The Protective Action of Metformin against Pro-Inflammatory Cytokine-Induced Human Islet Cell Damage and the Mechanisms Involved.
The Protective Action of Metformin against Pro-Inflammatory Cytokine-Induced Human Islet Cell Damage and the Mechanisms Involved.
复制标题
作者：
二甲双胍是一种广泛用于2型糖尿病（T2 D）的药物，已显示可保护暴露于葡萄糖和/或脂毒性条件的人β细胞以及来自T2 D供体的胰岛中的β细胞。我们评估了二甲双胍是否可以缓解促炎细胞因子（介导1型糖尿病（T1 D）中的β细胞损伤）诱导的人类β细胞应激，并使用鸟枪蛋白质组学研究了潜在机制。将人胰岛暴露于50 U/mL白细胞介素-1 β +1000 U/mL干扰素-γ 48 h，伴或不伴2.4 µg/mL二甲双胍。研究了葡萄糖刺激的胰岛素分泌（GSIS）和caspase 3/7活性，并进行了鸟枪标记的蛋白质组学分析。二甲双胍可阻止细胞因子诱导的GSIS减少和caspase 3/7活化。蛋白质组学分析在人类胰岛中鉴定了3000多种蛋白质。单独使用细胞因子改变了244种蛋白质的表达（145种上调，99种下调），而在二甲双胍存在下，二甲双胍暴露改变了231种蛋白质的表达（128种上调，103种下调）。在这两种条件下，我们发现的蛋白质中，参与囊泡运动，防御氧化应激（包括过氧化物酶），代谢，蛋白质合成，糖酵解及其调节，和细胞骨架蛋白。二甲双胍抑制与炎症、免疫反应、哺乳动物雷帕霉素靶蛋白（mTOR）信号传导和细胞衰老相关的通路。Western blot证实了部分变化。因此，二甲双胍阻止了促炎细胞因子在人β细胞中的部分有害作用，这伴随着胰岛蛋白质组修饰。这表明，除了用于T2 D之外，二甲双胍还可以考虑用于其他类型糖尿病（可能包括早期T1 D）的β细胞保护。
Metformin, a drug widely used in type 2 diabetes (T2D), has been shown to protect human β-cells exposed to gluco- and/or lipotoxic conditions and those in islets from T2D donors. We assessed whether metformin could relieve the human β-cell stress induced by pro-inflammatory cytokines (which mediate β-cells damage in type 1 diabetes, T1D) and investigated the underlying mechanisms using shotgun proteomics. Human islets were exposed to 50 U/mL interleukin-1β plus 1000 U/mL interferon-γ for 48 h, with or without 2.4 µg/mL metformin. Glucose-stimulated insulin secretion (GSIS) and caspase 3/7 activity were studied, and a shotgun label free proteomics analysis was performed. Metformin prevented the reduction of GSIS and the activation of caspase 3/7 induced by cytokines. Proteomics analysis identified more than 3000 proteins in human islets. Cytokines alone altered the expression of 244 proteins (145 up- and 99 down-regulated), while, in the presence of metformin, cytokine-exposure modified the expression of 231 proteins (128 up- and 103 downregulated). Among the proteins inversely regulated in the two conditions, we found proteins involved in vesicle motility, defense against oxidative stress (including peroxiredoxins), metabolism, protein synthesis, glycolysis and its regulation, and cytoskeletal proteins. Metformin inhibited pathways linked to inflammation, immune reactions, mammalian target of rapamycin (mTOR) signaling, and cell senescence. Some of the changes were confirmed by Western blot. Therefore, metformin prevented part of the deleterious actions of pro-inflammatory cytokines in human β-cells, which was accompanied by islet proteome modifications. This suggests that metformin, besides use in T2D, might be considered for β-cell protection in other types of diabetes, possibly including early T1D.
登录
查看更多内容
影响因子：
16.2
作者：
通讯作者：
--
影响因子：
3.4
作者：
Zhou JY;Dann GP;Liew CW;Smith RD;Kulkarni RN;Qian WJ
通讯作者：
Qian WJ
DOI：
10.1038/s41574-021-00568-0
发表时间：
2022-01
期刊：
Nature reviews. Endocrinology
影响因子：
--
作者：
Benninger RKP;Kravets V
通讯作者：
Kravets V
DOI：
10.1073/pnas.97.2.745
发表时间：
2000-01-18
影响因子：
11.1
作者：
Arunachalam, B;Phan, UT;Cresswell, P
通讯作者：
Cresswell, P
影响因子：
7.7
作者：
Cirulli, V;Zalatan, J;Crisa, L
通讯作者：
Crisa, L