Role of Circadian Misalignment in Beta-cell Failure in Type 2 Diabetes

昼夜节律失调在 2 型糖尿病 β 细胞衰竭中的作用

• 批准号: 10434723
• 负责人: ALEKSEY V MATVEYENKO
• 金额: $ 41.23万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434723
• 关键词: ARNTL gene; Adult; Animal Model; Apoptosis; Attenuated; Behavioral; Beta Cell; Cell Maturation; Cell Survival; Cell physiology; Cells; ChIP-seq; Circadian Dysregulation; Circadian Rhythms; Circadian desynchrony; Complications of Diabetes Mellitus; DNA; DNA Damage; DNA Repair; Data; Development; Diabetes Mellitus; Diagnosis; Disease; Epidemic; Exposure to; Failure; Follow-Up Studies; Functional disorder; Funding; GADD45G; Genes; Genetic; Genetic Transcription; Glucose; Glucose Intolerance; Goals; Growth; Health; Healthcare Systems; Human; Impairment; In Vitro; Incidence; Injury; Insulin; Insulin Resistance; Knowledge; Laboratories; Longevity; Mammals; Mediating; Mediator of activation protein; Metabolic syndrome; Molecular; Neonatal; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Persons; Predisposition; Prevalence; Preventive treatment; Regulation; Repression; Resistance; Role; Sleep; Societies; Structure of beta Cell of islet; System; Testing; Therapeutic; Transcriptional Regulation; Variant; Work; attenuation; blood glucose regulation; cell growth regulation; cell type; circadian; circadian pacemaker; diabetic; diabetogenic; diet-induced obesity; efficacy testing; epidemiology study; feeding; genetic approach; improved; in vivo; induced pluripotent stem cell; insulin secretion; islet; molecular clock; mouse model; novel; novel therapeutic intervention; postnatal; preservation; prevent; response; stressor; therapeutic evaluation; transcription factor

Environmental conditions associated with disruption of circadian rhythms are becoming increasingly prevalent in today's society. Importantly, multiple strands of evidence suggest that disruption of circadian rhythms predisposes to Type 2 diabetes mellitus (T2DM), mediated through deleterious effects on pancreatic β-cells. Epidemiological studies consistently show robust association between circadian disruption and increased prevalence of glucose intolerance, metabolic syndrome and T2DM. Our previous work in animal models demonstrated that either genetic or environmental disruption of the β-cell circadian clock function increases the propensity for the development of diabetes by compromising regulation β-cell function and mass. Moreover, recent preliminary data identified that the β-cell circadian clock functions to regulate the cellular response to DNA damage. Thus, common diabetogenic stressors (e.g. glucolipotoxicity) disproportionately induce DNA damage and β-cell failure in clock-disrupted β-cells. These cumulative observations led us to develop three specific aims with an overall objective of elucidating the role of the circadian clock in the regulation of β-cell response to DNA damage. Accordingly, Specific Aim 1 will test the hypothesis that the disruption of circadian rhythms (global and β-cell specific) increases β-cell vulnerability to DNA damage, and will also examine whether the circadian clock regulates DNA damage response through transcriptional control of the growth arrest and DNA-damage-inducible 45g (Gadd45g) gene in β-cells. Specific Aim 2 will test the hypothesis that neonatal (immature) β-cells are characterized by repressed circadian clock function that increases their vulnerability to DNA damaged-induced diabetogenic injury. The follow up studies will use the genetic approach to induce circadian clock function in immature human β-cells derived from induced pluripotent stem cells (iPSC), and will test the efficacy of this approach to improve the response to diabetogenic injury and functional maturation. Finally, Specific aim 3 will test the therapeutic potential of enhancing the β-cell circadian clock function in order to prevent DNA damage-induced β-cell attrition in circadian–disrupted adult β-cells. This will be achieved by developing a novel mouse model of conditional β-cell specific expression of Bmal1 and testing whether this approach results in attenuation of β-cell failure in response to concomitant exposure to circadian disruption and diet-induced obesity. Taken together, outlined specific aims: 1) will uncover a novel molecular mechanism responsible for circadian disruption-induced susceptibility to β-cell failure and 2) will use this knowledge to test a therapeutic approach to prevent β-cell failure under diabetogenic conditions.

在当今社会，与昼夜节律破坏相关的环境条件变得越来越普遍。重要的是，多种证据表明，昼夜节律的破坏容易导致 2 型糖尿病 (T2DM)，这是通过对胰腺 β 细胞的有害作用介导的。流行病学研究一致表明，昼夜节律紊乱与葡萄糖不耐受、代谢综合征和 T2DM 患病率增加之间存在密切关联。我们之前在动物模型中的研究表明，β细胞生物钟功能的遗传或环境破坏会损害β细胞功能和质量的调节，从而增加患糖尿病的倾向。此外，最近的初步数据表明，β 细胞生物钟的功能是调节细胞对 DNA 损伤的反应。因此，常见的糖尿病应激源（例如糖脂毒性）会不成比例地诱导时钟紊乱的 β 细胞 DNA 损伤和 β 细胞衰竭。这些累积的观察结果使我们制定了三个具体目标，总体目标是阐明生物钟在调节 β 细胞对 DNA 损伤的反应中的作用。因此，具体目标 1 将检验昼夜节律（全局节律和 β 细胞特异性）的破坏会增加 β 细胞对 DNA 损伤的脆弱性的假设，还将检查生物钟是否通过对 β 细胞中生长停滞和 DNA 损伤诱导 45g (Gadd45g) 基因的转录控制来调节 DNA 损伤反应。具体目标 2 将检验以下假设：新生儿（未成熟）β 细胞的生物钟功能受到抑制，从而增加了它们对 DNA 损伤引起的糖尿病性损伤的脆弱性。后续研究将利用遗传方法在诱导多能干细胞（iPSC）衍生的未成熟人类β细胞中诱导生物钟功能，并测试该方法改善对糖尿病损伤反应和功能成熟的功效。最后，具体目标 3 将测试增强 β 细胞生物钟功能的治疗潜力，以防止昼夜节律紊乱的成年 β 细胞中 DNA 损伤引起的 β 细胞损耗。这将通过开发一种 Bmal1 条件性 β 细胞特异性表达的新型小鼠模型来实现，并测试这种方法是否会导致 β 细胞因同时暴露于昼夜节律紊乱和饮食引起的肥胖而导致的衰竭减弱。总而言之，概述了具体目标：1）将揭示一种新的分子机制，该机制负责昼夜节律破坏引起的 β 细胞衰竭易感性；2）将利用这些知识来测试一种治疗方法，以预防糖尿病条件下的 β 细胞衰竭。