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: 10701803
• 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/10701803
• 关键词: Adolescence; Adolescent; Adult; Agonist; Area; Beds; Behavioral; Circadian Rhythms; Circadian desynchrony; Collaborations; Continuous Glucose Monitor; Coupled; Data; Diet; Dietary Intervention; Dietary intake; Eating; European; Fasting; Gene Frequency; Genes; Genetic; Genetic Carriers; Genotype; Glucose; Glucose tolerance test; Health; Home; Hour; Impairment; Individual; Insulin Resistance; 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; Photography; 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; cardiometabolism; circadian; circadian pacemaker; diabetes risk; diaries; dietary; experience; genetic variant; genome wide association study; glucose tolerance; high risk; high-risk adolescents; improved; improvement on sleep; 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.

项目总结 导致睡眠不足和昼夜节律失调的生理和心理社会因素可能会导致 青少年肥胖和代谢障碍的独特风险。我们的试验数据表明，睡眠不足 肥胖青少年的昼夜节律失调与代谢紊乱有关 通过口服葡萄糖耐量试验进行评估。一种可能的机制是不充分的 睡眠、昼夜节律失调和胰岛素敏感性降低(Si)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会导致血糖失调和 2型糖尿病(T2D)的风险增加。青少年，通常在褪黑激素之后/之前的几个小时内醒来 当褪黑素水平较高且可能发生食物摄取时，发病/抵消可能特别危险。一种常见的 褪黑素受体基因变异是成人SI和T2D降低的危险因素，可能有更大的影响 在较年轻的个体中，但该变异对青少年的功能影响尚未被研究。干预 增加睡眠时间可能会改善习惯性睡眠不足的青少年的睡眠质量，部分原因是通过调整他们的睡眠时间 生物钟对睡眠和饮食的定时，来自我的K23的初始数据表明这是 可行。我们的中心假设是，不足引起的代谢障碍和不良的饮食时机 睡眠和昼夜节律失调可以通过改善睡眠和昼夜节律健康来缓解。此外，我们 假设风险等位基因(G)的存在会增加习惯性睡眠不足的风险 青少年。我们建议通过增加更多的参与者来利用我们正在进行的K23研究，摄影 饮食日记，持续的血糖监测，和基因分型，以检查同时摄入食物和 在典型的睡眠不足一周后，硅上内源性褪黑素和血糖变异性升高， 延长睡眠一周后，食物摄入时间相对于褪黑素的变化，以及 不同的基因导致不同的风险。拟议的项目将提供额外的遗传学培训，建立新的 协作，并为一个重要的新研究领域提供试点数据，这将有助于推动PI 申请R01的研究独立性。这项研究将启动我们确定对策的努力 如行为睡眠或饮食干预、定时强光暴露和药物治疗 如褪黑激素激动剂，以减轻睡眠不足和昼夜节律失调对高胰岛素抵抗的影响 高危青少年，包括睡眠不足、进食晚和早、外源性褪黑素使用者、 MTNR1B G等位基因携带者。