Circadian disruption-induced mitochondrial dysfunction in diabetes

昼夜节律紊乱引起的糖尿病线粒体功能障碍

• 批准号: 10317856
• 负责人: Vijay K Yechoor
• 金额: $ 46.15万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10317856
• 关键词: ARNTL gene; Attenuated; Beta Cell; Cell Line; Cell physiology; Circadian Dysregulation; Circadian desynchrony; Complement; Coupling; Data; Development; Diabetes Mellitus; Dose; Enhancers; Ensure; Epidemic; Etiology; Failure; Fasting; Fatty acid glycerol esters; Feedback; Functional disorder; General Population; Genes; Genetic; Genetic Models; Genetic Transcription; Glucose; Human; Impairment; Incidence; Intervention; Jet Lag Syndrome; Lead; Light Exercise; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic dysfunction; Metabolic syndrome; Metabolism; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; Nuclear Receptors; Nutrient; PDH kinase; Pathway interactions; Pharmacology; Physiological; Plasma; Prediabetes syndrome; Production; Pyruvate; Regulation; Risk; Risk Factors; Secondary to; Stimulus; Structure of beta Cell of islet; Techniques; Testing; Therapeutic; Therapeutic Intervention; Transcriptional Regulation; Up-Regulation; base; blood glucose regulation; circadian; circadian pacemaker; circadian regulation; diabetes risk; diabetic; diabetic patient; environmental intervention; experimental study; feeding; flexibility; gain of function; gene therapy; improved; insulin secretion; islet; loss of function; mitochondrial dysfunction; molecular clock; molecular modeling; mortality; mouse model; overexpression; oxidation; prevent; shift work; social; stable isotope; transcription factor

Circadian disruption has been strongly associated with diabetes and metabolic syndrome. Recent human studies implicate β-cell dysfunction as a potential mechanism underlying the increased risk for diabetes with circadian disruption. It is, therefore, imperative to understand the interaction between the circadian clock and regulation of β-cell function to prevent diabetes. We have shown previously that genetic disruption of the circadian clock, by deletion of Bmal1, a non-redundant core clock gene, in mice, leads to β-cell failure and diabetes, secondary to impaired glucose-stimulated ATP production, uncoupling and impaired glucose-stimulated insulin secretion (GSIS). β-cells, normally, need to be “metabolically flexible” in being able to switch between substrates for energy production. However, it is unknown if circadian clock regulates this metabolic flexibility in β-cells. Our preliminary data suggests that circadian disruption, even for short periods, via an upregulation of Pdk (pyruvate dehydrogenase kinase), restricts pyruvate entry into mitochondria for oxidation and induces metabolic inflexibility, and impairment in glucose utilization by the pancreatic β-cells leading to diabetes. The overarching hypothesis for this proposal is that the circadian clock orchestrates the metabolic pathways in β-cells to ensure efficient stimulus-secretion coupling. New data from our lab indicates that circadian disruption leads to metabolic inflexibility in the β-cell wherein it is unable to utilize glucose effectively. We hence hypothesize that circadian disruption leads to impaired mitochondrial function resulting in impaired substrate utilization, metabolic inflexibility leading to β-cell failure and diabetes. We will use environmental means to induce circadian disruption in mice, complemented by inducible and β-cell specific genetic deletion and overexpression models of molecular clock (Bmal1 and Rev-erb alpha) along with pharmacological and genetic modulation of the molecular clock and the proposed target pathways including Pdk in human and mouse islets, to test mechanisms underlying the β- cell failure seen with circadian disruption, especially as it relates to substrate oxidation. We will use pharmacological interventions to target specific disrupted pathways to restore metabolic flexibility in circadian disrupted β-cells. The specific aims of the proposal are: (1) To test if circadian disruption leads to mitochondrial dysfunction and metabolic inflexibility in β-cells, using environmental and genetic circadian disruption models and investigate if Rev-erb alpha-Pdk axis mediate the circadian regulation of substrate utilization in β-cells. (2) To delineate circadian clock regulation of mitochondrial function in normal human β-cells and alteration in diabetic state using loss-of and gain-of-function studies of the molecular clock in normal and diabetic human islets. (3) Test targeted pharmacological interventions to reverse circadian disruption-induced β-cell mitochondrial dysfunction. This proposal will decipher the underlying mechanisms of β-cell failure with circadian disruption in mouse models, test their applicability in human islets and look at targeting specific pathways to improve β-cell function that lead to therapies to prevent and treat diabetes.

昼夜节律紊乱与糖尿病和代谢综合征密切相关。最新的人体研究 β细胞功能障碍是糖尿病发生昼夜节律风险增加的潜在机制 颠覆。因此，有必要了解生物钟和调节之间的相互作用。 β-细胞具有预防糖尿病的功能。我们之前已经证明，生物钟的基因破坏，通过 在小鼠中，非冗余核心时钟基因BMal1的缺失会导致β细胞衰竭和继发性糖尿病 葡萄糖刺激的ATP合成、解偶联和葡萄糖刺激的胰岛素分泌受损 (GSIS)。正常情况下，β细胞需要具有“代谢灵活性”，以便能够在不同的底物之间转换能量。 制作。然而，目前尚不清楚生物钟是否调节β细胞的这种代谢灵活性。我们的预赛 数据表明，昼夜节律的紊乱，即使是很短的时期，也是通过PDK(丙酮酸)的上调 脱氢酶)，限制丙酮酸进入线粒体进行氧化，并诱导代谢 缺乏灵活性，胰腺β细胞对葡萄糖的利用受损，导致糖尿病。最重要的是 这一提议的假设是，生物钟协调β细胞中的代谢途径，以确保 高效的刺激-分泌耦合。我们实验室的新数据表明，昼夜节律紊乱会导致新陈代谢 β细胞缺乏灵活性，不能有效地利用葡萄糖。因此我们假设昼夜节律 破坏会导致线粒体功能受损，导致底物利用、代谢受损 缺乏灵活性会导致β细胞衰竭和糖尿病。我们将使用环境手段来诱导昼夜节律的破坏 在小鼠中，辅以可诱导的和β细胞特异性的分子缺失和过度表达模型 时钟(BMal1和Rev-erbα)以及分子时钟的药理和遗传调节 建议的靶途径包括人和小鼠胰岛中的PDK，以测试β潜在的机制- 细胞衰竭表现为昼夜节律紊乱，特别是与底物氧化有关时。我们将使用 针对特定干扰途径的药物干预以恢复昼夜节律中的代谢灵活性 破坏了β细胞。该提案的具体目的是：(1)测试昼夜节律紊乱是否会导致线粒体 使用环境和遗传昼夜节律中断模型研究β细胞的功能障碍和代谢缺乏灵活性 并研究REV-ERBα-PDK轴是否参与β细胞底物利用的昼夜节律调节。(2) 正常人β细胞线粒体功能的昼夜节律及细胞周期的改变 利用正常人和糖尿病人分子钟功能丧失和功能获得研究糖尿病状态 小岛。(3)测试有针对性的药物干预以逆转昼夜节律中断诱导的β细胞 线粒体功能障碍。这一建议将用昼夜节律来破译β细胞衰竭的潜在机制 破坏小鼠模型，测试它们在人类胰岛中的适用性，并着眼于靶向特定的途径 改善β-细胞功能，从而获得预防和治疗糖尿病的治疗方法。