Resveratrol modulates pancreatic proteotoxic stress and metabolic dysfunction in human IAPP transgenic mice

Amylin is a peptide hormone co-secreted with insulin by pancreatic β-cells that regulates glucose homeostasis and satiety. In humans, amylin exhibits a strong propensity to aggregate, contributing to β-cell dysfunction and the development of type 2 diabetes mellitus (T2D). Emerging evidence suggests that amylin aggregates may exert systemic effects beyond the pancreas, potentially affecting peripheral tissues and the brain. However, in vivo evidence supporting this multi-organ involvement remains limited. In this study, we investigated the impact of human amylin aggregation across metabolic tissues using a transgenic mouse model expressing human IAPP (TghIAPP), fed either a standard diet (STD) or a high-fat diet (HFD), and evaluated the therapeutic potential of resveratrol. HFD-fed TghIAPP mice developed impaired glucose tolerance, increased amyloid aggregation, and enhanced markers of apoptosis and senescence in pancreatic islets. These alterations were associated with activation of endoplasmic reticulum (ER) stress pathways. Resveratrol treatment significantly reduced pancreatic amyloid burden, attenuated ER stress signaling, and improved markers of β-cell integrity. In the liver, TghIAPP mice exhibited increased lipid accumulation, inflammatory markers, and amyloid oligomer deposition, although the effects of resveratrol were modest and did not consistently reach statistical significance. In the brain, amyloid aggregates were detected in the hippocampus; however, resveratrol-induced changes in aggregate load and behavioral performance were limited and should be interpreted cautiously. Overall, these findings support a robust role for amylin aggregation in pancreatic dysfunction and highlight resveratrol as a modulator of pancreatic proteotoxic stress. The observed alterations in liver and brain suggest potential systemic effects of amylin aggregates that warrant further investigation.