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Diabetes. 2016 Jun;65(6):1741-51. doi: 10.2337/db15-0999. Epub 2016 Feb 11.

Impact of Common Diabetes Risk Variant in MTNR1B on Sleep, Circadian, and Melatonin Physiology.

Author information

1
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.
2
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.
3
Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA Institute of Aerospace Medicine, German Aerospace Center, Cologne, Germany.
4
Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA.
5
Computational Medicine Core, Center for Lung Biology, UW Medicine Sleep Center, Department of Medicine, University of Washington, Seattle, WA.
6
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA.
7
Department of Health Studies, The University of Chicago, Chicago, IL.
8
Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA School of Psychological Sciences, Monash University, Melbourne, Victoria, Australia.
9
Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD.
10
The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL.
11
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 Department of Social and Behavioral Sciences, Harvard School of Public Health, Boston, MA.
12
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 rsaxena@broadinstitute.org.

Abstract

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.

PMID:
26868293
PMCID:
PMC4878414
DOI:
10.2337/db15-0999
[Indexed for MEDLINE]
Free PMC Article

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