Primary Health Care: Open Access

The Vagal Nerve, Inflammation, and Diabetes: A Triad of Significance

Emily Ashford^{* *}Correspondence: Emily Ashford, Editorial Board, Primary Health Care: Open Access, UK, Email:

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Introduction

Diabetes mellitus is a chronic condition that disrupts the body's normal glucose utilization process, resulting in difficulties in managing and regulating blood glucose levels. This condition is categorized into two primary subtypes: type 1 and type 2.

Type 1 diabetes mellitus (T1DM)

It is also known as insulin-dependent diabetes mellitus, is an autoimmune disorder characterized by the destruction of insulin-producing beta cells in the pancreas by T lymphocytes. This destruction leads to a deficiency in insulin production, as the pancreas becomes incapable of generating insulin. The development of T1DM can be initiated by a combination of genetic and environmental factors. It can progress rapidly in the case of early-onset in children and adolescents or gradually in the case of lateonset in adults.

Type 2 diabetes mellitus (T2DM)

It is non-insulin dependent but is also characterized by insufficient insulin levels. However, the underlying cause of T2DM is an impaired interaction between insulin in the bloodstream and the cells' reduced sensitivity to insulin. Normally, insulin's primary function is to facilitate the entry of glucose from the bloodstream into cells. In T2DM, beta cells are under intense pressure to produce excess insulin in an attempt to lower elevated blood glucose levels, which result from cells' resistance to insulin. This strain on beta cells leads to their malfunction. The development of T2DM is predominantly influenced by factors such as obesity and aging. It is wellestablished that T2DM also has a stronger genetic component compared to T1DM. Typically, T2DM manifests in adulthood, but the increasing prevalence of obesity in youth has contributed to a rise in its occurrence among younger individuals as well.

The role of inflammation in Diabetes Mellitus

Inflammation represents the body's natural defense mechanism, activated in response to threats like bacteria and toxins. It serves to safeguard the body, promote tissue healing, and recovery. When inflammation is mild and shortlived, it plays a protective role. However, over recent decades, persistent systemic inflammation has been linked significantly to the initiation and advancement of major life-threatening conditions, including cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. Inflammation plays a pivotal role in the development and progression of diabetes. Studies have revealed a connection between chronic, low-grade inflammation and insulin resistance, a well-known characteristic of Type 2 Diabetes (T2DM). Inflammation triggers the activation of pro-inflammatory cytokine signals that interfere with the insulin receptors on beta cells within the pancreatic islets. This interference hinders the body's ability to respond effectively to insulin. Inflammation also disrupts the transmission of insulin signals within cells, making it more challenging for the body to respond adequately to insulin, a phenomenon known as insulin resistance, which is a hallmark of T2DM.

Role of the vagus nerve in DM

The vagus nerve, also known as the 10th cranial nerve, plays a significant role within the parasympathetic nervous system. Currently, the most effective non-invasive method for assessing vagal nerve activity is through the measurement of heart-rate variability (HRV), which involves observing the fluctuations in the time intervals between regular heartbeats. Remarkably, there exists a profound and robust correlation between HRV and actual vagal nerve activity, with a correlation coefficient of 0.88 .One indirect approach to investigating the vagus nerve's involvement in type 2 diabetes mellitus (T2DM) is by exploring the link between psychological stress and T2DM, as stress exhibits an inverse correlation with HRV, as supported by a review encompassing 37 studies. In a noteworthy longitudinal study featuring 12,844 Australian women initially devoid of diabetes, those who reported experiencing moderate to high levels of stress were found to have a 2.3-fold higher risk of developing diabetes later in life. Importantly, this association remained statistically significant even after accounting for factors such as hypertension, smoking, and other potential confounding variables.

The evidence linking vagal nerve activity with diabetes is supported by a comprehensive meta-analysis of 25 case-control studies involving 1356 diabetic patients and 1576 healthy controls. This analysis demonstrated that various heart-rate variability (HRV) parameters, both in the time domain (such as SDNN and RMSSD) and the frequency domain (including HighFrequency (HF) and low-frequency (LF) HRV), were significantly lower in diabetic patients compared to their healthy counterparts. Interestingly, blood glucose levels were found to be significantly associated with elevated levels of certain HRV parameters, such as HF-HRV and RMSSD.In addition to case-control studies, a unique longitudinal study conducted on 9192 individuals in Brazil further contributed to this evidence. It revealed that lower HRV, as measured by parameters like Standard Deviation of the NN (R-R) intervals (SDNN), RMSSD, proportion of NN intervals larger than 50 msec divided by the total number of NN (R-R) intervals (pNN50), HF-HRV, and LF-HRV, significantly predicted a higher risk of developing diabetes .Furthermore, while not an experimental study, another investigation compared diabetic patients with well-controlled blood glucose levels to diabetic patients with poorly controlled glucose levels and healthy controls in terms of HRV. This comparison likely provided additional insights into the relationship between vagal nerve activity and diabetes.

Vagal nerve activation: anti-Inflammatory effects

A recent article conducted an insightful review of the scientific literature regarding the vagal nerve's regulation of inflammation, often referred to as the cholinergic anti-inflammatory pathway. The foundation of this body of knowledge lies in the fields of neuroimmunology and psychoneuroimmunology. Multiple neurobiological pathways have been identified through which the vagal nerve effectively modulates and inhibits excessive inflammation. Firstly, vagal nerve paraganglia express receptors for peripheral interleukin-1 (IL-1), a prominent inflammatory cytokine that may play a crucial role in the progression of type 2 diabetes (T2DM). Following this initial recognition, several anti-inflammatory pathways are activated to manage peripheral inflammation.

The first pathway is a central neuro-hormonal route involving the Hypothalamic-Pituitary-Adrenal (HPA) axis. This pathway is initiated when afferent vagal signals convert the peripheral IL-1 signal into acetylcholine, subsequently activating the hypothalamus. This activation triggers the HPA axis to release cortisol, which exerts a well-known anti-inflammatory effect.The second pathway is an efferent neuro-immunological one, where efferent vagal fibers reach the celiac ganglion and transform into a sympathetic branch that innervates the spleen. Within the spleen, a subset of specialized T-cells known as "cholinergic T-cells," particularly CD4+ CD44high CD62low Chat EGFP+ cells, have been identified. These unique Tcells, like other T-cells, express beta-adrenergic receptors that receive sympathetic signals. When the beta-adrenergic receptor of these "cholinergic T-cells" is activated, they produce the vagal neurotransmitter Acetylcholine (Ach). Ach then binds to its receptor, the alpha-7-nicotinic Ach receptor, on splenic macrophages. This signaling ultimately leads to a reduction in the synthesis of pro-inflammatory cytokines by the macrophages. Additionally, it's suggested that there may be other routes through which the vagal nerve modulates inflammation. These potential pathways include direct innervation of the spleen by the vagus nerve, vagal stimulation of intestinal segments, and vagal stimulation of the adrenal gland, resulting in the secretion of dopamine. Further research is needed to clarify these additional mechanisms and their roles in the regulation of inflammation.

In addition to its significant anti-inflammatory role, the vagus nerve exerts a multitude of effects that position it as a factor of potentially greater importance than other risk factors in the context of diabetes. Activating the vagus nerve has been found to contribute to the reduction of food cravings in individuals with high appetites for food . Furthermore, heart rate variability (HRV) tends to increase with increased physical activity, including resistance exercise, particularly among middle-aged individuals. This increase in HRV is critical for the prevention of Type 2 Diabetes (T2DM).It's important to recognize that the vagus nerve exhibits robust and extensive bidirectional effects not only on behavioral lifestyle factors like diet, exercise, and smoking but also on biological mediators such as oxidative stress, inflammation, and sympathetic hyperactivity. These effects have been conceptualized within a neuroimmunological framework of lifethreatening diseases. This framework underscores the central role of the vagus nerve in predicting and preventing various diseases, underscoring its significance as a key player in maintaining health and well-being.

Effects of vagal nerve activation in Diabetes

While numerous studies have investigated the relationship between Heart Rate Variability (HRV) and Diabetes Mellitus (DM), there are relatively fewer studies that have explored the impact of vagal nerve activation on clinical outcomes in DM. These investigations include experiments conducted in animals and the application of HRV biofeedback in patients with DM, which I will now elaborate on.In animal studies, vagal stimulation can be achieved through vagomimetic activation at the cellular level using drugs and electrical vagal nerve stimulation. For instance, in an experimental study involving Sprague Dawley rats, celiac vagal transection was shown to reduce beta-cell proliferation by 50%. These findings suggest that the vagus nerve may have a significant influence on pancreatic beta-cell proliferation, which could be particularly important during periods of heightened demand for insulin .

Another study conducted on isolated beta cells demonstrated that muscarinic (vagal) stimulation resulted in increased glucose-induced betacell proliferation, while adrenergic stimulation had the opposite effect Furthermore, one study induced an animal model of type 2 diabetes (T2DM) and investigated the effects of implanted efferent Vagal Nerve Stimulation (eVNS) on glycemia. It was consistently observed that eVNS reduced glycemia, and a specific dose was found to be the most effective in achieving this outcome in these rats.

In another notable study, researchers replicated the effects of transcutaneous Auricular Vagal Nerve Stimulation (taVNS) in diabetic rats and compared it to a control stimulation group. The taVNS intervention resulted in several beneficial outcomes, including reduced body weight, lower levels of blood glucose, and a decrease in depressive-like behavior when compared to the control group. Furthermore, vagus nerve stimulation has been associated with improvements in glucose metabolism and insulin secretion. For example, it exerts a significant influence on GLP (glucagonlike peptide), an essential gastrointestinal hormone that plays a crucial role in glucose regulation by mediating the regulatory effects of both its peripheral and central production on metabolism.

However, it's important to note that studies investigating the impact of vagus nerve stimulation on glucose control have yielded inconsistent findings. Some studies have reported improved glucose management following vagus nerve stimulation, while others have not observed such beneficial effects. For instance, one study compared the effects of vagus nerve stimulation combined with pharmacotherapy versus pharmacotherapy alone in patients with epilepsy, where implanted vagus nerve stimulation has been approved for several decades. Interestingly, no significant differences in blood glucose levels were observed between the two groups. This variability in findings underscores the need for further research to better understand the nuanced effects of vagus nerve stimulation on glucose regulation and its potential implications for diabetes management.

Conclusion

There is a growing interest in utilizing Heart Rate Variability (HRV) as a potential risk marker for the development of diabetes, as well as an increasing focus on HRV-biofeedback as a promising technique for managing Diabetes Mellitus (DM). This interest is well-founded, especially considering that cardiovascular disease is a common complication of diabetes. Monitoring the progression of diabetes through HRV can offer valuable insights, given that diabetic patients often exhibit reduced HRV. Furthermore, reduced HRV is associated with a higher risk of cardiovascular disease and increased mortality following a myocardial infarction (MI) Another potential therapeutic application of HRV in the context of diabetes is the use of HRV-based interventions to enhance the regulation of blood glucose levels. For instance, research has demonstrated that HRV-based interventions such as yoga or exercises involving deep breathing can lead to improvements in both HRV and glucose regulation in individuals with Type 2 Diabetes (T2DM) . Integrating such interventions into diabetes treatment plans has the potential to reduce the risk of complications associated with diabetes. However, it's essential to emphasize that the effects of HRVbiofeedback on T2DM should be rigorously examined through Randomized Controlled Trials (RCTs). These trials would help establish a causal relationship and provide clinical evidence regarding the impact of vagal activation in the context of this condition.