Proinflammatory Cytokine Interleukin 1β Disrupts β-cell Circadian Clock Function and Regulation of Insulin Secretion
Proinflammatory Cytokine Interleukin 1β Disrupts β-cell Circadian Clock Function and Regulation of Insulin Secretion
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DOI：
10.1210/endocr/bqaa084
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发表时间：
2021-01-01
期刊：
影响因子：
4.8
通讯作者：
Matveyenko, Aleksey, V
中科院分区：
文献类型：
--
作者：
Javeed, Naureen;Brown, Matthew R.;Matveyenko, Aleksey, V
细胞内在生物钟是胰岛素分泌和整体葡萄糖稳态的重要调节因子。β细胞中的生物钟是否在暴露于促炎细胞因子等致糖尿病压力源后受到干扰，以及这些扰动是否在糖尿病的发展过程中具有特征，目前尚不清楚。为了解决这个问题，我们研究了糖尿病病理生理中常见的细胞因子介导的炎症对β细胞生物钟的生理和分子调节的影响。具体来说，我们提供的证据表明，关键的致糖尿病细胞因子IL-1 β破坏β细胞生物钟的功能，并损害葡萄糖刺激的胰岛素分泌的昼夜节律调节。IL-1 β对生物钟的有害影响是由于关键的昼夜节律转录因子Bmal1及其调节因子nad依赖性去乙酰化酶Sirtuin 1 （SIRT1）的表达受损。此外，我们还发现人类2型糖尿病与β细胞BMAL1和SIRT1免疫反应性降低有关，提示胰岛炎症、昼夜节律紊乱和β细胞衰竭之间存在潜在的因果关系。这些数据表明，β细胞中的生物钟在暴露于促炎应激源后受到干扰，并强调了以昼夜节律系统为治疗靶点治疗糖尿病β细胞衰竭的潜力。
Intrinsic beta-cell circadian clocks are important regulators of insulin secretion and overall glucose homeostasis. Whether the circadian clock in beta-cells is perturbed following exposure to prodiabetogenic stressors such as proinflammatory cytokines, and whether these perturbations are featured during the development of diabetes, remains unknown. To address this, we examined the effects of cytokine-mediated inflammation common to the pathophysiology of diabetes, on the physiological and molecular regulation of the beta-cell circadian clock. Specifically, we provide evidence that the key diabetogenic cytokine IL-1 beta disrupts functionality of the beta-cell circadian clock and impairs circadian regulation of glucose-stimulated insulin secretion. The deleterious effects of IL-1 beta on the circadian clock were attributed to impaired expression of key circadian transcription factor Bmal1, and its regulator, the NAD-dependent deacetylase, Sirtuin 1 (SIRT1). Moreover, we also identified that Type 2 diabetes in humans is associated with reduced immunoreactivity of beta-cell BMAL1 and SIRT1, suggestive of a potential causative link between islet inflammation, circadian clock disruption, and beta-cell failure. These data suggest that the circadian clock in beta-cells is perturbed following exposure to proinflammatory stressors and highlights the potential for therapeutic targeting of the circadian system for treatment for beta-cell failure in diabetes.