Fernández Claudia, Nacher Montserrat, Rivera Kevin, Marín-Cañas Sandra, Sorribas Maria, Moreno-González Gabriel, Estil Les Elisabet, San José Patricia, Téllez Noèlia, Montanya Eduard
Department of Clinical Sciences, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
Bellvitge Biomedical Research Institute, (IDIBELL).
Diabetes Obes Metab. 2025 Oct;27(10):5782-5792. doi: 10.1111/dom.16632. Epub 2025 Aug 4.
Loss of β-cell identity can contribute to the reduction of functional β-cell mass in type 2 diabetes. Sulfonylureas show shorter durability of antihyperglycaemic action and higher rates of secondary failure compared to other antihyperglycaemic agents, suggesting that they could accelerate the decline of β-cell functional mass in type 2 diabetes. We aimed to investigate the impact of chronic exposure to sulfonylureas on β-cell identity.
Islets from human multi-organ donors were cultured for 4-7 days at 5.6 mM glucose with or without glibenclamide. β-cell function (glucose stimulated insulin secretion, GSIS), apoptosis (TUNEL) and gene (RT-qPCR) and protein expression (immunofluorescence, genetic β-cell tracing and Western Blot) were determined.
Human islets exposed to glibenclamide showed increased insulin secretion at low glucose, reduced GSIS, increased apoptosis, endoplasmic reticulum (ER) stress, and loss of β-cell identity indicated by reduced gene and protein expression of key β-cell identity markers and insulin. There were no changes in the expression of disallowed or progenitor-related genes. Genetic β-cell tracing showed a similar percentage of insulin-expressing cells in control and sulfonylurea-treated islets. Addition of the chemical chaperone 4-phenylbutyrate (PBA) to the culture medium prevented glibenclamide-induced ER stress and the downregulation of key β-cell transcription factors, indicating that ER stress mediates, at least partially, the negative effects of glibenclamide on β-cell identity.
Chronic exposure of human islets to glibenclamide induced the loss of β-cell identity, which was mediated by ER stress, impaired β-cell function, and increased β-cell apoptosis. These negative effects of glibenclamide may contribute to the secondary failure of sulfonylureas and accelerate the decline of functional β-cell mass in patients with type 2 diabetes.
β细胞身份丧失可能导致2型糖尿病患者功能性β细胞量减少。与其他降糖药物相比，磺脲类药物的降糖作用持续时间较短，继发失效发生率较高，这表明它们可能会加速2型糖尿病患者β细胞功能量的下降。我们旨在研究长期暴露于磺脲类药物对β细胞身份的影响。
将来自人类多器官供体的胰岛在5.6 mM葡萄糖条件下培养4 - 7天，分别添加或不添加格列本脲。测定β细胞功能（葡萄糖刺激的胰岛素分泌，GSIS）、细胞凋亡（TUNEL）以及基因（RT-qPCR）和蛋白质表达（免疫荧光、基因β细胞追踪和蛋白质免疫印迹）。
暴露于格列本脲的人胰岛在低糖条件下胰岛素分泌增加，GSIS降低，细胞凋亡增加，内质网（ER）应激增加，关键β细胞身份标志物和胰岛素的基因及蛋白质表达降低表明β细胞身份丧失。禁止或祖细胞相关基因的表达没有变化。基因β细胞追踪显示，对照和磺脲类药物处理的胰岛中表达胰岛素的细胞百分比相似。向培养基中添加化学伴侣4 - 苯基丁酸（PBA）可预防格列本脲诱导的ER应激以及关键β细胞转录因子的下调，表明ER应激至少部分介导了格列本脲对β细胞身份的负面影响。
人胰岛长期暴露于格列本脲会导致β细胞身份丧失，这是由ER应激介导的，损害了β细胞功能并增加了β细胞凋亡。格列本脲的这些负面影响可能导致磺脲类药物继发失效，并加速2型糖尿病患者功能性β细胞量的下降。
