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 inlaboratory 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.
Original language | English (US) |
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Pages (from-to) | 1741-1751 |
Number of pages | 11 |
Journal | Diabetes |
Volume | 65 |
Issue number | 6 |
DOIs | |
State | Published - Jun 1 2016 |
Funding
This study was conducted with support from the National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK089378 to R.S. and F.A.J.L.S.), support from Harvard Catalyst of the Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH Award 8UL1TR00017005 to F.A.J.L.S. and R.S.), support from the NHLBI (T32HL07901) and the National Institute on Aging (NIA) (F32 AG316902) to K.S., and financial contributions from Harvard University and its affiliated academic health care centers. J.M.L., S.R., and R.S. were further supported by the following grants: NHLBI R21 HL121728 (R.S.), NIDDK F32 DK102323 (J.M.L.), and NHLBI R01 HL113338 and NHLBI R01 HL098433 (S.R.). F.A.J.L.S. was further supported by the NHLBI (R01HL094806 and R01HL118601) and the NIDDK (R01DK099512). A.-M.C. was also supported by the NHLBI (K01 HL115458). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, or the NIH. The CARe study and SHHS are supported by the NHLBI cooperative agreements U01HL53941 (Boston University), U01HL53916 (University of California, Davis), U01HL53934 (University of Minnesota), U01HL53937 and U01HL63429 (Johns Hopkins University), and U01HL63463 (Case Western Reserve University). The following funding contributed to phenotype data collection in in-laboratory studies: NIA (R01AG06072, R01AG06072, and P01AG009975), NHLBI (R01HL077453, R01HL080978, R01HL093279, R01HL094654, and R01HL077399), Air Force Office of Scientific Research (FA9550), NIH (R21AT002571, R01NS054277, and R01MH45130), National Space Biomedical Research Institute (HFP01601), Brain and Behavior Research Foundation Young Investigator Award, and General Clinical Research Center (M01RR02635). J.F.D. was supported by the NIA (R01AG044416), the NHLBI (R01HL093279 and R01HL094654), and the Brigham and Women's Hospital Brigham Research Institute Fund to Sustain Research Excellence. Investigators were also funded by financial contributions from Brigham and Women's Hospital and from Harvard University and its affiliated academic health care centers. This study was also funded by the NHLBI (01EHLE114088, K24EHL105664, R01HL09327, R01HL09465, and RC2EHL101340), the National Space Biomedical Research Institute (HFP02802), and the NIH (M01RR02635 and R01EGME10501). C.A. reports receiving a research award/prize from Sanofi and lecturing fees from Brown Medical School/Rhode Island Hospital, Ausmed Education, and Rio Tinto. She has also received contract research funding from Pacific Brands and VicRoads through an agreement with Monash University. She has served as consultant to the Rail, Tram and Bus Union, the National Transport Commission, the Transport Accident Commission, and the Victoria Police. She is a participant in the Cooperative Research Centre for Alertness, Safety and Productivity. C.A.C. has received consulting fees from or served as a paid member of scientific advisory boards for the Boston Celtics, the Boston Red Sox, Citgo, the Cleveland Browns, Merck, Novartis, Purdue Pharma LP, Quest Diagnostics, Inc., Teva Pharmaceuticals Industries Ltd., Valero Inc., and Vanda Pharmaceuticals, Inc. He also owns an equity interest in LifeTrac, Inc., Somnus Therapeutics, Inc., and Vanda Pharmaceuticals, Inc. and has received royalties from McGraw Hill, Penguin Press/Houghton Mifflin Harcourt, and Philips Respironics, Inc. He has also received grants and research support from Cephalon, the National Football League Charities, Philips Respironics, ResMed Foundation, the San Francisco Bar Pilots, and Sysco. He has received lecture fees from the American Academy of Sleep Medicine, American Academy of Dental Sleep Medicine, Harvard School of Public Health, Integritas Communications Group, Montefiore Medical Center, Stanford Center for Sleep Sciences and Medicine, and the University of Buffalo. The Harvard Medical School Division of Sleep Medicine (HMS/DSM), which C.A.C. directs, has received gifts from many outside organizations and individuals including the Concord Music Company, Delos Living, Flux Software, Jordan's Furniture, King Koil, Leggett and Platt, Merck Neurosciences, Metro Naps, Novartis Consumer Health, Optum, Patient Point, Philips Home Healthcare Solutions, ResMed, Simmons Bedding, Sleep Apnea Treatment Centers of America, Sleep Med, Turner Broadcasting, UnitedHealthcare Clinical Services, and Vanda Pharmaceuticals. The HMS/DSM Sleep and Health Education Program has received educational grant funding from Cephalon, Takeda Pharmaceuticals, Sanofi, and Sepracor. C.A.C. is the incumbent of an endowed professorship provided to Harvard University by Cephalon and holds a number of process patents in the field of sleep/circadian rhythms (e.g., photic resetting of the human circadian pacemaker). Since 1985, he has also served as an expert witness on various legal cases related to sleep and/or circadian rhythms including Bombardier, Inc., Citgo, Greyhound, Michael Jackson's mother and children, Purdue Pharma, United Parcel Service (UPS), and Valero Inc. O.M.B. reports investigator-initiated research grant support from Cephalon (now Teva) that partially supported this work. Unrelated to this work, O.M.B. discloses investigator-initiated research grant support from Sepracor (now Sunovion), personal fees from Takeda Pharmaceuticals North America, expert witness testimony for Dinsmore LLC, serving on the scientific advisory board for Matsutani America, and receiving travel support and/or honoraria from the Wake Forest University Medical Center, American Academy of Craniofacial Pain, NHLBI, NIDDK, National Postdoctoral Association, Oklahoma State University, Oregon Health and Science University, SUNY Downstate Medical Center, American Diabetes Association, New York University, and Academy of Nutrition and Dietetics outside of the submitted work.
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism