Stimulation to secrete insulin induces pancreatic β-cell dysfunction through Tfe3 activation

During progression of diabetes, pancreatic β-cells gradually lose their ability to produce and secrete insulin. Dysfunction of β-cells is tightly associated with reduced expression of a set of glucose-stimulated insulin secretion (GSIS)-related genes, particularly the gene encoding Mafa, a transcription factor critical for β-cell functionality. However, the mechanisms underlying GSIS-related gene downregulation remain elusive. Here, we show that continuous supplementation of the drinking water of mice with glucose leads to nuclear accumulation of Tfe3, a transcription factor that responds to stress of the Golgi and lysosomes, in β-cells. This change was associated with Mafa downregulation and impairment of glucose tolerance. Acute stimulation of insulin secretion in vitro also induces Tfe3 activation and downregulates Mafa and GSIS-related genes. Activated Tfe3 binds to β-cell-specific enhancer regions of Mafa and other GSIS-related genes and suppresses the enhancer activity. Thus, stimulation to secrete insulin alters transcriptional program in β-cells toward dysfunction through Tfe3 activation.