Urolithin B: Two-way attack on IAPP proteotoxicity with implications for diabetes

Area of Science:

• Metabolic diseases
• Protein aggregation
• Cellular homeostasis

Background:

• Diabetes mellitus is a global metabolic disease characterized by Islet Amyloid Polypeptide (IAPP) aggregation.
• IAPP proteotoxicity contributes to beta-cell dysfunction and death, representing an underexplored therapeutic target.
• Polyphenols can inhibit protein aggregation, but often have poor bioavailability.

Purpose of the Study:

• To investigate (poly)phenol metabolites for their potential to inhibit IAPP aggregation.
• To identify novel therapeutic small molecules for diabetes.

Main Methods:

• In silico, cell-free, and cell-based assays were employed.
• A collection of in-house (poly)phenol metabolites was screened.
• Urolithin B was identified and characterized for its effects on IAPP aggregation and cellular pathways.

Main Results:

• Urolithin B was identified as a potent inhibitor of IAPP aggregation.
• Urolithin B altered IAPP fibril formation and morphology.
• Urolithin B modulated protein clearance, mitochondrial function, and cell cycle, rescuing cells from IAPP-induced damage.

Conclusions:

• Urolithin B is a novel small molecule that targets IAPP aggregation.
• Urolithin B demonstrates potential as a therapeutic agent for diabetes by mitigating IAPP-mediated cellular dysfunction.
• Derived from dietary ellagic acid metabolism, urolithin B has potential applications in nutrition, nutraceuticals, and pharmacology.