Bitter Phytochemicals Acutely Lower Blood Glucose Levels by Inhibition of Glucose Absorption in the Gut

Kimberly Marie Palatini Jackson, Reham Mhawish and Slavko Komarnytsky

Objectives
The objective of this study was to confirm the ability of diverse classes of plant phytochemicals associated with bitter tastes to alleviate postprandial hyperglycemia in a C57BL/6J mouse model of diet-induced obesity, and to determine the effect of TAS2R activation on glucose absorption, GPCR signaling, and gastrointestinal hormone expression. 

Methods
Mice (n = 32) were then randomized into 2 groups with ad libitum access to low-fat diet (LFD, n = 8) or high-fat diet (HFD, n = 24) diet for 8 weeks. Blood was collected by cardiac puncture after CO2 inhalation. Gastrointestinal (stomach, duodenum, jejunum, ileum, cecum, and colon) and metabolic (liver, gastrocnemius muscle, and epididymal fat) tissues were collected to determine the temporal sequence and signaling events responsible for the observed changes in physiology and metabolism. 

Results
Our study confirms prior observations with plant bitters using 24 model compounds by demonstrating acute lower peak blood glucose values and improved glucose tolerance following intragastric, but not intraperitoneal, treatment. The administration of the synthetic bitter compound denatonium benzoate yielded similar results that were attenuated by co-application of the allosteric inhibitor of the bitter TAS2R receptors. We also show that these effects occur dose-dependently; associate with reduced glucose uptake, increased intracellular [Ca2+] fluxes, and enhanced GLP-1 expression; and are attenuated by the TAS2R inhibitor in the neuroendocrine STC-1 intestinal cells.

Conclusions
These findings support the view that inhibition of glucose transport from the intestinal lumen to the blood by TAS2R bitter receptor signaling in the gut may represent a common mechanism in the acute response to oral ingestion of bitter phytochemicals. 

Reference
Palatini Jackson, K.M.; Mhawish, R.; Komarnytsky, S. Bitter Phytochemicals Acutely Lower Blood Glucose Levels by Inhibition of Glucose Absorption in the Gut. Endocrines. 5, 304–322. 2024. doi.org/10.3390/endocrines5030022