Human islet amyloid polypeptide ‐induced β‐cell cytotoxicity is linked to formation of α‐sheet structure

AbstractType 2 diabetes (T2D) results from insulin secretory dysfunction arising in part from the loss of pancreatic islet β-cells. Several factors contribute to β-cell loss, including islet amyloid formation, which is observed in over 90% of individuals with T2D. The amyloid is comprised of human islet amyloid polypeptide (hIAPP). Here we provide evidence that early in aggregation, hIAPP forms toxic oligomers prior t o formation of amyloid fibrils. The toxic oligomers contain α-sheet secondary structure, a nonstandard secondary structure associated with toxic oligomers in other amyloid diseases.De novo, synthetic α-sheet compounds designed to be nontoxic and complementary to the α-sheet structure in the toxic oligomers inhibit hIAPP aggregation and neutralize oligomer-mediated cytotoxicity in cell-based assays.In vivo administration of an α-sheet design to mice for four weeks revealed no evidence of toxicity nor did it elicit an immune response. Furthermore, the α-sheet designs reduced endogenous islet amyloid formation and mitigation of amyloid-associated β-cell loss in cultured islets isolated from an hIAPP transgenic mouse mode l of islet amyloidosis. Characterization of the involvement of α-sheet in early aggregation of hIAPP and oligomer toxicity contributes to elucidation of the molecular mechanisms underlying amyloid-associated β-cell loss.

Source: Protein Science - December 8, 2023 Category: Biochemistry Authors: Cheng ‐Chieh Hsu, Andrew T. Templin, Tatum Prosswimmer, Dylan Shea, Jinzheng Li, Barbara Brooks‐Worrell, Steven E. Kahn, Valerie Daggett Tags: RESEARCH ARTICLE Source Type: research