**2.3 Acetylcholine and metabolic diseases**

### *2.3.1 Diabetes*

Type 1 diabetes (T1D) is an autoimmune condition characterized by autoreactive T lymphocytes destroying insulin-producing -cells in the pancreatic islets of Langerhans. The illness begins with the loss of -cells in individuals with a genetic predisposition and under particular environmental conditions, followed by the migration and activation of inflammatory cells (T and B cells, myeloid, and natural killer cells) to the islets, resulting in insulitis [35]. The vagus nerve innervates the pancreas via parasympathetic nerve terminals that produce the neurotransmitter acetylcholine (ACh). ACh, in turn, can bind to the nAChRs and mAChRs expressed on pancreatic cells, controlling pancreatic metabolic activities such as glucose homeostasis. Increased vagal activity stimulates insulin production by activating mAChRs on pancreatic cells. Although -cells appear to express a variety of muscarinic receptor subtypes, M3 mAChR is the most numerous and the one that mediates insulin release. M3 mAChR of pancreatic cells deficient mice had poor glucose tolerance and considerably lower insulin secretion. Mice overexpressing pancreatic M3 mAChR, on the other hand, had increased glucose tolerance and insulin production. There is additional evidence that pancreatic -cells functionally express distinct nAChR subunits although the role of these receptors in -cell function is still debated. While some studies found that nAChR agonists had no effect on hyperglycemia or -cell function, others found that administering particular 7nAChR agonists lowered hyperglycemia in diabetic animal models [36]. The vagus nerve also connects the central nervous system and the immune system via the cholinergic anti-inflammatory pathway, where ACh inhibits the production of pro-inflammatory cytokines (TNF, IL-6, HMGB1), reducing the inflammatory response in sepsis and inflammatory disorders. The 7nAChR, in particular, has been linked to the suppression of pro-inflammatory cytokine production by macrophages, as well as other immunological processes such as T cell death and the suppressive activity of T regulatory cells. In addition, the presence of a cholinergic system in non-neuronal cells, including immunocompetent cells, has been well established. These cells include the enzymes choline acetyltransferase

(Chat) and acetylcholinesterase (AChE), as well as the choline transporters required for ACh synthesis. Furthermore, immune cells express both muscarinic and nicotinic ACh receptors, suggesting that the cholinergic system is involved in immune response control. The 7nAChR is expressed on neutrophils, macrophages, B and T cells, and dendritic cells, as well as enterocytes, endothelium, and microglial cells, and has been linked to the pathophysiology of autoimmune disorders. Activating the cholinergic nerve system with particular acetylcholinesterase inhibitors (AChEI) prevents the occurence of hyperglycemia and experimental diabetes [36].

#### *2.3.2 Diabetes heart disease*

Diabetes heart disease (DHD) is the leading cause of mortality in diabetics, accounting for more than 80% of fatalities. This high fatality rate is notable in light of major advances in modern health-care systems and diabetes therapy. Insulin sensitivity and metabolic disturbances in type 2 diabetes mellitus (T2DM) restrict glucose homeostasis in the heart by downregulating the expression of glucose transporter-4 (GLUT-4). Continued exposure to metabolic changes worsens vascular permeability, leading to coronary artery disease (CAD) and coronary microvascular disease (CMVD). CAD and CMVD reduce coronary artery blood circulation and myocardium perfusion, increasing heart muscle stress and promoting the onset of DHD [37]. Prior literature has shown that cardiomyocytes have a robust inherent cholinergic machinery called the non-neuronal cholinergic system (NNCS). The NNCS in cardiomyocytes is made up of many components that work together to keep acetylcholine (ACh) homeostasis and allow ACh to serve as an autocrine/paracrine mediator. These components are choline acetyltransferase (ChAT) to synthesize ACh; choline transporter1 (CHT1) for the reuptake of choline into the cardiomyocytes for ACh synthesis; vesicular ACh transporter (VAChT) to store and release ACh; acetylcholinesterase (AChE) to degrade ACh in the extracellular space as well as type-2 muscarinic ACh receptor (M2AChR) for ACh binding and signal transduction. ACh secreted by cardiomyocytes functions as an autocrine/paracrine mediator. Its interaction with M2AChR activates the pro-survival phosphatidylinositol-3-kinase (PI3K)/ protein kinase B (Akt)/hypoxia-inducible factor 1-alpha (HIF1) signaling cascade. It has been observed that activating this pathway increases the activation of downstream effectors such as (1) glucose transporter-4 (GLUT-4) to promote glucose absorption and energy preservation and (2) vascular endothelial growth factor (VEGF) to promote angiogenesis. However, the role of cardiac NNCS in DHD pathogenesis is uncertain. This is especially important since diabetes is linked to impaired glucose homeostasis, cell survival, and angiogenesis [38].

#### *2.3.3 Adipose tissue dysfunction (obesity-related diseases)*

The nicotinic acetylcholine receptor 3 subtype (3-nAChR) is essential for controlling inflammatory responses. Inflammation causes adipose tissue malfunction, which raises a likelihood of cardiac and metabolic illness.

Obesity is now recognized as a key contributor to a variety of chronic illnesses, incorporating inflammatory & blood-vascular & disorders [39]. Increase in the body's most efficient energy storage tissue called White Adipose Tissue (WAT) leads to obesity because of the fact that WAT produces adipokines. These adipokines are responsible for several pathological processes like inflammation and insulin resistance. Furthermore, obesity causes aberrant productions of inflammatory cytokines and

### *Role of Acetylcholine in Chronic Diseases DOI: http://dx.doi.org/10.5772/intechopen.110663*

other adipokines from WAT, which can be interpreted as adipose tissue malfunction. Obesity-induced adipose tissue dysfunction always results in persistent low-grade inflammation, which frequently leads to poor organ connections and metabolic abnormalities in various tissues. Indeed, adipose tissue inflammation has been linked to cardiovascular disease and insulin resistance. Diverse adipokines generated by adipose tissue can also alter liver, skeletal muscle, and cardiac functions. Nicotinic acetylcholine receptors (nAChRs) are integral membrane proteins that are members of the ligand-gated ion channel superfamily that mediates and/or modulates cellular signaling. nAChRs are generated in mammals by the assembly of particular combinations of five transmembrane subunits chosen from a pool of 16 homologous polypeptides (α1-7, α9-10, β1-4, δ, ε, γ). Various physiological activities may be mediated by nAChRs assembled with different subunits. It has been proposed that nAChRs, particularly 7-nAChR, play a key regulatory role in the cholinergic anti-inflammatory pathway. The role of nAChRs in regulating adipose tissue functions has also been investigated. TNF- alpha (tumor necrosis factor) production from adipocytes was lowered by activating nAChRs, indicating that nAChRs may alleviate adipose inflammation. Bai et al. hypothesized that in high-fat diet-fed ApoE/mice with 3-nAChR blocked and in IL-6-stimulated adipocytes with α3-nAChR gene silenced, the productions of leptin, resistin, triglyceride, cholesterol, and low-density lipoprotein were significantly increased, but the generations of adiponectin and high-density lipoprotein were significantly deceased [40]. Meanwhile, inflammatory cytokine production was significantly increased. Furthermore, JAK2/STAT3 activation was engaged in the α3-nAChR-dependent signaling pathways in the control of adipose tissue dysfunction.
