Melatonin and Receptor Gene Variant: Linking Circadian System and Type 2 Diabetes

褪黑激素和受体基因变异：昼夜节律系统与 2 型糖尿病的联系

• 批准号: 9129655
• 负责人: RICHA SAXENA
• 金额: $ 76.33万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-19 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9129655
• 关键词: Address; Affinity; Biological; Circadian Rhythms; Clinical; Clinical assessments; Cross-Over Studies; Data; Delayed Sleep Phase Syndrome; Development; Double-Blind Method; Eating; Food; Genes; Genetic; Genetic Risk; Genetic Variation; Genotype; Glucose; Goals; Health; Hormones; Human; Ice; Insulin; Intervention; Islets of Langerhans; Jet Lag Syndrome; Laboratories; Laboratory Study; Ligands; Light; Link; Mediating; Melatonin; Melatonin Receptors; Metabolic; Metabolism; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Participant; Phenotype; Placebo Control; Plasma; Protocols documentation; Randomized; Receptor Gene; Receptor, Melatonin, MT2; Recommendation; Research; Risk; Role; Sampling; Signal Transduction; Sleep; Sleep disturbances; Sleeplessness; System; Testing; Therapeutic; Time; Translations; Variant; Work; base; blood glucose regulation; clinically relevant; design; diabetes risk; evidence base; fight against; genetic variant; genome wide association study; glucose metabolism; glucose tolerance; glycemic control; improved; in vivo; indexing; innovation; insight; insulin secretion; insulin sensitivity; interest; intravenous glucose tolerance test; novel; personalized approach; prevent; risk variant; shift work; sis Genes; trait

 DESCRIPTION (provided by applicant): Our recent discovery of MTNR1B, encoding for the high-affinity melatonin receptor MT2, as a novel genetic risk variant for type 2 diabetes (T2D) and glycemic traits in genome wide association studies (GWAS) has sparked great interest in the role of melatonin in glycemic control. However, the exact mechanism is not yet understood. A major limitation in all previous GWAS is that the clinical assessment of T2D and of the glycemic traits are based on daytime assessments, when circulating concentrations of the ligand of the MT2 receptor, i.e., melatonin, are near-undetectable. The observed phenotypes of the MTNR1B risk variant may thus be the proverbial tip of the ice berg compared to its potential impact during the night when endogenous melatonin concentrations are approximately 20-fold higher or following exogenous melatonin administration. Indeed, while in GWAS we find the magnitude of effect of the MTNR1B risk variant on 2-h glucose concentrations following OGTT to be approximately 0.07 mmol/L, in our preliminary data, following exogenous melatonin administration in the morning elevating circulating levels to or beyond nighttime concentrations, this impact was approximately 15-fold larger (1.00 mmol/L). In this proposal, we overcome a number of limitations in prior work, and we aim to test the hypotheses that: (1) exogenous melatonin administration at a time that melatonin levels are normally low worsens glucose tolerance and insulin sensitivity; (2) this effect is stronger in the carriers of the common MTNR1B risk SNP compared to non-carriers; (3) the interaction of melatonin administration and genetic variance on glucose tolerance depends on time of day; (4) suppression of nighttime melatonin concentrations by light exposure during simulated night work improves glucose tolerance; and (5) this beneficial effect is stronger in the carriers of the common MTNR1B risk SNP compared to non-carriers. The hypotheses will be tested under highly controlled in-laboratory studies. To further investigate underlying mechanisms, we will perform parallel studies using ex vivo human pancreatic islets. This research will provide mechanistic insights into the effects of elevated melatonin concentrations concurrent with food intake as occurs in the 10% of the work force engaged in night shift work, in the millions of people who consume food after dinner when endogenous melatonin levels are elevated, and in people using exogenous melatonin against sleep disturbances, jet lag, and delayed sleep phase syndrome. In addition this research may help in the development of evidence-based countermeasures such as light exposure in the fight against T2D in shift workers and night eaters.

 描述（由申请人提供）：我们最近在全基因组关联研究 (GWAS) 中发现了编码高亲和力褪黑激素受体 MT2 的 MTNR1B，作为 2 型糖尿病 (T2D) 和血糖特征的新型遗传风险变异体，引发了巨大的关注。人们对褪黑激素在血糖控制中的作用感兴趣，但其确切机制尚不清楚，之前所有 GWAS 的一个主要限制是 T2D 和 T2D 的临床评估。血糖特征基于白天评估，此时 MT2 受体配体（即褪黑激素）的循环浓度几乎检测不到，因此，与其潜力相比，观察到的 MTNR1B 风险变异表型可能只是冰山一角。事实上，当内源性褪黑激素浓度大约高出 20 倍时或在施用外源性褪黑激素后，我们发现了影响的程度。 OGTT 后 2 小时葡萄糖浓度的 MTNR1B 风险变异约为 0.07 mmol/L，根据我们的初步数据，在早上施用外源性褪黑激素将循环水平提高到或超过夜间浓度后，这种影响大约是 15 倍（1.00 mmol/L）。在这项建议中，我们克服了先前工作中的许多限制，我们的目标是测试以下假设：（1）外源性褪黑激素给药时间为褪黑激素水平通常较低，导致葡萄糖耐量和胰岛素敏感性恶化；(2) 与非携带者相比，这种效应在常见 MTNR1B 风险 SNP 的携带者中更强；(3) 褪黑激素的施用和遗传变异对葡萄糖耐量的相互作用取决于(4) 模拟夜间工作期间光照可抑制夜间褪黑激素浓度，从而改善葡萄糖耐量；(5) 这种有益效果在常见 MTNR1B 风险 SNP 的携带者中更为明显；与非携带者相比，这些假设将在高度受控的实验室研究中进行测试，为了进一步研究潜在的机制，我们将使用离体人类胰岛进行平行研究，该研究将为褪黑激素浓度升高的影响提供机制见解。与食物摄入同时发生的情况有 10% 从事夜班工作的劳动力、数百万人在晚餐后内源性褪黑激素水平升高时进食，以及使用外源性褪黑激素影响睡眠的人。此外，这项研究可能有助于制定基于证据的对策，例如通过光照来对抗轮班工人和夜食者的 T2D。