Sensing and Communicating β‐Cell Stress in the Context ofEtiology: New Opportunities for Therapeutic Impact
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
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
Abstract
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. Type 1 diabetes (T1D) results from the immune‐mediated destruction of insulin‐producing pancreatic β‐cells. Recent human studies show that early β‐cell stress maladaptations precede overt immune cell infiltration. DOC2B, a vesicle secretion regulatory protein that supports β‐cell functionality and resilience against stress, declines early in T1D, promoting β‐cell dysfunction and immune cell access. graphical