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

在当今社会，与昼夜节律紊乱相关的环境条件正变得越来越普遍。重要的是，多条证据表明，昼夜节律的紊乱容易导致2型糖尿病(T2 DM)，这是通过对胰腺β细胞的有害影响而介导的。流行病学研究一直表明，昼夜节律紊乱与糖耐量异常、代谢综合征和T2 DM患病率增加之间存在强烈的相关性。我们之前在动物模型中的工作表明，β细胞昼夜节律时钟功能的遗传或环境干扰通过损害调节β细胞功能和质量而增加发生糖尿病的倾向。此外，最近的初步数据证实，β细胞的生物钟功能调节细胞对dna损伤的反应。因此，常见的糖尿病应激源(如糖毒性)不成比例地导致时钟扰乱的β细胞中的β损伤和DNA细胞衰竭。这些累积的观察使我们形成了三个特定的目标，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，特定目标1将检验这样一种假设，即昼夜节律(全球和β细胞特有的)的破坏增加了β细胞对dna损伤的易感性，并还将检验生物钟是否通过转录控制β细胞中的生长停滞和dna损伤诱导的45G(Gadd45G)基因来调节dna损伤反应。特定目的2将验证这样的假设，即新生(未成熟)β细胞的特征是生物钟功能受到抑制，从而增加了它们对DNA损伤诱导的糖尿病损伤的易感性。后续研究将使用遗传方法在诱导多能干细胞(IPSC)来源的未成熟人类β细胞中诱导生物钟功能，并将测试该方法在提高对糖尿病损伤和功能成熟的反应方面的有效性。最后，特殊目标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β损伤导致的β细胞在昼夜节律紊乱的成年细胞中的磨损。这将通过开发一种新的条件β细胞特异性表达BMal1的小鼠模型来实现，并测试这种方法是否会导致β细胞衰竭的减弱，以应对伴随的昼夜节律中断和饮食诱导的肥胖。综上所述，概述的具体目标：1)将揭示一种新的分子机制，负责昼夜节律中断诱导的β细胞衰竭的易感性；2)将利用这一知识测试一种治疗方法，以防止在非生理性条件下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.