Impact of common diabetes risk variant in MTNR1B on sleep, circadian, and melatonin physiology

Jacqueline M. Lane, Anne Marie Chang, Andrew C. Bjonnes, Daniel Aeschbach, Clare Anderson, Brian E. Cade, Sean W. Cain, Charles A. Czeisler, Sina A. Gharib, Joshua J. Gooley, Daniel J. Gottlieb, Struan F A Grant, Elizabeth B. Klerman, Diane S. Lauderdale, Steven W. Lockley, Miriam Munch, Sanjay Patel, Naresh M. Punjabi, Shanthakumar M.W. Rajaratnam, Melanie Rueger & 11 others Melissa A. St. Hilaire, Nayantara Santhi, Karin Scheuermaier, Eliza Van Reen, Phyllis C. Zee, Steven A. Shea, Jeanne F. Duffy, Orfeu M. Buxton, Susan Redline, Frank A J L Scheer, Richa Saxena

Research output: Contribution to journalArticleResearchpeer-review

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 languageEnglish
Pages (from-to)1741-1751
Number of pages11
JournalDiabetes
Volume65
Issue number6
DOIs
Publication statusPublished - 1 Jun 2016

Cite this

Lane, J. M., Chang, A. M., Bjonnes, A. C., Aeschbach, D., Anderson, C., Cade, B. E., ... Saxena, R. (2016). Impact of common diabetes risk variant in MTNR1B on sleep, circadian, and melatonin physiology. Diabetes, 65(6), 1741-1751. https://doi.org/10.2337/db15-0999
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. / Impact of common diabetes risk variant in MTNR1B on sleep, circadian, and melatonin physiology. In: Diabetes. 2016 ; Vol. 65, No. 6. pp. 1741-1751.
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title = "Impact of common diabetes risk variant in MTNR1B on sleep, circadian, and melatonin physiology",
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.",
author = "Lane, {Jacqueline M.} and Chang, {Anne Marie} and Bjonnes, {Andrew C.} and Daniel Aeschbach and Clare Anderson and Cade, {Brian E.} and Cain, {Sean W.} and Czeisler, {Charles A.} and Gharib, {Sina A.} and Gooley, {Joshua J.} and Gottlieb, {Daniel J.} and Grant, {Struan F A} and Klerman, {Elizabeth B.} and Lauderdale, {Diane S.} and Lockley, {Steven W.} and Miriam Munch and Sanjay Patel and Punjabi, {Naresh M.} and Rajaratnam, {Shanthakumar M.W.} and Melanie Rueger and {St. Hilaire}, {Melissa A.} and Nayantara Santhi and Karin Scheuermaier and {Van Reen}, Eliza and Zee, {Phyllis C.} and Shea, {Steven A.} and Duffy, {Jeanne F.} and Buxton, {Orfeu M.} and Susan Redline and Scheer, {Frank A J L} and Richa Saxena",
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Lane, JM, Chang, AM, Bjonnes, AC, Aeschbach, D, Anderson, C, Cade, BE, Cain, SW, Czeisler, CA, Gharib, SA, Gooley, JJ, Gottlieb, DJ, Grant, SFA, Klerman, EB, Lauderdale, DS, Lockley, SW, Munch, M, Patel, S, Punjabi, NM, Rajaratnam, SMW, Rueger, M, St. Hilaire, MA, Santhi, N, Scheuermaier, K, Van Reen, E, Zee, PC, Shea, SA, Duffy, JF, Buxton, OM, Redline, S, Scheer, FAJL & Saxena, R 2016, 'Impact of common diabetes risk variant in MTNR1B on sleep, circadian, and melatonin physiology' Diabetes, vol. 65, no. 6, pp. 1741-1751. https://doi.org/10.2337/db15-0999

Impact of common diabetes risk variant in MTNR1B on sleep, circadian, and melatonin physiology. / 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.

In: Diabetes, Vol. 65, No. 6, 01.06.2016, p. 1741-1751.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Impact of common diabetes risk variant in MTNR1B on sleep, circadian, and melatonin physiology

AU - Lane, Jacqueline M.

AU - Chang, Anne Marie

AU - Bjonnes, Andrew C.

AU - Aeschbach, Daniel

AU - Anderson, Clare

AU - Cade, Brian E.

AU - Cain, Sean W.

AU - Czeisler, Charles A.

AU - Gharib, Sina A.

AU - Gooley, Joshua J.

AU - Gottlieb, Daniel J.

AU - Grant, Struan F A

AU - Klerman, Elizabeth B.

AU - Lauderdale, Diane S.

AU - Lockley, Steven W.

AU - Munch, Miriam

AU - Patel, Sanjay

AU - Punjabi, Naresh M.

AU - Rajaratnam, Shanthakumar M.W.

AU - Rueger, Melanie

AU - St. Hilaire, Melissa A.

AU - Santhi, Nayantara

AU - Scheuermaier, Karin

AU - Van Reen, Eliza

AU - Zee, Phyllis C.

AU - Shea, Steven A.

AU - Duffy, Jeanne F.

AU - Buxton, Orfeu M.

AU - Redline, Susan

AU - Scheer, Frank A J L

AU - Saxena, Richa

PY - 2016/6/1

Y1 - 2016/6/1

N2 - 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.

AB - 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.

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