Cucurbitacin B Induces Hypoglycemic Effect in Diabetic Mice by Regulation of AMP-Activated Protein Kinase Alpha and Glucagon-Like Peptide-1 via Bitter Taste Receptor Signaling

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.

Cucurbitacin B Suppresses Hyperglycemia Associated with a High Sugar Diet and Promotes Sleep in Drosophila melanogaster

“…Cuc-B induces hypoglycemic effect in diabetic mice via bitter taste receptor signaling at enteroendocrine L-cells in mice ( Kim et al, 2018 ). Hemolymph glucose levels in control and Gr33a 1 mutant male flies fed with cuc-B and caffeine were measured to assess the capacity of these compounds to alleviate hyperglycemia in Drosophila ( Figs.…”

“…Here, we demonstrated that the regulation of hemolymph glucose levels depended on how much cuc-B-treated food was consumed by the flies. Given that the Gr33a-GAL4 reporter is known to be expressed in the intestine and midgut enteroendocrine cells ( Park and Kwon, 2011 ), including the peripheral neurons of the labellum and legs, hyperglycemia suppression might be positively controlled by bitter taste receptors in the intestinal cells similar to mice ( Kim et al, 2018 ). However, there are several arguments against this explanation.…”

Treatment approach to type 2 diabetes: Past, present and future

“…Thus, it is important to emphasize that this is not the sole promising novel drug class. This is indicated by findings from the research on the first-in-class drug, an adenosine monophosphate (AMP)-activated protein kinase activator, targeting one of the key players in the process of energy balance preservation, especially during caloric disturbances[113], and, finally, findings on the first monoclonal antibody, bimagrumab, that blocks the myostatin type II receptor, which results in fat reduction[114].…”

Association between consumption of vegetables and COVID-19 mortality at a country level in Europe

“…Although less well studied, cucumber acts as an antioxidant on insulin resistance and its related diseases 22-24 . Cucurbitacin B, a natural compound that exists in edible plants (bitter melons, cucumbers, pumpkins and zucchini), has anti-inflammatory and hypoglycemic properties through the activation of Nrf2 25,26 . These results and those of the recent study on fermented foods suggest a strong link between Nrf2 and the protection against severe forms of COVID-19.…”

“…properties through the activation of Nrf2 25,26 . These results and those of the recent study on fermented foods suggest a strong link between Nrf2 and the protection against severe forms of COVID-19.…”