Towards molecular understanding of type 2 diabetes – Resolving the structure and dynamics of the cytotoxic intermediate of the human Islet Amyloid Polypeptide

Type 2 diabetes starts as insulin resistance, which is an ineffective use of insulin on the cellular level, but eventually the pancreatic β-cells that make insulin fail. Aggregation of the human islet amyloid polypeptide (hIAPP) into amyloid fibrils contributes to the β-cell loss.

The most cytotoxic, however, are not the fibrils but a short-lived, prefibrillar intermediate that forms much earlier in the aggregation process.

The intermediate has never been isolated and its structure has not been solved, as most structural biology techniques are characterized by insufficient time-resolution and long acquisition times.

Consequently, we lack the fundamental understanding of how these short-lived species contribute to the β-cell loss in diabetes.

In the proposed project, I develop a novel approach of stabilizing and isolating the short-lived intermediate of hIAPP. combine unique features of 2D-IR spectroscopy and high resolution cryo-EM and 2D-NMR techniques to deliver the first structural model of the transient intermediate of hIAPP.

Ultimately, my goal is to determine the possible mechanisms of the toxic action of the hIAPP intermediate to the β-cells.The results of the proposed research project will have scientific impact in the fields of chemistry, biophysics, and diabetes research.

Structural models of the toxic species will advance our understanding of amyloid diseases and open up for novel drug development studies.