Anti-diabetic drug pioglitazone reduces Islet amyloid aggregation overload in the Drosophila neuronal cells

Abstract

Amyloid-proteinopathy is observed in type 2 diabetes, where Islet amyloid polypeptide is secreted atypically and impedes cellular homeostasis. The thiazolidinediones family is reported to influence amyloid-beta aggregations. However, research on drug-based stimulation of insulin signaling to alleviate Islet amyloid aggregations is lacking. To understand the impact of pioglitazone on islet amyloid aggregation, we conducted an in vivo and in silico analysis. For in vivo analysis, we generated a transgenic Drosophila harboring the preproform of human Islet amyloid polypeptide (IAPP) that can be ectopically expressed in a spatio-temporal manner. We show that the unprocessed form of IAPP also has the propensity to form aggregates and cause degeneration. Pioglitazone feeding effectively reduces the burden of Islet amyloid aggregations in the larval brain. In silico analysis shows that there is a higher protein-ligand binding energy for IAPP with pioglitazone than amyloid-beta. These results suggests that pioglitazone might be repurposed as a drug to cure islet amyloidogenesis.

Keywords: Drosophila; Islet amyloids; Neuronal cells; Pioglitazone; Type 2 diabetes.