Aggregation kinetics define the temporal window of IAPP proteotoxicity

Area of Science:

• Biochemistry
• Cell Biology
• Endocrinology

Background:

• Islet amyloid polypeptide (IAPP) aggregation into amyloid is linked to beta-cell dysfunction in type 2 diabetes.
• The exact toxic species and its temporal persistence remain unclear, with competing models involving mature fibrils or transient intermediates.

Purpose of the Study:

• To directly test competing models of IAPP-induced beta-cell toxicity.
• To determine the relationship between IAPP aggregation kinetics and the timing of cellular dysfunction.

Main Methods:

• Combined time-resolved beta-cell functional assays with biophysical measurements of IAPP aggregation.
• Investigated multiple perturbations (concentration, temperature) and sequence variants, including the diabetes-associated S20G variant.

Main Results:

• Maximal beta-cell toxicity occurred during the lag phase of IAPP aggregation and decreased as fibrils formed.
• The duration of beta-cell dysfunction scaled linearly with the lag phase length.
• Altering aggregation kinetics predictably shifted the toxicity window; the S20G variant showed higher peak toxicity in a compressed timeframe.

Conclusions:

• Transient lag-phase intermediates, not mature fibrils or growth phase processes, are the primary drivers of beta-cell dysfunction.
• IAPP aggregation kinetics quantitatively predict the onset, peak, and termination of toxicity, establishing a link between aggregation timing and cellular damage.