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

 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MTNR 1B（编码高亲和力褪黑激素受体MT 2）作为2型糖尿病（T2 D）和血糖性状的新型遗传风险变体，这引发了人们对褪黑激素在血糖控制中的作用的极大兴趣。然而，确切的机制还不清楚。所有先前的GWAS中的主要限制是T2 D和血糖特征的临床评估是基于日间评估，当MT 2受体的配体的循环浓度，即，褪黑激素几乎检测不到观察到的MTNR 1B风险变异的表型可能因此是众所周知的贝格一角相比，其潜在的影响，在夜间内源性褪黑激素浓度约高20倍或外源性褪黑激素管理。事实上，虽然在GWAS中，我们发现MTNR 1B风险变体对OGTT后2小时葡萄糖浓度的影响程度约为0.07 mmol/L，但在我们的初步数据中，在早晨给予外源性褪黑激素将循环水平升高至或超过夜间浓度后，这种影响约为15倍（1.00 mmol/L）。在该提议中，我们克服了先前工作中的许多限制，并且我们的目标是测试以下假设：（1）在褪黑激素水平通常较低的时间给予外源褪黑激素会降低葡萄糖耐量和胰岛素敏感性;（2）与非携带者相比，这种作用在常见MTNR 1B风险SNP的携带者中更强;（3）褪黑激素给药和遗传变异对葡萄糖耐量的相互作用依赖于一天中的时间：（4）在模拟夜间工作期间通过光照抑制夜间褪黑激素浓度改善葡萄糖耐量;和（5）与非携带者相比，这种有益效果在常见MTNR 1B风险SNP的携带者中更强。将在高度对照的实验室研究中检验假设。为了进一步研究潜在的机制，我们将使用离体人胰岛进行平行研究。这项研究将提供机制的见解褪黑激素浓度升高的影响，同时与食物摄入量发生在10%的劳动力从事夜班工作，在数百万人谁吃晚饭后，内源性褪黑激素水平升高，并在人们使用外源性褪黑激素对睡眠障碍，时差，和睡眠相位延迟综合征。此外，这项研究可能有助于制定基于证据的对策，例如在轮班工人和夜间进食者中对抗T2 D的光暴露。

 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.