Inceptor binds to and directs insulin towards lysosomal degradation in β cells

Area of Science:

• Endocrinology
• Molecular Biology
• Stem Cell Research

Background:

• Blunted first-phase insulin secretion and insulin deficiency signal beta-cell dysfunction and diabetes.
• Understanding insulin homeostasis mechanisms is crucial for restoring beta-cell function and insulin production.

Purpose of the Study:

• To identify molecular regulators of insulin homeostasis and beta-cell function.
• To investigate the role of the insulin inhibitory receptor (inceptor) in insulin regulation and beta-cell turnover.

Main Methods:

• Utilized human induced pluripotent stem cell (SC)-derived islets.
• Generated inceptor knockout (IIR KO) SC beta-cells.
• Investigated inceptor localization and function using immunofluorescence and subcellular fractionation.
• Assessed insulin content and glucose-stimulated insulin secretion (GSIS).
• Tested the effect of a monoclonal antibody targeting inceptor.

Main Results:

• Inceptor acts as an insulin-binding receptor, directing insulin for lysosomal degradation.
• IIR KO enhanced SC beta-cell differentiation, survival, insulin content, and GSIS.
• Inceptor localizes to clathrin-coated vesicles, trans-Golgi network, and secretory granules.
• Targeting inceptor with a monoclonal antibody increased insulin content and improved GSIS.

Conclusions:

• Inceptor is a key regulator of beta-cell insulin turnover through lysosomal degradation.
• Inhibiting inceptor presents a potential therapeutic strategy for enhancing insulin production and secretion in diabetes.
• This study elucidates fundamental mechanisms of beta-cell insulin regulation.