The N-degron pathway regulates glucose and insulin homeostasis through the lysosomal degradation of RXRA/RXRα via SQSTM1/p62

Key Points

• To explore the role of the N-degron pathway in glucose and insulin homeostasis through SQSTM1-mediated lysosomal degradation of RXRA.
• Utilized ATB1002 to activate SQSTM1 as an N-recognin in mice models of prediabetes and T2D.
• Examined the effects of SQSTM1 agonists on RXRA degradation and insulin secretion.
• Assessed glucose-stimulated insulin responses in treated models.
• SQSTM1 activation led to significant lysosomal degradation of RXRA in prediabetic and T2D models.
• Enhanced insulin secretion and responsiveness were observed following SQSTM1 agonist treatment.
• Findings suggest potential therapeutic avenues for managing T2D through SQSTM1 modulation.