Lane Jacqueline M, Chang Anne-Marie, Bjonnes Andrew C, Aeschbach Daniel, Anderson Clare, Cade Brian E, Cain Sean W, Czeisler Charles A, Gharib Sina A, Gooley Joshua J, Gottlieb Daniel J, Grant Struan F A, Klerman Elizabeth B, Lauderdale Diane S, Lockley Steven W, Munch Miriam, Patel Sanjay, Punjabi Naresh M, Rajaratnam Shanthakumar M W, Rueger Melanie, St Hilaire Melissa A, Santhi Nayantara, Scheuermaier Karin, Van Reen Eliza, Zee Phyllis C, Shea Steven A, Duffy Jeanne F, Buxton Orfeu M, Redline Susan, Scheer Frank A J L, Saxena Richa
Center for Human Genetic Research and Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA Program in Medical and Population Genetics, Broad Institute, Cambridge, MA Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA.
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA Department of Biobehavioral Health, Pennsylvania State University, University Park, PA.
Diabetes. 2016 Jun;65(6):1741-51. doi: 10.2337/db15-0999. Epub 2016 Feb 11.
The risk of type 2 diabetes (T2D) is increased by abnormalities in sleep quantity and quality, circadian alignment, and melatonin regulation. A common genetic variant in a receptor for the circadian-regulated hormone melatonin (MTNR1B) is associated with increased fasting blood glucose and risk of T2D, but whether sleep or circadian disruption mediates this risk is unknown. We aimed to test if MTNR1B diabetes risk variant rs10830963 associates with measures of sleep or circadian physiology in intensive in-laboratory protocols (n = 58-96) or cross-sectional studies with sleep quantity and quality and timing measures from self-report (n = 4,307-10,332), actigraphy (n = 1,513), or polysomnography (n = 3,021). In the in-laboratory studies, we found a significant association with a substantially longer duration of elevated melatonin levels (41 min) and delayed circadian phase of dim-light melatonin offset (1.37 h), partially mediated through delayed offset of melatonin synthesis. Furthermore, increased T2D risk in MTNR1B risk allele carriers was more pronounced in early risers versus late risers as determined by 7 days of actigraphy. Our results provide the surprising insight that the MTNR1B risk allele influences dynamics of melatonin secretion, generating a novel hypothesis that the MTNR1B risk allele may extend the duration of endogenous melatonin production later into the morning and that early waking may magnify the diabetes risk conferred by the risk allele.
睡眠数量和质量异常、昼夜节律失调以及褪黑素调节异常会增加2型糖尿病（T2D）的风险。昼夜节律调节激素褪黑素（MTNR1B）受体中的一种常见基因变异与空腹血糖升高和T2D风险增加有关，但睡眠或昼夜节律紊乱是否介导这种风险尚不清楚。我们旨在测试MTNR1B糖尿病风险变异体rs10830963是否与实验室强化方案（n = 58 - 96）中的睡眠或昼夜生理指标相关，或与来自自我报告（n = 4307 - 10332）、活动记录仪（n = 1513）或多导睡眠图（n = 3021）的睡眠数量、质量和时间测量的横断面研究相关。在实验室研究中，我们发现与褪黑素水平升高的持续时间显著延长（41分钟）和暗光褪黑素偏移的昼夜节律相位延迟（1.37小时）存在显著关联，部分是通过褪黑素合成的延迟偏移介导的。此外，根据7天的活动记录仪测定，MTNR1B风险等位基因携带者中T2D风险增加在早起者与晚起者中更为明显。我们的结果提供了一个惊人的见解，即MTNR1B风险等位基因影响褪黑素分泌的动态变化，产生了一个新的假设，即MTNR1B风险等位基因可能会将内源性褪黑素产生的持续时间延长到早晨更晚的时候，并且早起可能会放大风险等位基因带来的糖尿病风险。
