Sensing and Communicating β-Cell Stress in the Context of T1D Etiology: New Opportunities for Therapeutic Impact.

Abstract

Type 1 diabetes (T1D) has traditionally been viewed as an immune-driven disease. However, evidence from pre-onset T1D individuals suggests that pancreatic β-cells show reduced metabolic gene expression and stress responses before substantial immune entry. In this review, we examine how chronically stressed β-cells are detectable in a reshaped local microenvironment prior to overt immune cell infiltration, a period defined as a "pre-immune" niche. During this period, pre-onset β-cells exhibit early extracellular matrix (ECM) remodeling capabilities, endoplasmic reticulum and Golgi stress, a shift in their soluble-factor secretome and extracellular outputs, including release of extracellular vesicles with distinct cargo. Loss of the double C2-like domain containing protein B (DOC2B), a regulator of vesicle trafficking and membrane fusion, may contribute to these processes. Beyond its canonical role in regulated insulin exocytosis, DOC2B negatively regulates cytokine-induced CXCL10 expression in β-cells via inhibition of IKKβ-STAT1 signaling, and its loss increases activation of these pathways. DOC2B loss in cancer models promotes the formation of filopodia, protrusive structures capable of ECM engagement for matrix metalloproteinase-mediated degradation; similarly, we consider whether changes in β-cells could influence maladaptive interactions with the peri-islet matrix during early T1D. Together, these concepts position DOC2B as a potential additional point of β-cell vulnerability; further study may help guide early biomarker development and inform long-term strategies for intercepting T1D before clinical onset.