The amyloid oligomer modulator anle138b has disease modifying effects in a human IAPP transgenic mouse model of type 2 diabetes mellitus (hIAPP Ob/Ob mice)

Abstract

SummaryCytotoxic aggregates of human islet amyloid polypeptide (hIAPP) contribute to type 2 diabetes mellitus (T2DM) pathogenesis by damaging pancreatic islet β cells and reducing insulin production. Anle138b is an amyloid oligomer modulator with disease modifying properties in mouse models of neurodegenerative diseases linked to protein aggregation and with favorable results in phase 1 clinical studies. We tested whether anle138b has disease modifying properties in a severe hIAPP transgenic mouse model of T2DM. Oral administration of anle138b in hIAPP Ob/Ob mice reduced hyperglycemia, decreased glycated hemoglobin levels, increased islet β-cell mass and improved islet function compared to non-treated mice. In contrast, anle138b administration did not affect these parameters in non-transgenic Ob/Ob mice, indicating that the anti-diabetic effects of anle138b are hIAPP-dependent.In vitro, anle138b inhibited hIAPP aggregation and toxic effects of hIAPP on mitochondria. These results indicate that anle138b is a promising drug candidate for treating and/or preventing T2DM -associated pathology.