Dracorhodin perchlorate protects pancreatic β‐cells against glucotoxicity‐ or lipotoxicity‐induced dysfunction and apoptosis in vitro and in vivo

Abstract

Glucotoxicity or lipotoxicity leads to hyperglycemia and insulin secretion deficiency, which are important causes for the onset of type 2 diabetes mellitus (T2DM). Thus, the restoration of β‐cell function is a long‐sought goal in diabetes research. Previous studies have implicated pancreatic and duodenal homeobox 1 gene (Pdx1) in β‐cell function and insulin secretion. In this study, we established a Pdx1 promoter‐dependent luciferase system and identified the natural compound dracorhodin perchlorate (DP) as an effective promotor of Pdx1 expression. We further demonstrated that DP could significantly inhibit β‐cell apoptosis induced by 33 mm glucose or 200 μm palmitate by interfering with endoplasmic reticulum stress and mitochondrial pathways and enhance insulin secretion as well. These effects were associated with enhanced activities of Erk1/2, which in turn promoted Pdx1 expression and increased the ratio of Bcl2/Bax, since inhibition of the Erk1/2 pathway abolished the DP‐induced expression of Pdx1 and suppression of apoptosis. In addition, our in vivo results in diabetic mice indicated that DP treatment lowered blood glucose, raised insulin levels, enhanced Pdx1 expression and increased islet size and number in the pancreas of diabetic mice. Our findings suggest that Pdx1 is a potential target molecule of DP in the treatment of T2DM via the inhibition of glucotoxicity‐ or lipotoxicity‐ induced β‐cell apoptosis and the attenuation of insulin secretion dysfunction.

Tectorigenin enhances PDX1 expression and protects pancreatic β-cells by activating ERK and reducing ER stress

“…Glucotoxicity and lipotoxicity are among the main reasons leading to insufficient pancreatic βcell mass and β-cell dysfunction in T2DM (33,49). Besides, those conditions are associated with the downregulation of PDX1 in β-cells (17,50). Our analyses revealed that under both normal and toxic glycolipid conditions in vitro, TG might promote PDX1 expression and exert significant protective effects on islet β-cells against apoptosis by stimulating the ERK signaling.…”

“…Currently, there are only limited drugs available that can protect islet β-cells and treat diabetes. PDX1 is an important anti-diabetes drug target (17,47), which has a vital role in maintaining islet β-cell function and survival (48). Herein, we reported that TG, a natural compound, could promote the expression of PDX1 in islet β-cells, and effectively prevent and rescue β-cells from glucotoxicity and lipotoxicity in vitro and in vivo.…”

“…ERK signaling has been reported to be involved in the regulation of PDX1 expression in islet β-cells (17,28). Thus, in this study, we examined whether TG regulates the PDX1 expression also by activating ERK signaling.…”

“…1A). TG was selected by screening compounds that promote PDX1 expression using PDX1 promoter-dependent luciferase reporter gene vector (PGL3-PDX1-luc, unpublished data) (17).…”

“…However，Novel, safe and more efficient drugs aiming to protect and maintain islet β-cells are still in urgent need. To this end, in our previous study, we performed a small natural compound screening based on the PDX1 gene promoter-driven luciferase reporter screening system so as to identify new natural compounds that could promote PDX1 expression and protect islet β-cells (17). Tectorigenin (TG), a naturally occurring isoflavone compound isolated from the Pueraria thomsonii Benth (18), was identified as one of the promising candidate compounds that can significantly promote the activity of PDX1 gene promoter.…”