Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans
Open accessAbstract
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.
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Studies in highly controlled laboratory conditions have found that eating during the biological night causes metabolic changes, including increased postprandial glucose.
“Studies performed in highly controlled laboratory conditions have found that eating during the biological night causes metabolic changes, including increased postprandial glucose (3,8,9).”
From Interplay of Dinner Timing and <i>MTNR1B</i> Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial (2022) · cites this paper as [8]
The circadian effect on glucose tolerance and b-cell responsivity appeared to be independent of melatonin signaling, because melatonin levels were low during the circadian evening in previous studies.
“The circadian effect appeared to be independent of melatonin signaling, because melatonin levels were low during the circadian evening ($2000-2200 h) in the previous studies (8,32).”
From Interplay of Dinner Timing and <i>MTNR1B</i> Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial (2022) · cites this paper as [8]
The decrease in insulin sensitivity is mostly caused by the behavioral cycle, while the circadian system dominates the deterioration in glucose tolerance and b-cell responsivity.
“Furthermore, it has been shown that such a decrease in insulin sensitivity is mostly caused by the behavioral cycle, while the circadian system dominates the deterioration in glucose tolerance and b-cell responsivity (8,32).”
From Interplay of Dinner Timing and <i>MTNR1B</i> Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial (2022) · cites this paper as [8]
In humans, a circadian misalignment protocol with a 12-h shift of all meals resulted in elevated blood glucose and reduced insulin levels after the evening dinner.
“In humans, a circadian misalignment protocol with a 12-h shift of all meals resulted in elevated blood glucose and reduced insulin levels after the evening dinner [263].”
From Effects of diet, lifestyle, Chrononutrition and alternative dietary interventions on postprandial Glycemia and insulin resistance (2022) · cites this paper as [263]
In experimental studies, a combination of circadian misalignment and sleep restriction reduces insulin sensitivity, increases inflammation, and impairs glucose tolerance.
“In experimental studies, a combination of circadian misalignment and sleep restriction has been shown to reduce insulin sensitivity (124), increase inflammation (112), and impair glucose tolerance (125).”
From Chronotype: Implications for Epidemiologic Studies on Chrono-Nutrition and Cardiometabolic Health (2019) · cites this paper as [124]
In a realistic simulated night work protocol, circadian misalignment decreased glucose tolerance, independent of effects of the circadian phase and of the behavioral cycle.
“Recently we showed, using a realistic simulated night work protocol including several consecutive shifts of night work under room light intensity (90 lux), that circadian misalignment decreased glucose tolerance, independent of effects of the circadian phase and of the behavioral cycle (72).”
From Circadian rhythms, metabolism, and chrononutrition in rodents and humans (2016) · cites this paper as [72]
The effects of circadian misalignment were sustained for several days upon repeated exposure.
“This study further supported the notion that the effects of circadian misalignment cannot be fully explained by disturbances in sleep and showed that these effects were sustained for several days upon repeated exposure.”
From Circadian rhythms, metabolism, and chrononutrition in rodents and humans (2016) · cites this paper as [72]
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- Authors
- Morris, C. J., Yang, J. N., Garcia, J. I., Myers, S., Bozzi, I., Wang, W., Buxton, O. M., Shea, S. A., & Scheer, F. A. J. L.
- Affiliations
- Brigham and Women's Hospital (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-04-13
- Volume
- 112
- Issue
- 17
- Pages
- E2225-34
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4418873
- OpenAlex
- W2081139788
- Cited by
- 523
- References
- 67
- Citations by year
- 2026: 77 · 2025: 58 · 2024: 53 · 2023: 45 · 2022: 48 · 2021: 52 · 2020: 48 · 2019: 36 · 2018: 34 · 2017: 33 · 2016: 26 · 2015: 13
- FWCI
- 19.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Heart, Lung, and Blood Institute (HL094806, HL118601, HL076446)
- National Aeronautics and Space Administration (NCC 9-58)
- HHS | NIH | National Institute on Aging (P01 AG009975)
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (DK099512)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and Work-Related Fatigue
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- circadian misalignment, circadian system, glucose tolerance, postprandial blood glucose, circadian phase, shift work, diabetes risk, beta-cell function, insulin sensitivity, sleep
- MeSH terms
- Adult, Blood Glucose, Circadian Rhythm, Diabetes Mellitus, Female, Glucose Tolerance Test, Humans, Male, Middle Aged, Sleep, Postprandial Period, Insulin-Secreting Cells
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