Over the last few years, incretin-based therapies have emerged as important agents in the treatment of type 2 diabetes (T2D). These agents exert their effect via the incretin system, specifically targeting the receptor for the incretin hormone glucagon-like peptide 1 (GLP-1). Two classes of incretin-based therapies are available: GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. However, there are currently no clinical drugs that directly increase endogenous GLP-1 secretion. Although several nutrients induce GLP-1 secretion, there is little evidence to suggest that non-nutritive compounds directly increase GLP-1 secretion. In the present study, we demonstrated that the natural product ZYM01 from the Bougainvillea glabraChoisy (which was used for hypoglycemic by the Dai ethnic group in China) had a good hypoglycemic effect and a significant islet protection function in diabetic mouse model. ZYM01 treatment (50 mg•kg-1 •day-1) decreased plasma levels of glucose, body weight and food intake; ameliorated OGT and plasma lipid profiles; augmented plasma insulin levels; alleviated islets pathological morphology; and reduced liver lipid accumulation in db/db diabetic mouse model. Furthermore, ZYM01 enhanced GLP-1 release in C57BL/6 mice and exerted an acute hypoglycemic effect through the secretion of GLP-1 in vivo since the exendin 9-39, a GLP-1R antagonist could completely block the acute hypoglycemic effect of ZYM01. Also, in cultured STC-1 cells, ZYM01 increased intracellular calcium and promoted GLP-1 secretion in a dose- dependent manner accompanied by elevated levels of phosphorylated Erk signaling.
In summary, our study found that ZYM01 exerted the hypoglycaemic and islets protective effects, which were associated with an enhanced release of GLP-1 mediated by the activation of the Erk signaling. These findings firmly identified ZYM01 as a new viable therapeutic option for diabetes control.
Y. Sun: None. J. Li: None. J. Li: None.