5.1 TRPA1: insulin secretion
TRPA1 is expressed in the rat pancreatic islets and RINm5F cells (rat β-cell line). The 4-hydroxyalkenals like 4-hydroxynonenal (4-HNE) are commonly produced lipid peroxidation products that induce the generation of reactive oxygen species (ROS). These highly cytotoxic aldehydes accumulate in the body during T2DM. As previously reported, 4-HNE activates TRPA1 (Table 1). Application of AITC and 4-hydroxynonenal (4-HNE) induces a transient increase in calcium influx and insulin secretion in RINm5F cells(Numazawa et al., 2012). In a similar experiment, treatment with TRPA1 agonists like methylglyoxal (MG), 4-hydroxynonenal (4-HNE), prostaglandins (PGJ2) and H2O2 induces calcium influx and insulin secretion in cultured cells. These effects were inhibited by TRPA1 antagonists suggesting a potential role of TRPA1 channel in insulin secretion(Cao et al., 2012).
Sulphonyl urea derivative (SD) stimulates insulin release from pancreatic islets and shows anti-hyperglycemic effects. Glibenclamide is an anti-diabetic drug that belongs to the sulphonyl urea family. Glibenclamide stimulates insulin release by blocking ATP dependent potassium channels in pancreatic β-cells(Lamprianou et al., 2016). Babeset al . reported that this drug can activate recombinant human TRPA1 in HEK293 cells and also induces calcium influx in a subpopulation of AITC sensitive cultured mouse sensory neurons. These responses were found to be abolished both in the presence of TRPA1 antagonist HC-030031 as well as in the absence of extracellular calcium. TRPA1 antagonists abolish the insulin secretion, calcium and sodium influx suggesting a potential role of TRPA1 in secretion as well as exocytosis of insulin upon stimulation(Babes et al.2013).
Roux-en gastric bypass surgery (RYGB) helps diabetic patients to deal with insulin resistance by the upregulation of glucose-stimulated insulin release (GSIS)(Salinari et al., 2013). RYGB also restores TRPA1 expression in diabetic GK rats and improves glucose homeostasis. It has been reported that RYGB increases the bile acid (BA) levels in both type 2 diabetic patients and diabetic rats. Bile acid stimulates the glucose stimulated insulin release by restoration of TRPA1 expression in diabetic rats after RYGB. The nuclear farnesoid X receptor (FXR), is a ligand activated transcription factor which recruits histone acetyl-transferase steroid receptor co-activator 1 (SRC-1) to promote the acetylation of histone 3 (ACH3) at the TRPA1 promoter (Düfer et al., 2012; Renga, Mencarelli et al., 2010). Thus, BA/FXR/SRC1 axis plays an important role in the upregulation of gene expression of TRPA1 after RYGB. TRPA1 stimulates insulin secretion in diabetic β-cells and ameliorates hyperglycemia. It has been demonstrated that enhanced TRPA1 expression play an important role in glucose stimulated insulin secretion after RYGB in diabetic GK rats(Kong et al.. 2019).
Estrogen metabolites like catechol also activate TRPA1 and stimulate calcium influx as well as insulin secretion. HEK293 cells expressing TRPA1 showed increased calcium influx and inward ion current when treated with catechol: 2-hydroxyesterone where these effects were diminished in the presence of pharmacological antagonists of TRPA1. 2- and 4-hydroxylated metabolites of estradiol and estrone leads to glucose stimulated insulin secretion (GSIS) in isolated pancreatic islets and insulin-secreting INS-1 cells(Ma et al. 2019).
Due to the increasing prevalence of diabetes, incretins gain interest over the years, as these hormones help in glucose homeostasis and also insulin secretion(Chia & Egan, 2020). Incretins belong to that class of the hormones which are secreted by enteroendocrine cells upon receiving stimulus from the intestine in the form of nutrients. GLP-1 is one of the incretins which is secreted by L-type of cells present in the intestine(Lim & Brubaker, 2006). TRPA1 transcripts have been identified in the L-cells of the small intestine. Activation of TRPA1 by AITC, carvacrol and PUFA stimulate calcium influx, membrane depolarization and GLP-1 secretion in primary murine intestinal cultures and GLUTag cells(Emery et al. 2015). TRPA1 stimulated GLP-1 secretion could be used as a target to treat diabetes as the majority of the TRPA1 agonists are spices and food-based compounds. GPR119, a G-protein coupled receptor present on intestinal L cells synthesizes and secrete GLP-1. It has been reported that AS1269574, a GPR119 agonist stimulates the secretion of GLP-1 independent of GPR119. In STC-1 cells, AS1269574 mediated GLP-1 secretion through the activation of TRPA1 which was found to be abolished in the presence of TRPA1 channel blockers (Chepurny et al. 2016).
Diabetes is associated with hyperglycemia. Glucose uptake is facilitated by glucose transporters (GLUT) across the cell membranes, GLUT4 a subtype of GLUT transporter, regulates glucose level in the blood in response to insulin. Decreasing GLUT4 protein leads to hyperglycemia, therefore targeting GLUT4 translocation to the membrane could help to combat diabetes. Chronic administration of cinnamaldehyde (20mg/kg body weight) to the streptozotocin induced diabetic rats improved glycogen storage in muscles and liver. The two mechanisms involved were reported, one is upregulation of GLUT4 receptor in skeletal muscle tissue and the other is, the attenuation of phosphoenolpyruvate carboxykinase (PEPCK) enzyme in the liver and kidney(P. Anand et al. 2010). Cinnamaldehyde also stimulated insulin secretion in-vitro conditions (primary pancreatic islets culture) at a very high glucose concentration (10mM). Cinnamon extract lowers down circulating blood glucose levels in Db/Db mice and slows down the progress of the disease by upregulation of PPAR-γ and adiponectin. PPAR-γ and adiponectin improves blood lipid profile and increases insulin sensitivity(S. H. Kim & Choung, 2010). Also, cinnamon extract improves insulin sensitivity in the brain and improves glucose homeostasis in the HFD fed mice(Sartorius et al. 2014). Although these reports do not show the direct involvement of TRPA1 channel, but being a potent activator of TRPA1 channel, cinnamaldehyde mediated anti-diabetic effects could be further investigated for TRPA1.
Another TRPA1 agonist that has been extensively studied for the treatment of diabetes is AITC. AITC has been reported to improve insulin secretion in diabetic rats (Sahin et al., 2019). Type 2 diabetes is associated with insulin resistance. Circulating FFA diminishes insulin signaling cascade and glucose uptake. In-vivo study on HFD mice showed positive effects of AITC on circulating levels of blood glucose by protecting the development of insulin resistance and stimulation of insulin secretion from the pancreas. Blood glucose levels were found to be lowered along with the inhibition of lipid peroxidation (Ahn, Lee et al., 2014). TRPA1 agonist AITC has been reported to have anti-diabetic, anti-inflammatory and anti-oxidant properties. These reports do not connect all this information with TRPA1 but considering previous reports TRPA1 channel could be explored.
AMPK is known to modulate the expression of many ion channel proteins in the cell under different stress conditions. The use of AMPK activators downregulates the expression of TRPA1 on the membrane. Both short-term topical, as well as long term systemic administration of AMPK activators, prevented mechanical allodynia in diabetic mice and expression of TRPA1 on the membrane was also normalized(S. Wang et al., 2018).
Conclusion
Obesity has been accepted as a very serious health problem which impairs the quality of life due to its association with other life-threatening diseases including type 2 diabetes, cancer, dyslipidemia and many more. Obesity is present worldwide affecting the social and economic status of both developed as well as developing countries. Health care costs associated with the treatment of obesity and related comorbidities foists an extra burden on the nation. Despite available treatments, there is a burgeoning demand for the development of new nutraceuticals with minimum side effects. TRPA1 channel has emerged as an attractive target for the prevention of obesity and associated complications. Activation of TRPA1 by a vast range of natural stimuli, its expression in the entire body (neuronal and non-neuronal tissues) and established role in the control of body weight, secretion of satiety hormones, insulin secretion, BAT thermogenesis has given a new direction to this area of research. Even though comprehensive studies have been done for TRPA1 in different aspects, some intriguing facts are yet to be discovered. The gating mechanism of TRPA1 in response to non-electrophilic activators is poorly understood. TRPA1 homologues have been reported in different mammalian species, which have different structures and activation patterns to the agonists. The development of new TRPA1 based modulators either for obesity or related complications cannot be done without coherent studies. Additionally, we still do not understand the intracellular trafficking of the TRPA1 and regulation by intracellular factors.
TRPA1 is a calcium permeable channel. From the available literature, calcium influx has been marked as a characteristic feature of TRPA1 dependent secretion of gut hormones and insulin either in-vitroor in-vivo conditions (Figure 3). Many TRPA1 agonists have been cited to prevent type 2 diabetes and insulin resistance but a little has been explored to discover the direct role of TRPA1 in these preventive effects. Undoubtedly, dietary modulation of TRPA1 in the gastrointestinal tract and pancreas has shown the potential to combat obesity and T2DM (Table 2). At the same time, it is very crucial to determine the final concentrations of these dietary agonists that could reach to the target organs harboring TRPA1. Thus, TRPA1 modifications through its natural and/or dietary agonists offer an alternative approach for the use of TRPA1 agonism to counteract obesity and associated complications.