Deshmukh Aneesh, Chang Kevin, Cuala Janielle, Hernandez Campos Maria J, Mahmood Shayan, Verma Riva, Georgia Senta, Loconte Valentina, White Kate L
Department of Chemistry, Bridge Institute, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA.
Medical Biophysics Program, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Structure. 2025 Aug 19. doi: 10.1016/j.str.2025.07.022.
Insulin secretory granule (ISG) maturation is a crucial aspect of insulin secretion and glucose homeostasis. The regulation of this maturation remains poorly understood, especially how secretory stimuli affect ISG maturity and subcellular localization. In this study, we used soft X-ray tomography (SXT) to quantitatively map ISG morphology, density, and location in single INS-1E and mouse pancreatic β cells under the effect of various secretory stimuli. We found that the activation of glucokinase (GK), gastric inhibitory polypeptide receptor (GIPR), glucagon-like peptide-1 receptor (GLP-1R), and G protein-coupled receptor 40 (GPR40) promotes ISG maturation. Each stimulus induces unique structural remodeling in ISGs, by altering size and density, depending on the specific signaling cascades activated. These distinct ISG subpopulations mobilize and redistribute in the cell, altering the overall cellular structural organization. Our results provide insight into how current diabetes and obesity therapies impact ISG maturation and may inform the development of future treatments that target maturation specifically.
胰岛素分泌颗粒（ISG）成熟是胰岛素分泌和葡萄糖稳态的一个关键方面。对这种成熟的调节仍知之甚少，尤其是分泌刺激如何影响ISG成熟度和亚细胞定位。在本研究中，我们使用软X射线断层扫描（SXT）来定量绘制在各种分泌刺激作用下单个INS-1E和小鼠胰腺β细胞中ISG的形态、密度和位置。我们发现，葡萄糖激酶（GK）、胃抑制多肽受体（GIPR）、胰高血糖素样肽-1受体（GLP-1R）和G蛋白偶联受体40（GPR40）的激活促进ISG成熟。每种刺激通过改变大小和密度，根据激活的特定信号级联反应，在ISG中诱导独特的结构重塑。这些不同的ISG亚群在细胞中移动和重新分布，改变了整体细胞结构组织。我们的结果为当前糖尿病和肥胖症治疗如何影响ISG成熟提供了见解，并可能为未来专门针对成熟的治疗方法的开发提供信息。
