 2015), migraine (Grimsrud and Halker Singh 2018), and tinnitus (De Ridder et al. 2014).

Based on the anti‐inflammatory effects of the parasympathetic nervous system (Tracey 2002; Komegae et al. 2018), currently explored therapeutic targets for VNS also include a variety of inflammatory diseases, such as rheumatoid arthritis (Koopman et al. 2017) and Crohn’s disease (Bonaz et al. 2016).

Currently, VNS is FDA‐approved for the treatment of therapy‐refractory epilepsy (Nune et al. 2015) and major depression (Cristancho et al. 2011).

In these conditions the cervical vagus nerve is chronically stimulated through an implanted device (Giordano et al. 2017) and the therapeutic effects are thought to be mediated through afferent signaling to the central nervous system (Groves and Brown 2005; Krahl and Clark 2012).

However, in a previous study (Meyers et al. 2016), we demonstrated that afferent signaling evoked by cervical VNS inhibits insulin secretion and markedly increases resting blood glucose levels in anesthetized rats, raising the question if patients treated with cervical VNS are at risk of developing glucose intolerance.

Specifically, selective afferent cervical VNS (achieved by stimulating the cranial end of the sectioned cervical vagus nerve) caused a marked and sustained increase in blood glucose levels without concomitant increase in insulin serum concentration.

The same hyperglycemic response was observed during stimulation of the intact cervical vagus nerve that was not dissected and, thus consisted of combined afferent and efferent VNS.

In contrast, selective efferent stimulation (achieved by stimulating the peripheral end of the sectioned cervical vagus nerve) caused a small temporary increase in blood glucose concentration followed by an increase in serum insulin levels.

The latter finding is consistent with a study by Peitl et al. (2005) that also demonstrated an increase in insulin plasma levels during electrical stimulation of the peripheral end of the cervical vagus nerve in anesthetized rats.

Afferent signaling was not tested in this study because the cranial end or the intact vagus nerve was not stimulated.

Thus, the conclusion of our previous study (Meyers et al. 2016) was that selective efferent VNS may potentially be effective in treating type 2 diabetes through stimulation of pancreatic insulin release, while stimulating the intact nerve (combined efferent and afferent VNS) may reduce glucose tolerance by suppression of insulin release via afferent VNS.

Indeed, studies in animals suggest that chronic stimulation of vagal nerve branches other than the cervical vagus nerve may have beneficial effects on glucose metabolism.

For example, chronic bilateral stimulation of the subdiaphragmatic vagal nerves improved insulin sensitivity in diet‐induced obesity in mini‐pigs (Malbert et al. 2017) and transcutaneous auricular vagus nerve stimulation prevented the increase in blood glucose levels and glycosylated HbA1c in Zucker diabetic fatty rats (Li et al. 2014).

Thus, it is possible that stimulation of more peripheral branches of the vagus nerve (e.g., subdiaphragmatic) improves glucose metabolism through efferent signaling to metabolic end‐organs, such as the pancreas or the liver.

However, in the majority of the patients treated with VNS, stimulation occurs at the site of the cervical vagus nerve and both, efferent and afferent nerve fibers are activated.

Thus, despite the reports from animal studies suggesting beneficial metabolic effects of VNS at more peripheral sites than the cervical vagus nerve (Li et al. 2014; Malbert et al. 2017) or with selective efferent cervical VNS (Peitl et al. 2005; Meyers et al. 2016), the question if non‐selective (combined efferent and afferent) VNS at the site of the cervical vagus nerve may deteriorate glucose tolerance and place patients at risk for type 2 diabetes is highly relevant and important because our previous study demonstrated inhibition of insulin release despite marked increases in blood glucose levels during non‐selective (intact nerve) and selective afferent (dissected nerve) cervical VNS.

To further explore this question, we hypothesized that chronic cervical VNS of the intact vagus nerve inhibits glucose‐induced insulin release and, thus, impairs glucose tolerance in conscious rats.

To test this hypothesis, we performed glucose tolerance tests during VNS and sham stimulation in conscious chronically instrumented rats.

Sectioning the vagus nerve to achieve selective afferent or efferent VNS required us to perform our previous study (Meyers et al. 2016) during anesthesia.

Anesthesia can potentially inhibit insulin release (Desborough et al. 1993).

Thus, it was important to test the hypothesis of our current study in conscious animals.

Journal information: Proceedings of the National Academy of Sciences
Provided by Northwell Health’s Feinstein Institute for Medical Research


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