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

 描述(申请人提供)：我们最近发现的MTNR1B，编码高亲和力的褪黑素受体MT2，作为一种新的2型糖尿病(T2D)和全基因组关联研究(GWAS)中的血糖性状的遗传风险变异，引起了人们对褪黑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。所有以前的GWA的一个主要局限性是，临床对T2D和血糖性状的评估是基于白天的评估，当时循环中MT2受体的配体，即褪黑素的浓度几乎检测不到。因此，观察到的MTNR1B风险变异的表型可能是众所周知的冰山一角，而不是当内源性褪黑素浓度大约高出20倍时或在外源性褪黑素注射后，它在夜间的潜在影响。事实上，虽然我们发现MTNR1B风险变异对口服葡萄糖耐量试验后2小时血糖浓度的影响幅度约为0.07mmo1/L，但在我们的初步数据中，早上外源性褪黑素注射将循环水平提高到或超过夜间浓度后，这种影响大约大15倍(1.00 mmoL/L)。在这个建议中，我们克服了以前工作中的一些限制，我们的目标是检验以下假设：(1)在褪黑素水平通常较低的时候给予外源性褪黑素会恶化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MTNR1B风险SNP携带者中更强；(3)褪黑素给药和遗传变异对糖耐量的交互作用取决于一天中的不同时间；(4)模拟夜间工作期间通过光照暴露抑制夜间褪黑素浓度改善糖耐量；(5)与非携带者相比，MTNR1B常见风险SNP携带者的这种有益作用更强。这些假说将在高度受控的实验室研究中进行验证。为了进一步研究潜在的机制，我们将使用体外人胰岛进行平行研究。这项研究将为在食物摄取的同时增加褪黑素浓度的影响提供机械性见解，这种影响发生在从事夜班工作的10%的劳动力中，在数百万晚餐后进食的人中内源性褪黑素水平上升，以及在使用外源性褪黑素对抗睡眠障碍、时差和睡眠延迟综合征的人中。此外，这项研究可能有助于开发循证对策，例如在夜班工人和夜食者中暴露在与T2D的斗争中。

 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.