Abstract
Taste receptors exist in several organs from tongue to colon and have diverse functions dependent on specific cell type. In enteroendocrine L-cells, stimulation of taste receptor signaling induces incretin hormones. Among incretin hormones, glucagon-like peptide-1 (GLP-1) induces insulinotropic action by activating GLP-1 receptor of pancreatic β-cells. However, GLP-1 mimetic medicines have reported clinical side effects, such as autoimmune hepatitis, acute kidney injury, pancreatitis, and pancreatic cancer. Here, we hypothesized that if natural components in ethnomedicines can activate agonistic action of taste receptor; they may stimulate GLP-1 and therefore, could be developed as safe and applicable medicines to type 2 diabetes mellitus (T2DM) with minimal side effects. Cucurbitacin B (CuB) is composed of triterpenoid structure and its structural character, that represents bitterness, can stimulate AMP-activated protein kinase (AMPK) pathway. CuB ameliorated hyperglycemia by activating intestinal AMPK levels and by inducing plasma GLP-1 and insulin release in diabetic mice. This hypoglycemic action was decreased in dorsomorphin-injected mice and α-gustducin null mice. Moreover, systemic inhibition study in differentiated NCI-H716 cell line showed that CuB-mediated GLP-1 secretion was involved in activation of AMPK through α-gustducin and Gβγ-signaling of taste receptors. In summary, we conclude that, CuB represents novel hypoglycemic agents by activation of AMPK and stimulation of GLP-1 in differentiated enteroendocrine L-cells. These results suggest that taste receptor signaling-based therapeutic agents within tremendously diverse ethnomedicines, could be applied to developing therapeutics for T2DM patients.
Highlights
Bitter taste instinctively causes aversion, which helps protect humans from ingesting toxic substances (Chandrashekar et al, 2000)
cucurbitacin B (CuB) induced duodenal AMPactivated protein kinase (AMPK) activation (Figure 1H). These results suggest that CuB may attenuate hyperglycemia by regulating fasting glucose levels and stimulating Glucagon-like peptide-1 (GLP-1) release in diabetic mouse model
These results suggest that CuB, which has a potent activator of AMPK, and bitterness, stimulates plasma GLP-1 release by activating AMPK and by stimulating GLP-1 release through G-protein α subunit of gustducin (Gα-gust)
Summary
Bitter taste instinctively causes aversion, which helps protect humans from ingesting toxic substances (Chandrashekar et al, 2000). When bitter chemicals are consumed, the stomach induces a repulsive behavior after detecting bitter taste on brush cells, and the gastrointestinal tract provides a protection mechanism by preventing ingestion (Janssen et al, 2011). Enteroendocrine cells in the epithelium of the stomach and intestines secrete more than 50 different peptides as functional hormones (Gribble and Reimann, 2016). Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are postprandially co-secreted in enteroendocrine L-cells (L-cells) of the gut (Gribble and Reimann, 2016). GLP1, discovered in 1985 as a second incretin hormone, is secreted through taste receptor signaling in L-cells, and induces insulinotrophic action (Schmidt et al, 1985). In L-cells, the downstream signaling of taste receptor results in stimulation of neurotransmitters, such as GLP-1 and regulation associated with opening of ion channels, such as transient receptor potential channel 5 (TRPM5) and calcium influx (Kinnamon, 2012)
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