Examining a mechanism for insulin resistance in short sleeping adolescents: Melatonin, food intake, and the role of a melatonin receptor gene variant (MTNR1B)

检查睡眠不足的青少年的胰岛素抵抗机制：褪黑激素、食物摄入和褪黑激素受体基因变异 (MTNR1B) 的作用

• 批准号: 10525121
• 负责人: Stacey Lynn Simon
• 金额: $ 11.66万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-10 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10525121
• 关键词: Adolescence; Adolescent; Adult; Agonist; Alleles; Area; Beds; Behavioral; Circadian Rhythms; Circadian desynchrony; Collaborations; Coupled; Data; Diet; Dietary Intervention; Dietary intake; Eating; European; Fasting; Gene Frequency; Genes; Genetic; Genotype; Glucose; Glucose tolerance test; Health; Home; Hour; Impairment; Individual; Insulin Resistance; Lead; Light; Melatonin; Melatonin Receptors; Mentored Patient-Oriented Research Career Development Award; Metabolic; Metabolic Diseases; Minor; Modernization; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Obesity; Participant; Pathologic; Pharmacological Treatment; Physiological; Process; Psychosocial Factor; Puberty; Receptor, Melatonin, MT2; Research; Risk; Risk Factors; Role; Salivary; Sampling; Schools; Sleep; Sleep Deprivation; Testing; Time; Training; Variant; Woman; Youth; awake; base; cardiometabolism; circadian; circadian pacemaker; diabetes risk; diaries; dietary; experience; genetic variant; genome wide association study; glucose monitor; glucose tolerance; high risk; high-risk adolescents; improved; insulin sensitivity; pressure; psychosocial; receptor expression; reduced food intake; risk variant; sleep onset

PROJECT SUMMARY Physiological and psychosocial factors that result in insufficient sleep and circadian misalignment may confer a unique risk towards obesity and dysmetabolism in youth. Our pilot data demonstrates that insufficient sleep and circadian misalignment in adolescents with obesity are associated with metabolic dysregulation as assessed via oral glucose tolerance test. One possible mechanism for the relationship between insufficient sleep, circadian misalignment, and reduced insulin sensitivity (Si) is the timing of dietary intake and circulating melatonin levels. Dietary intake during times of high melatonin may lead to glucose dysregulation and increased risk of type 2 diabetes (T2D). Adolescents, often awake in the hours of wake after/before melatonin onset/offset when melatonin levels are high and food intake may occur, may be particularly at risk. A common melatonin receptor gene variant is a risk factor for reduced Si and T2D in adults, and may have greater effect in younger individuals, but the functional impact of the variant in adolescents has not been studied. Intervening to increase sleep duration may improve Si in habitually short sleeping adolescents in part by aligning their circadian clock to the timing of sleep and eating occasions, and initial data from my K23 demonstrates this is feasible. Our central hypothesis is that the dysmetabolism and adverse dietary timing induced by insufficient sleep and circadian misalignment can be mitigated by improving sleep and circadian health. Further, we hypothesize that presence of the risk allele (G) will confer additional risk in habitually short sleeping adolescents. We propose to leverage our ongoing K23 study by adding additional participants, photographic diet diaries, continuous glucose monitoring, and genotyping to examine the effect of concurrent food intake and elevated endogenous melatonin on Si and glycemic variability after one week of typical insufficient sleep, change in timing of food intake relative to melatonin following a one-week sleep extension manipulation, and differential risk due to genotype. The proposed project will provide additional training in genetics, build new collaborations, and provide pilot data for an important new area of study that will help move the PI towards research independence in applying for an R01. This study will launch our efforts to determine countermeasures such as behavioral sleep or dietary interventions, timed bright light exposure, and pharmacological treatments such as melatonin agonists to mitigate the effect of insufficient sleep and circadian misalignment on IR for high risk adolescents, including those obtaining insufficient sleep, late and early eaters, exogenous melatonin users, and MTNR1B G allele carriers.

项目摘要 导致睡眠不足和昼夜节律未对准的生理和社会心理因素可能会赋予 年轻人对肥胖症和非代谢的独特风险。我们的飞行员数据表明​​睡眠不足 肥胖青少年的昼夜节律错位与代谢失调有关 通过口服葡萄糖耐量测试评估。不足之间关系的一种可能机制 睡眠，昼夜节律的未对准和胰岛素敏感性降低是饮食摄入和循环的时机 褪黑激素水平。高褪黑激素时期的饮食摄入可能导致葡萄糖失调和 增加2型糖尿病的风险（T2D）。青少年，经常在褪黑激素之前/之前醒来时醒来 当褪黑激素水平高并且可能发生食物摄入量时，发作/偏移可能尤其处于危险之中。常见 褪黑激素受体基因变体是成年人降低Si和T2D的危险因素，并且可能具有更大的作用 在年轻人中，但是尚未研究这种变体在青少年中的功能影响。干预 为了增加睡眠持续时间，在习惯短暂的睡眠青少年中可以改善SI的部分来对齐 昼夜节时间到睡眠和饮食场合的时间，我的K23的初始数据表明这是 可行的。我们的中心假设是，由不足引起的非代谢和不良饮食时机 可以通过改善睡眠和昼夜节律来减轻睡眠和昼夜节律的未对准。此外，我们 假设存在风险等位基因（g）的存在将在习惯短暂的睡眠中赋予额外的风险 青少年。我们建议通过添加其他参与者，摄影来利用我们正在进行的K23研究 饮食日记，连续的葡萄糖监测和基因分型，以检查并发食物摄入的影响和 典型睡眠不足之后，SI和血糖变异性上的内源性褪黑激素升高， 一周的睡眠延长操纵后，相对于褪黑激素的食物摄入时间变化，并且 基因型引起的差异风险。拟议的项目将提供遗传学的其他培训，建立新的 协作，并为重要的新研究领域提供试验数据，这将有助于将PI转移到 研究独立性申请R01。这项研究将启动我们确定对策的努力 例如行为睡眠或饮食干预措施，明亮的光暴露和药理治疗 例如褪黑激动剂，以减轻睡眠不足和昼夜节律对IR的影响不足的影响。 冒险的青少年，包括那些无法获得足够睡眠，晚食者和早期食客，外源褪黑激素使用者的人， 和mtnr1b g等位基因载体。