Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.
Department of Biomedicine, University of Basel, Basel, Switzerland.
Diabetologia. 2023 Nov;66(11):2062-2074. doi: 10.1007/s00125-023-05993-6. Epub 2023 Aug 31.
AIMS/HYPOTHESIS: Glutamate-induced cytotoxicity (excitotoxicity) has been detected in pancreatic beta cells. The cystine/glutamate antiporter System x exports glutamate to the extracellular space and is therefore implicated as driving excitotoxicity. As of yet, it has not been investigated whether System x contributes to pancreatic islet function.
This study describes the implications of deficiency of System x on glucose metabolism in both constitutive and myeloid cell-specific knockout mice using metabolic tests and diet-induced obesity. Pancreatic islets were isolated and analysed for beta cell function, glutathione levels and ER stress.
Constitutive System x deficiency led to an approximately threefold decrease in glutathione levels in the pancreatic islets as well as cystine shortage characterised by upregulation of Chac1. This shortage further manifested as downregulation of beta cell identity genes and a tonic increase in endoplasmic reticulum stress markers, which resulted in diminished insulin secretion both in vitro and in vivo. Myeloid-specific deletion did not have a significant impact on metabolism or islet function.
CONCLUSIONS/INTERPRETATION: These findings suggest that System x is required for glutathione maintenance and insulin production in beta cells and that the system is dispensable for islet macrophage function.
目的/假设：谷氨酸诱导的细胞毒性（兴奋性毒性）已在胰岛β细胞中检测到。胱氨酸/谷氨酸反向转运蛋白 System x 将谷氨酸输出到细胞外间隙，因此被认为是导致兴奋性毒性的原因。到目前为止，尚未研究 System x 是否对胰岛功能有影响。
本研究使用代谢试验和饮食诱导肥胖，描述了系统性 x 缺乏对组成型和髓样细胞特异性敲除小鼠葡萄糖代谢的影响。分离胰岛并分析β细胞功能、谷胱甘肽水平和内质网应激。
组成型 System x 缺乏导致胰岛中的谷胱甘肽水平下降约三倍，胱氨酸缺乏表现为 Chac1 的上调。这种缺乏进一步表现为β细胞特征基因的下调和内质网应激标志物的持续增加，导致体外和体内胰岛素分泌减少。髓样细胞特异性缺失对代谢或胰岛功能没有显著影响。
结论/解释：这些发现表明，System x 是β细胞中谷胱甘肽维持和胰岛素产生所必需的，而该系统对于胰岛巨噬细胞功能是可有可无的。
