Metabolism-insulin secretion coupling in pancreatic beta-cells: the protective role of urolithin B towards IAPP aggregation, insulin release and mitochondrial respiration

Abstract

Intracellular aggregation and pancreatic deposition of Islet Amyloid Polypeptide (IAPP, or amylin) is an important trigger of β-cell dysfunction in type 2 diabetes and prevention of this process represents an attractive strategy to improve β-cell functionality. (Poly)phenols, particularly small molecule polyphenol metabolites (SMPMs) resulting from the metabolism by the colonic microbiota, have emerged as promising lead molecules.This study aimed to identify SMPMs inhibiting IAPP aggregation and to elucidate their activity towards the improvement of β-cell function. Docking analyzes revealed urolithin B (UroB) as the SMPM with the highest potential to interact with IAPP. In cell-free assays, UroB modulated the aggregation kinetics of IAPP fibril formation probably due to its accommodation in the hydrophobic pocket of IAPP monomer. The cytoprotective effects of UroB were then investigated in INS-1 832/3 pancreatic β-cells challenged with in vitro pre-formed IAPP aggregates. The pre-treatment of cells with 50 μM urolithin B for 12 h ameliorated IAPP-impaired cell viability and improved redox homeostasis and membrane integrity. Transcriptomic analysis pointed out Ca2+-signaling, and insulin secretion as top molecular pathways enriched in IAPP-exposed cells treated with UroB compared to the untreated control. Corroborating this, UroB protected against Ca2+ imbalance and mitochondrial dysregulation, resulting in improved glucose stimulated insulin secretion. Monitoring of oxygen consumption rate showed that UroB restored the mitochondrial respiration function in cells damaged by IAPP aggregates. Particularly, UroB re-established the energetic demand of the cells under baseline conditions, restored the ATP levels produced by the mitochondria, and rescued the spare respiratory capacity of cells subjected to IAPP insult. These effects translate into an increased capacity of cells to respond to energetic demands and, consequently, an improved cell fitness.Overall, our data revealed that UroB inhibits IAPP aggregation and modulates diverse cellular mechanisms assisting β-cells to deal with IAPP damage. This study discloses a novel set of molecules, the SMPMs, with the potential to prevent IAPP proteotoxicity and to promote metabolic homeostasis. This research is funded by Fundação Ciência Tecnologia (FCT) by grant UIDB/04567/2020. R. Menezes is supported by the Science Employment Stimulus program from FCT. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.