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

Pancreas/duodenum homeobox protein 1 (PDX1) is an important transcription factor that regulates islet beta-cell proliferation, differentiation, and function. Reduced expression of PDX1 is thought to contribute to beta-cell loss and dysfunction in diabetes. Thus, promoting PDX1 expression can be an effective strategy to preserve beta-cell mass and function. Previously, we established aPDX1promoter-dependent luciferase system to screen agents that can promote PDX1 expression. Natural compound tectorigenin (TG) was identified as a promising candidate that could enhance the activity of the promoter for thePDX1gene. In this study, we first demonstrated that TG could promote the expression of PDX1 in beta-cells via activating extracellular signal-related kinase (ERK), as indicated by increased phosphorylation of ERK; this effect was observed under either normal or glucotoxic/lipotoxic conditions. We then found that TG could suppress induced apoptosis and improved the viability of beta-cells under glucotoxicity and lipotoxicity by activation of ERK and reduction of reactive oxygen species and endoplasmic reticulum (ER) stress. These effects held truein vivoas well: prophylactic or therapeutic use of TG could obviously inhibit ER stress and decrease islet beta-cell apoptosis in the pancreas of mice given a high-fat/high-sucrose diet (HFHSD), thus dramatically maintaining or restoring beta-cell mass and islet size, respectively. Accordingly, both prophylactic and therapeutic use of TG improved HFHSD-impaired glucose metabolism in mice, as evidenced by ameliorating hyperglycemia and glucose intolerance. Taken together, TG, as an agent promoting PDX1 expression exhibits strong protective effects on islet beta-cells bothin vitroandin vivo.