Sex‐Specific Regulation of Glycemic Homeostasis by Theabrownin from Pu‐erh Tea

ABSTRACT Theabrownin (TB) from Pu‐erh tea has demonstrated efficacy in alleviating hyperglycemia, yet its mechanism remains incompletely understood. In our study, we found that Pu‐erh tea or TB intervention effectively lowered postprandial blood glucose levels in females with normal and impaired glucose tolerance (IGT), as well as in hyperglycemic mouse models. Specifically, oral administration of Pu‐erh tea or TB led to the inhibition of small intestinal α‐glucosidase activity in a female‐specific manner. TB's inhibition of α‐glucosidase in vivo was significantly enhanced by mucin 2 (MUC2), a protein enriched in female intestinal mucin and upregulated by estradiol. Through noncovalent interactions, TB binds to MUC2 to form a complex, significantly boosting its inhibitory effect on α‐glucosidase in females. These findings reveal the sex‐specific molecular mechanism underlying the blood glucose‐lowering effects of TB from Pu‐erh tea, offering a promising intervention for maintaining glycemic balance in individuals with IGT or type 2 diabetes. Additionally, our study highlights the importance of considering sex differences in the judicious use of supplements or pharmacotherapy.