RAGE binds preamyloid IAPP intermediates and mediates pancreatic β cell proteotoxicity

Area of Science:

• Endocrinology
• Cell Biology
• Metabolic Disease Research

Background:

• Islet amyloidosis, caused by islet amyloid polypeptide (IAPP) accumulation, drives beta cell toxicity, worsening type 2 diabetes and transplant outcomes.
• Mechanisms of IAPP-induced cellular stress and potential therapeutic targets remain unclear.

Purpose of the Study:

• To identify the receptor-mediated mechanism underlying islet amyloidosis-induced proteotoxicity.
• To investigate the role of the receptor for advanced glycation endproducts (RAGE) in human IAPP (h-IAPP)-induced beta cell dysfunction.

Main Methods:

• Correlative analysis of RAGE expression in human diabetic pancreas and cellular/mouse models.
• Biochemical assays to assess binding of RAGE to toxic IAPP species.
• In vitro and in vivo experiments using soluble RAGE (sRAGE), RAGE-blocking antibodies, and genetic RAGE deletion.

Main Results:

• Increased RAGE expression correlated with h-IAPP-induced beta cell inflammation, toxicity, and apoptosis.
• RAGE selectively bound toxic h-IAPP intermediates, not amyloid fibrils.
• sRAGE, RAGE antibodies, and RAGE deletion protected against h-IAPP toxicity, inflammation, and metabolic dysfunction in vitro and in vivo.

Conclusions:

• RAGE acts as a receptor mediating h-IAPP-induced proteotoxicity and beta cell dysfunction.
• Targeting the IAPP/RAGE axis represents a promising therapeutic strategy for metabolic diseases characterized by islet amyloidosis.