The β-cell assassin: IAPP cytotoxicity.

Area of Science:

• Biochemistry and Molecular Biology
• Cell Biology
• Endocrinology

Background:

• Islet amyloid polypeptide (IAPP) aggregation into cytotoxic oligomers and amyloid fibrils is implicated in type 2 diabetes mellitus (T2DM).
• The precise triggers and mechanisms underlying IAPP amyloid formation remain largely undetermined.
• Cytotoxicity is primarily linked to early-stage oligomeric and multimeric forms of IAPP during fibrillogenesis.

Purpose of the Study:

• To elucidate the mechanisms of human IAPP (hIAPP) folding and assembly into cytotoxic structures.
• To investigate the role of membrane interactions in promoting hIAPP β-sheet conformation and cytotoxicity.
• To differentiate between intracellular and extracellular pathways of hIAPP-induced cytotoxicity.

Main Methods:

• Detailed biophysical studies comparing fibrillogenic hIAPP with non-fibrillogenic rodent IAPP (rIAPP).
• Assessment of IAPP interaction with synthetic membranes to study conformational changes.
• Analysis of intracellular protein handling pathways, including the unfolded protein response (UPR) and degradation pathways, in transgenic rodent models.

Main Results:

• Membrane interactions promote hIAPP β-sheet assembly, potentially via a transient α-helical intermediate.
• Intracellular defects in proIAPP handling, UPR function, or degradation pathways can lead to apoptosis in transgenic models.
• Extracellular IAPP amyloidosis correlates directly with β-cell apoptosis in T2DM islets, with fragments, fibrils, and multimers disrupting membranes.
• No evidence supports IAPP overexpression as a cause of T2DM.

Conclusions:

• Defects in intracellular IAPP processing can induce cytotoxicity, although IAPP overexpression is not observed in T2DM.
• Extracellular IAPP aggregation and membrane disruption play a significant role in β-cell apoptosis in T2DM.
• Inhibitors of fibrillogenesis are valuable research tools but their therapeutic potential for T2DM remains uncertain.