Melatonin decreases human adipose tissue insulin sensitivity
Open accessAbstract
Melatonin is a pineal hormone that modulates the circadian system and exerts soporific and phase‐shifting effects. It is also involved in many other physiological processes, such as those implicated in cardiovascular, endocrine, immune, and metabolic functions. However, the role of melatonin in glucose metabolism remains contradictory, and its action on human adipose tissue (AT) explants has not been demonstrated. We aimed to assess whether melatonin (a pharmacological dose) influences insulin sensitivity in human AT. This will help better understand melatonin administration's effect on glucose metabolism. Abdominal AT (subcutaneous and visceral) biopsies were obtained from 19 participants with severe obesity (age: 42.84 ± 12.48 years; body mass index: 43.14 ± 8.26 kg/m 2) who underwent a laparoscopic gastric bypass. AT biopsies were exposed to four different treatments: control (C), insulin alone (I) (10 nM), melatonin alone (M) (5000 pg/mL), and insulin plus melatonin combined (I + M). All four conditions were repeated in both subcutaneous and visceral AT, and all were performed in the morning at 8 a.m. (n = 19) and the evening at 8 p.m. (in a subsample of n = 12). We used western blot analysis to determine insulin signaling (using the pAKT/tAKT ratio). Furthermore, RNAseq analyses were performed to better understand the metabolic pathways involved in the effect of melatonin on insulin signaling. As expected, insulin treatment (I) increased the pAKT/tAKT ratio compared with control (p < .0001). Furthermore, the addition of melatonin (I + M) resulted in a decrease in insulin signaling as compared with insulin alone (I); this effect was significant only during the evening time (not in the morning time). Further, RNAseq analyses in visceral AT during the evening condition (at 8 p.m.) showed that melatonin resulted in a prompt transcriptome response (around 1 h after melatonin addition), particularly by downregulating the insulin signaling pathway. Our results show that melatonin reduces insulin sensitivity in human AT during the evening. These results may partly explain the previous studies showing a decrease in glucose tolerance after oral melatonin administration in the evening or when eating late when endogenous melatonin is present.
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A recent ex vivo study found that melatonin induces insulin resistance in human adipose tissue explants, and the degree of insulin resistance varied according to a circadian rhythm ex vivo, suggesting a time-of-day-dependent effect.
“A recent ex vivo study found that melatonin induces insulin resistance in human adipose tissue explants (22). The degree of insulin resistance varied according to a circadian rhythm ex vivo, suggesting a time-of-day–dependent effect.”
From Melatonin Impairs Glucose Tolerance, First-Phase Insulin Secretion, and Insulin Feedback Inhibition; Interaction With <i>MTNR1B</i> Diabetes Risk Variant (2026) · cites this paper as [22]
The Results report that melatonin reduced an insulin-response measure in human adipose tissue explants, with a significant effect only at 9 p.m. The Experiments section describes morning and evening testing, which supports a time-of-day-dependent effect, but two testing times do not establish that the degree of insulin resistance followed a circadian rhythm ex vivo. No page numbers were available in our copy. (LLM, conf=0.86)
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Qian, J., Stefanovski, D., Andersen, P. A. K., Vujovic, N., Kelly, L., Lepson, J., Nguyen, H., Byrne, S., Wang, W., Mandrup-Poulsen, T., et al. (2026) · Diabetes Care · doi:10.2337/dc26-0164
Self-citation
- Authors
- Zambrano, C., Garitaonaindia, M. T., Salmerón, D., Pérez‐Sanz, F., Tchio, C., Picinato, M. C., de Medina, F. S., Luján, J., Scheer, F. A. J. L., Saxena, R., Martínez‐Augustin, O., & Garaulet, M.
- Affiliations
- Instituto Murciano de Investigación Biosanitaria (ES)
- Department of Biochemistry and Molecular Biology II, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Ibs Granada, Instituto de Nutrición y Tecnología de los Alimentos (INYTA) José Mataix University of Granada Granada Spain
- Research Biomedical Institute of Murcia (IMIB)‐Arrixaca Murcia Spain
- Broad Institute (US)
- Universidade Federal do Oeste da Bahia (BR)
- Department of Pharmacology, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Ibs Granada Universidad de Granada Granada Spain
- General Surgery Service, Hospital Quirónsalud Murcia Murcia Spain
- Massachusetts General Hospital (US)
- Universidad de Granada (ES)
- Brigham and Women's Hospital (US)
- Corresponding author
- Garaulet, Marta
- ORCID
- Venue
- Journal of Pineal Research
- Publisher
- Wiley
- Published
- 2024-06-11
- Volume
- 76
- Issue
- 5
- Pages
- e12965-e12965
- ISSN
- 0742-3098 (ISSN-L)
- 1600-079X
- OpenAlex
- W4399544031
- Cited by
- 10
- References
- 10
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 1
- FWCI
- 2.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Pineal Research (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Hispana (publishedVersion, cc-by-nc-nd)
- Institutional Repository of the University of Granada (University of Granada) (submittedVersion, cc-by-nc-nd)
- Funders
- Junta de Andalucía (CTS-164, 10.13039/501100011033, MCIN / AEI / 10.13039/501100011033, UGR20, CTS235, A-AGR-468-UGR20, P20-00695)
- Instituto de Salud Carlos III (MCIN/ AEI /10.13039/501100011033, /10.13039/501100011033, P20-00695, A-AGR-468-UGR20, PI21/00952, AEI/10.13039/501100011033, PID2020-112768RB-I00)
- European Regional Development Fund (UGR20, MCIN/AEI/10, 10.13039/501100011033, 13039/501100011033, AEI/10.13039/501100011033, 501100011033, MCIN/ AEI/ 10.13039/501100011033)
- Agencia Estatal de Investigación (AEI//10.13039/501100011033/, 501100011033, 10.13039/501100011033, MCIN/AEI/10.13039/501 100 011 033, 13039, .13039/501100011033, PID2020-112768RB-I00, MCIN / AEI/10, 10.13039, AEI/10)
- National Heart, Lung, and Blood Institute (R01HL140574, L60 HL165650)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK105072, NIDDK R01DK105072, R01DK102696)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- melatonin, insulin sensitivity, human adipose tissue, insulin signaling, Akt phosphorylation, visceral adipose tissue, subcutaneous adipose tissue, obesity, circadian timing, glucose metabolism, transcriptomic response, late eating
- MeSH terms
- Adipose Tissue, Adult, Female, Humans, Insulin, Insulin Resistance, Male, Melatonin, Middle Aged
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