Cigarette smoke exposure impairs β-cell function through activation of oxidative stress and ceramide accumulation.,Molecular Metabolism

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Cigarette smoke exposure impairs β-cell function through activation of oxidative stress and ceramide accumulation.
Molecular Metabolism ( IF 7.0 ) Pub Date : 2020-03-13 , DOI: 10.1016/j.molmet.2020.100975
Xin Tong ₁ , Zunaira Chaudhry ₂ , Chih-Chun Lee ₂ , Robert N Bone ₂ , Sukrati Kanojia ₂ , Judith Maddatu ₂ , Paul Sohn ₃ , Staci A Weaver ₄ , Morgan A Robertson ₅ , Irina Petrache ₆ , Carmella Evans-Molina ₇ , Tatsuyoshi Kono ₈

Affiliation

Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
Indiana Bioscience Research Institute, Indianapolis, IN, USA.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, National Jewish Health, Denver, CO, USA.
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA; Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA.

Objectives

Epidemiological studies indicate that first- and second-hand cigarette smoke (CS) exposure are important risk factors for the development of type 2 diabetes (T2D). Additionally, elevated diabetes risk has been reported to occur within a short period of time after smoking cessation, and health risks associated with smoking are increased when combined with obesity. At present, the mechanisms underlying these associations remain incompletely understood. The objective of this study was to test the impact of CS exposure on pancreatic β-cell function using rodent and in vitro models.

Methods

Beginning at 8 weeks of age, C57BL/6 J mice were concurrently fed a high-fat diet (HFD) and exposed to CS for 11 weeks, followed by an additional 11 weeks of smoking cessation with continued HFD. Glucose tolerance testing was performed during CS exposure and during the cessation period. Cultured INS-1 β-cells and primary islets were exposed ex vivo to CS extract (CSE), and β-cell function and viability were tested. Since CS increases ceramide accumulation in the lung and these bioactive sphingolipids have been implicated in pancreatic β-cell dysfunction in diabetes, islet and β-cell sphingolipid levels were measured in islets from CS-exposed mice and in CSE-treated islets and INS-1 cells using liquid chromatography-tandem mass spectrometry.

Results

Compared to HFD-fed, ambient air-exposed mice, HFD-fed and CS-exposed mice had reduced weight gain and better glucose tolerance during the active smoking period. Following smoking cessation, CS-mice exhibited rapid weight gain and had accelerated worsening of their glucose tolerance. CS-exposed mice had higher serum proinsulin/insulin ratios, indicative of β-cell dysfunction, significantly lower β-cell mass (p = 0.017), reduced β-cell proliferation (p = 0.006), and increased islet ceramide content compared to non-smoking control mice. Ex vivo exposure of isolated islets to CSE was sufficient to increase islet ceramide levels, which was correlated with reduced insulin gene expression and glucose-stimulated insulin secretion, and increased β-cell oxidative and endoplasmic reticulum (ER) stress. Treatment with the antioxidant N-acetylcysteine markedly attenuated the effects of CSE on ceramide levels, restored β-cell function and survival, and increased cyclin D2 expression, while also reducing activation of β-cell ER and oxidative stress.

Conclusions

Our results indicate that CS exposure leads to impaired insulin production, processing, secretion and reduced β-cell viability and proliferation. These effects were linked to increased β-cell oxidative and ER stress and ceramide accumulation. Mice fed HFD continued to experience detrimental effects of CS exposure even during smoking cessation. Elucidation of the mechanisms by which CS exposure impairs β-cell function in synergy with obesity will help design therapeutic and preventive interventions for both active and former smokers.

中文翻译：

香烟烟雾暴露会通过激活氧化应激和神经酰胺积累来损害 β 细胞功能。

目标

流行病学研究表明，接触一手和二手香烟烟雾 (CS) 是 2 型糖尿病 (T2D) 发展的重要危险因素。此外，据报道，在戒烟后的短时间内会发生糖尿病风险升高，并且与肥胖相关的健康风险会增加。目前，这些关联背后的机制仍未完全了解。本研究的目的是使用啮齿动物和体外模型测试 CS 暴露对胰腺 β 细胞功能的影响。

方法

从 8 周龄开始，C57BL/6 J 小鼠同时喂食高脂肪饮食 (HFD) 并暴露于 CS 11 周，然后再戒烟 11 周并继续进行 HFD。在 CS 暴露期间和停止期间进行葡萄糖耐量测试。培养的 INS-1 β 细胞和原代胰岛离体暴露于 CS 提取物 (CSE)，并测试 β 细胞功能和活力。由于 CS 增加了肺部神经酰胺的积累，并且这些生物活性鞘脂与糖尿病中的胰腺 β 细胞功能障碍有关，因此在 CS 暴露小鼠的胰岛和 CSE 处理的胰岛和 INS-1 中测量了胰岛和 β 细胞鞘脂水平细胞使用液相色谱-串联质谱法。

结果

与 HFD 喂养、环境空气暴露的小鼠相比，HFD 喂养和 CS 暴露的小鼠在主动吸烟期间体重增加减少，葡萄糖耐受性更好。戒烟后，CS 小鼠体重迅速增加，葡萄糖耐量恶化加速。与未接触 CS 的小鼠相比，接触 CS 的小鼠血清胰岛素原/胰岛素比率更高，表明 β 细胞功能障碍，β 细胞质量显着降低 (p = 0.017)，β 细胞增殖减少 (p = 0.006)，胰岛神经酰胺含量增加-吸烟控制小鼠。离体胰岛离体暴露于 CSE 足以增加胰岛神经酰胺水平，这与胰岛素减少相关基因表达和葡萄糖刺激的胰岛素分泌，以及增加的 β 细胞氧化和内质网 (ER) 应激。用抗氧化剂 N-乙酰半胱氨酸治疗显着减弱了 CSE 对神经酰胺水平的影响，恢复了 β 细胞功能和存活，并增加了细胞周期蛋白 D2 的表达，同时还减少了 β 细胞 ER 的激活和氧化应激。

结论

我们的结果表明，CS 暴露会导致胰岛素生成、加工、分泌受损，并降低 β 细胞活力和增殖。这些影响与增加的 β 细胞氧化和 ER 应激以及神经酰胺积累有关。即使在戒烟期间，喂食 HFD 的小鼠仍继续经历 CS 暴露的不利影响。阐明 CS 暴露损害 β 细胞功能与肥胖协同作用的机制将有助于设计针对活跃吸烟者和既往吸烟者的治疗和预防干预措施。

更新日期：2020-03-13

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