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Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans

  1. Frank A. J. L. Scheera,b,1
  1. aMedical Chronobiology Program, Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Boston, MA 02115;
  2. bDivision of Sleep Medicine, Harvard Medical School, Boston, MA 02115;
  3. cDepartment of Biobehavioral Health, Pennsylvania State University, University Park, PA 16802; and
  4. dOregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239

  1. Edited by Joseph S. Takahashi, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, and approved March 20, 2015 (received for review October 1, 2014)

Significance

It is established that glucose tolerance decreases from the morning to the evening, and that shift work is a risk factor for diabetes. However, the relative importance of the endogenous circadian system, the behavioral cycle (including the sleep/wake and fasting/feeding cycles), and circadian misalignment on glucose tolerance is unclear. We show that the magnitude of the effect of the endogenous circadian system on glucose tolerance and on pancreatic β-cell function was much larger than that of the behavioral cycle in causing the decrease in glucose tolerance from morning to evening. Also, independent from circadian phase and the behavioral cycle, circadian misalignment resulting from simulated night work lowered glucose tolerance—without diminishing effects upon repeated exposure—with direct relevance for shift workers.

Abstract

Glucose tolerance is lower in the evening and at night than in the morning. However, the relative contribution of the circadian system vs. the behavioral cycle (including the sleep/wake and fasting/feeding cycles) is unclear. Furthermore, although shift work is a diabetes risk factor, the separate impact on glucose tolerance of the behavioral cycle, circadian phase, and circadian disruption (i.e., misalignment between the central circadian pacemaker and the behavioral cycle) has not been systematically studied. Here we show—by using two 8-d laboratory protocols—in healthy adults that the circadian system and circadian misalignment have distinct influences on glucose tolerance, both separate from the behavioral cycle. First, postprandial glucose was 17% higher (i.e., lower glucose tolerance) in the biological evening (8:00 PM) than morning (8:00 AM; i.e., a circadian phase effect), independent of the behavioral cycle effect. Second, circadian misalignment itself (12-h behavioral cycle inversion) increased postprandial glucose by 6%. Third, these variations in glucose tolerance appeared to be explained, at least in part, by different mechanisms: during the biological evening by decreased pancreatic β-cell function (27% lower early-phase insulin) and during circadian misalignment presumably by decreased insulin sensitivity (elevated postprandial glucose despite 14% higher late-phase insulin) without change in early-phase insulin. We explored possible contributing factors, including changes in polysomnographic sleep and 24-h hormonal profiles. We demonstrate that the circadian system importantly contributes to the reduced glucose tolerance observed in the evening compared with the morning. Separately, circadian misalignment reduces glucose tolerance, providing a mechanism to help explain the increased diabetes risk in shift workers.

Footnotes

  • ↵1To whom correspondence may be addressed. Email: cjmorris{at}partners.org or fscheer{at}rics.bwh.harvard.edu.

  • Author contributions: C.J.M. and F.A.J.L.S. designed research; C.J.M., J.N.Y., J.I.G., S.M., I.B., and F.A.J.L.S. performed research; C.J.M., W.W., and F.A.J.L.S. analyzed data; and C.J.M., O.M.B., S.A.S., and F.A.J.L.S. wrote the paper.

  • Conflict of interest statement: O.M.B. has received two investigator-initiated grants from Sepracor (now Sunovion; ESRC-0004 and ESRC-0977; ClinicalTrials.gov identifiers NCT00555750 and NCT00900159) and two investigator-initiated grants from Cephalon (now Teva; ClinicalTrials.gov identifier NCT00895570); received Speaker’s Bureau, continuing medical education (CME) and non-CME lecture honoraria, and an unrestricted educational grant from Takeda Pharmaceuticals North America; served as a consultant and expert witness for Dinsmore and received consulting fees for serving on the Scientific Advisory Board of Matsutani America and consulting fees from the Wake Forest University Medical Center; received speaking fees and/or travel support for speaking from American Academy of Craniofacial Pain, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Postdoctoral Association, Oklahoma State University, Oregon Health & Science University, State University of New York Downstate Medical Center, American Diabetes Association, and New York University.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1418955112/-/DCSupplemental.

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