Intrinsic β-cell circadian clocks are important regulators of insulin secretion and overall glucose homeostasis. Whether the circadian clock in β-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 β-cell circadian clock. Specifically, we provide evidence that the key diabetogenic cytokine IL-1β disrupts functionality of the β-cell circadian clock and impairs circadian regulation of glucose-stimulated insulin secretion. The deleterious effects of IL-1β 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 β-cell BMAL1 and SIRT1, suggestive of a potential causative link between islet inflammation, circadian clock disruption, and β-cell failure. These data suggest that the circadian clock in β-cells is perturbed following exposure to proinflammatory stressors and highlights the potential for therapeutic targeting of the circadian system for treatment for β-cell failure in diabetes.

中文翻译：

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促炎细胞因子白细胞介素 1β 破坏 β 细胞生物钟功能和胰岛素分泌调节。

内在 β 细胞生物钟是胰岛素分泌和整体葡萄糖稳态的重要调节器。β 细胞中的生物钟是否在暴露于促糖尿病应激物（如促炎细胞因子）后受到扰动，以及这些扰动是否在糖尿病的发展过程中出现，仍然未知。为了解决这个问题，我们研究了糖尿病病理生理学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。具体而言，我们提供的证据表明，关键的致糖尿病细胞因子 IL-1β 会破坏 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-1β 对生物钟的有害影响归因于关键的生物钟转录因子 Bmal1 及其调节剂 NAD 依赖性脱乙酰酶 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 的免疫反应性降低有关，这表明胰岛炎症、生物钟紊乱和 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性压力源后会受到干扰，并突出了生物钟系统治疗糖尿病 β 细胞衰竭的治疗靶向的潜力。我们还发现，人类 2 型糖尿病与 β 细胞 BMAL1 和 SIRT1 的免疫反应性降低有关，这表明胰岛炎症、生物钟紊乱和 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性压力源后会受到干扰，并突出了生物钟系统治疗糖尿病 β 细胞衰竭的治疗靶向的潜力。我们还发现，人类 2 型糖尿病与 β 细胞 BMAL1 和 SIRT1 的免疫反应性降低有关，这表明胰岛炎症、生物钟紊乱和 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性压力源后会受到干扰，并突出了生物钟系统治疗糖尿病 β 细胞衰竭的治疗靶向的潜力。