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

与昼夜节律紊乱相关的环境条件在当今社会变得越来越普遍。重要的是，多种证据表明，昼夜节律的破坏通过对胰腺β细胞的有害影响介导，易患2型糖尿病（T2DM）。流行病学研究一致表明，昼夜节律紊乱与葡萄糖耐受不良、代谢综合征和2型糖尿病患病率增加之间存在密切关联。我们之前在动物模型上的工作表明，基因或环境对β细胞生物钟功能的破坏通过损害β细胞功能和质量的调节，增加了糖尿病发展的倾向。此外，最近的初步数据表明，β细胞生物钟可以调节细胞对DNA损伤的反应。因此，常见的致糖尿病应激源（如糖脂毒性）在生物钟紊乱的β细胞中不成比例地诱导DNA损伤和β细胞衰竭。这些累积的观察结果使我们发展出三个特定的目标，其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，Specific Aim 1将验证昼夜节律的破坏（全局和β细胞特异性）增加β细胞对DNA损伤的易感性的假设，并将研究生物钟是否通过转录控制β细胞中生长停滞和DNA损伤诱导45g （Gadd45g）基因来调节DNA损伤反应。特异性目的2将验证一个假设，即新生儿（未成熟）β细胞的特征是生物钟功能受到抑制，这增加了它们对DNA损伤诱导的糖尿病性损伤的脆弱性。后续研究将使用遗传方法诱导来自诱导多能干细胞（iPSC）的未成熟人类β细胞的昼夜节律时钟功能，并将测试该方法在改善对糖尿病性损伤和功能成熟的反应方面的功效。最后，特异性目标3将测试增强β细胞昼夜节律时钟功能的治疗潜力，以防止DNA损伤诱导的β细胞在昼夜节律紊乱的成人β细胞中的磨损。这将通过开发一种新的Bmal1条件β细胞特异性表达小鼠模型来实现，并测试这种方法是否会导致β细胞衰竭的衰减，以应对伴随的昼夜节律中断和饮食诱导的肥胖。综上所述，概述了具体目标：1)将揭示负责昼夜节律中断诱导β细胞衰竭易感性的新分子机制；2)将利用这一知识来测试一种治疗方法，以防止糖尿病发病条件下β细胞衰竭。

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.