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

与昼夜节律的破坏相关的环境条件在当今社会中变得越来越普遍。重要的是，多条证据表明，昼夜节律的破坏易患2型糖尿病（T2DM），通过对胰腺β细胞的有害作用介导。流行病学研究一致显示昼夜节律紊乱与葡萄糖耐受不良、代谢综合征和T2DM患病率增加之间存在强相关性。我们之前在动物模型中的工作表明，β细胞生物钟功能的遗传或环境破坏通过损害β细胞功能和质量的调节而增加糖尿病发展的倾向。此外，最近的初步数据表明，β细胞生物钟的功能是调节细胞对DNA损伤的反应。因此，常见的致糖尿病应激源（例如，葡萄糖脂毒性）不成比例地诱导生物钟破坏的β细胞中的DNA损伤和β细胞衰竭。这些累积的观察使我们制定了三个具体目标，总体目标是阐明生物钟在β细胞对DNA损伤反应的调节中的作用。因此，具体目标1将检验昼夜节律（整体和β细胞特异性）的破坏增加β细胞对DNA损伤的脆弱性的假设，并且还将检查昼夜节律钟是否通过β细胞中的生长停滞和DNA损伤诱导型45g（Gadd45g）基因的转录控制来调节DNA损伤应答。具体目标2将检验以下假设：新生儿（未成熟）β细胞的特征在于受抑制的生物钟功能，这增加了其对DNA损伤诱导的糖尿病损伤的脆弱性。后续研究将使用遗传方法在源自诱导多能干细胞（iPSC）的未成熟人β细胞中诱导生物钟功能，并将测试该方法改善对糖尿病致损伤和功能成熟的反应的功效。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，以防止昼夜节律破坏的成人β细胞中DNA损伤诱导的β细胞磨损。这将通过开发Bmal1的条件β细胞特异性表达的新型小鼠模型并测试该方法是否导致响应于同时暴露于昼夜节律破坏和饮食诱导的肥胖的β细胞衰竭的减弱来实现。综上所述，概述的具体目标：1）将揭示一种负责昼夜节律破坏诱导的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，以预防糖尿病条件下的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.