Westholm Efraim, Karagiannopoulos Alexandros, Kattner Nicole, Al-Selwi Yara, Merces George, Shaw James A M, Wendt Anna, Eliasson Lena
Islet Cell Exocytosis, Lund University Diabetes Centre (LUDC), Department of Clinical Sciences-Malmö, Lund University, Malmö, Sweden.
Clinical Research Centre (CRC), Skåne University Hospital, Malmö, Sweden.
iScience. 2024 Aug 20;27(9):110767. doi: 10.1016/j.isci.2024.110767. eCollection 2024 Sep 20.
Intra-islet crosstalk has become a focus area to fully understand the regulation of insulin secretion and impaired β-cell function in type 2 diabetes (T2D). Here, we put forward evidence for insulin-like growth factor binding protein 7 (IGFBP7) as a potential protein involved in autocrine and paracrine β-cell regulation. We showed presence of IGFBP7 in granules of both human α- and β-cells and measured elevated gene expression as well as IGFBP7 protein in T2D. Insulin secretion was reduced in human islets, and the human β-cell line EndoC-βH1, after 72-h incubation with IGFBP7. Mechanistically reduced insulin secretion by IGFBP7 is attributed to reduced p21-activated kinase 1 (PAK1) protein, and decreased oxygen consumption and ATP-production. Knockdown of IGFBP7 in EndoC-βH1 cells verified reduced IGFBP7 levels in the medium, as well as improved insulin secretion. Finally, IGFBP7 knockdown in islets from T2D donors improved insulin secretion, making IGFBP7 a potential drug target in diabetes.
胰岛内的细胞间相互作用已成为全面理解胰岛素分泌调节以及2型糖尿病（T2D）中β细胞功能受损的一个重点研究领域。在此，我们提出证据表明胰岛素样生长因子结合蛋白7（IGFBP7）是参与β细胞自分泌和旁分泌调节的一种潜在蛋白。我们发现IGFBP7存在于人类α细胞和β细胞的颗粒中，并检测到在T2D中其基因表达以及IGFBP7蛋白水平升高。在与IGFBP7孵育72小时后，人类胰岛以及人类β细胞系EndoC-βH1的胰岛素分泌减少。从机制上来说，IGFBP7导致胰岛素分泌减少归因于p21激活激酶1（PAK1）蛋白减少，以及氧消耗和ATP生成降低。在EndoC-βH1细胞中敲低IGFBP7可证实培养基中IGFBP7水平降低，以及胰岛素分泌改善。最后，在T2D供体的胰岛中敲低IGFBP7可改善胰岛素分泌，这使得IGFBP7成为糖尿病的一个潜在药物靶点。
