Speakers - DEWC2025

Abstract

Abstract: 
The prevalence of type 2 diabetes mellitus (T2DM) is increasing concurrently with the aging population, although its etiology remains to be elucidated.
An analysis of a human islet cell microarray dataset identified gene YBX1 as potentially associated with T2DM. Subsequently, the single-cell transcriptomes of the pancreas from spontaneous T2DM cynomolgus monkeys and db/db mice were mapped to delineate cellular differences in the diseased state. To delve deeper, YBX1 knockout or overexpression mice specific for islet β-cell were generated using Crispr-Cas9 technology and AAV virus injection. Mechanistic studies were conducted using murine primary islets and MIN6 cell lines. 

YBX1 expression is significantly reduced in pancreatic islets of patients with type 2 diabetes mellitus (T2DM) and in multiple preclinical models, including cynomolgus monkeys with T2DM, mice fed a high-fat diet (HFD), and db/db mice. YBX1 knockdown exacerbates metabolic dysfunction, while its overexpression enhances insulin secretion and glucose clearance both in vitro and in vivo. Specific YBX1 manipulation in β-cells confirms its anti-aging effects. Mechanistically, YBX1 stabilizes PDX1 mRNA by binding to its 3′UTR, thereby inhibiting ferroptosis and reducing cytosolic mtDNA release via the PDX1-TFAM axis. This action suppresses the cytosolic mtDNA-cGAS-STING pathway, delaying β-cell senescence and alleviating T2DM. Additionally, we demonstrate that the ferroptosis inhibitor Fer-1 effectively inhibits extracellular mtDNA release and reverses pancreatic β-cell aging. 

Elucidating how YBX1 enhances islet β-cell function, via its impact on ferroptosis and cytosolic mtDNA-related β-cell senescence, offers a novel T2DM prevention and treatment strategy.