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Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes
Open accessAbstract
Type 2 diabetes (T2D) is a global pandemic. Genome-wide association studies (GWASs) have identified >100 genetic variants associated with the disease, including a common variant in the melatonin receptor 1 b gene (MTNR1B). Here, we demonstrate increased MTNR1B expression in human islets from risk G-allele carriers, which likely leads to a reduction in insulin release, increasing T2D risk. Accordingly, in insulin-secreting cells, melatonin reduced cAMP levels, and MTNR1B overexpression exaggerated the inhibition of insulin release exerted by melatonin. Conversely, mice with a disruption of the receptor secreted more insulin. Melatonin treatment in a human recall-by-genotype study reduced insulin secretion and raised glucose levels more extensively in risk G-allele carriers. Thus, our data support a model where enhanced melatonin signaling in islets reduces insulin secretion, leading to hyperglycemia and greater future risk of T2D. The findings also imply that melatonin physiologically serves to inhibit nocturnal insulin release.
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“The MTNR1B risk variant rs10830963 has a strong association with fasting glucose and confers increased expression of the melatonin receptor in human pancreatic islets (11).”
From Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial (2022) · cites this paper as [11]
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“This melatonin receptor is a G-protein-coupled receptor that mainly acts via interfering with the formation of cAMP through inhibitory G proteins, inhibiting adenylate cyclase and subsequently inhibiting insulin release (11).”
From Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial (2022) · cites this paper as [11]
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“The MTNR1B risk variant rs10830963 has a strong association with fasting glucose and confers increased expression of the melatonin receptor in human pancreatic islets (11).”
From Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial (2022) · cites this paper as [11]
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“This difference might be partly due to the 3.5-fold higher melatonin concentrations, as supported by our earlier trial in which acute melatonin administration impaired glucose tolerance and in vitro b-cell experiments showing decreased insulin secretion due to melatonin (10,11,18,28).”
From Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial (2022) · cites this paper as [11]
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“results shown in insulin-secreting cells (11) that demonstrated that MTNR1B overexpression augmented the inhibition of insulin release exerted by melatonin.”
From Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial (2022) · cites this paper as [11]
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“Thus, our study supports the hypothesis that melatonin contributes to impaired glucose homeostasis by inhibiting insulin secretion”
From Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial (2022) · cites this paper as [11]
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“Furthermore, while previous studies have shown that the association with fasting glucose during the day (typically morning) is robust and reproducible (11)”
From Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial (2022) · cites this paper as [11]
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“Genetic polymorphismmay be particularly important as some patients may be predisposed to have a pancreas that is sensitive to insulin-inhibiting effects of nocturnal melatonin (Tuomi et al., 2016).”
BackgroundPleiotropic Effects of Melatonin
Mahmood, D. (2019) · Drug Research · doi:10.1055/a-0656-6643 · Cited by 52
“, also suggested that melatonin physiologically could inhibit insulin release during the nighttime.[68] Previously, McMullan et al.”
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Human Pluripotent Stem Cells to Model Islet Defects in Diabetes
Balboa, D., Iworima, D. G., & Kieffer, T. J. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.642152 · Cited by 49
“A genetic variant increasing the expression of MTNR1B has been shown to lower cAMP levels in beta cells, leading to reduced insulin secretion (68).”
BackgroundPace, N. P., Vassallo, J., & Calleja‐Agius, J. (2020) · Early Human Development · doi:10.1016/j.earlhumdev.2020.105219 · Cited by 44
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Melatonin Uptake by Cells: An Answer to Its Relationship with Glucose?
Mayo, J. C., Aguado, A. I. W., Cernuda‐Cernuda, R., Álvarez-Artime, A., Cepas, V., Quirós-González, I., Hevia, D., & Sainz, R. M. (2018) · Molecules · doi:10.3390/molecules23081999 · Cited by 42
“However, whether this is due as has been suggested to an excess of melatonin signaling [175] or rather, on the contrary, to a defective receptor function is still a matter of debate [176].”
BackgroundAssociations between chronotype, MTNR1B genotype and risk of type 2 diabetes in UK Biobank
Tan, X. W., Ciuculete, D. M., Schiöth, H. B., & Benedict, C. (2019) · Journal of Internal Medicine · doi:10.1111/joim.12994 · Cited by 41
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“thesis; cAMP is a stimulator of insulin release [18].”
BackgroundFrom Genetic Association to Molecular Mechanisms for Islet-cell Dysfunction in Type 2 Diabetes
Mattis, K. K., & Gloyn, A. L. (2020) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.12.045 · Cited by 39
McHill, A. W., Hull, J. T., McMullan, C. J., & Klerman, E. B. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00319 · Cited by 38
“In addition, protocols providing exogenous melatonin have found decreases in insulin secretion and sensitivity (56, 57), and individuals carrying a common variant in the melatonin receptor 1b gene have increased risk for impaired glucose regulation (58, 59), further supporting the hypothesis relating the circadian tim…”
BackgroundSkawratananond, S., Xiong, D. X., Zhang, C., Tonk, S. S., Pinili, A., Delacruz, B., Pham, P., Smith, S. C., Navab, R., & Reddy, P. H. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102732 · Cited by 41
Untimely oxidative stress in β-cells leads to diabetes – Role of circadian clock in β-cell function
Lee, J. M., Ma, K., Moulik, M., & Yechoor, V. K. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.02.022 · Cited by 40
Goñi, L., Sun, D., Heianza, Y., Wang, T., Huang, T., Martínez, J. A., Shang, X., Bray, G. A., Smith, S. R., Sacks, F. M., et al. (2018) · European Journal of Nutrition · doi:10.1007/s00394-018-1660-y · Cited by 36
Lined multifocal wearers prefer progressive addition lenses.
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“Another more recent study reported a decreased hepatic insulin sensitivity and an increased insulin secretion in MT2 KOmice (Tuomi et al., 2016).”
BackgroundQiu, X., Liang, T., Wu, Z., Zhu, Y., Gao, W., Gao, B., Qiu, J., Wang, X., Chen, T., Deng, Z., et al. (2022) · International Journal of Biological Sciences · doi:10.7150/ijbs.65973 · Cited by 34
“Melatonin receptor signaling pathways have been found to be related to several diseases, such as type II diabetes mellitus[52], multiple sclerosis[53] and tumor recurrence[54].”
BackgroundSleep Control, GPCRs, and Glucose Metabolism
Tsuneki, H., Sasaoka, T., & Sakurai, T. (2016) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2016.06.011 · Cited by 35
“An increase in the expression of the MT2 receptor found in the islets of humans with a common diabetes risk variant in MTNR1B (rs10830963) was found to enhance the melatonin-induced inhibition of insulin release in insulin-secreting cells [62].”
BackgroundReutrakul, S., Siwasaranond, N., Nimitphong, H., Saetung, S., Chirakalwasan, N., Chailurkit, L., Srijaruskul, K., Ongphiphadhanakul, B., & Thakkinstian, A. (2017) · Chronobiology International · doi:10.1080/07420528.2016.1278382 · Cited by 33
“However, positive effects of melatonin on glucose metabolism were not unanimous as a recent study revealed that melatonin blocks insulin release in mouse islets and clonal insulin-secreting cells (Tuomi et al., 2016).”
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Building Cognition-Aware Systems
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“Chronically high levels of mental load and circadian disruptions can further lead to depression, burnout, and even diabetes [31].”
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Mulder, H. (2017) · Diabetologia · doi:10.1007/s00125-017-4249-8 · Cited by 33
Association of melatonin & MTNR1B variants with type 2 diabetes in Gujarat population
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A new prospective on the role of melatonin in diabetes and its complications
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Melatonin in energy control: Circadian time‐giver and homeostatic monitor
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“99 Temporal mismatches between the nocturnal secretion of pineal melatonin and the daily feeding/fasting cycle may have deleterious effects on human glycemic control.”
BackgroundWhat do we really know about the safety and efficacy of melatonin for sleep disorders?
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“These findings are underpinned by the effects of a gain of function mutation (BG allele^) of the melatonin receptor gene MTNR1B, which is prodiabetic, after overexpression in pancreatic beta cells [66, 67].”
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Xia, A., Zhu, H., Zhao, Z., Liu, H., Wang, P.-H., Ji, L., & Xu, J. (2023) · Nutrients · doi:10.3390/nu15061406 · Cited by 28
“Studies have revealed that the rs10830963G allele greatly enhances the expression of MT2 [58,60–62], with NEUROD1 and FOXA2 [22,63] serving as two important transcription factors in this process.”
BackgroundInfluentialThe case for too little melatonin signalling in increased diabetes risk
Bonnefond, A., & Froguel, P. (2017) · Diabetologia · doi:10.1007/s00125-017-4255-x · Cited by 29
Li‐Gao, R., Hughes, D. A., van Klinken, J. B., de Mutsert, R., Rosendaal, F. R., Mook-Kanamori, D. O., Timpson, N. J., & van Dijk, K. W. (2021) · Diabetes · doi:10.2337/db21-0397 · Cited by 27
“The G-allele carriers exhibited a stronger inhibition of insulin secretion after melatonin treatment (43).”
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Circadian Clock-Controlled Checkpoints in the Pathogenesis of Complex Disease
Li, M., Xin, H., Yuan, Y., Yang, X., Li, H., Tian, D., Zhang, H., Zhang, Z., Han, T.-L., Chen, Q., et al. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.721231 · Cited by 29
Distribution and density of melatonin receptors in human main pancreatic islet cell types
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Pancreatic Islet Transcriptional Enhancers and Diabetes
Cebola, I. (2019) · Current Diabetes Reports · doi:10.1007/s11892-019-1230-6 · Cited by 26
A Wake-up Call for Type 2 Diabetes?
Persaud, S. J., & Jones, P. M. (2016) · New England Journal of Medicine · doi:10.1056/nejmcibr1607950 · Cited by 25
Metadata
- Authors
- Tuomi, T., Nagorny, C. L. F., Singh, P., Bennet, H., Yu, Q., Alenkvist, I., Isomaa, B., Östman, B., Söderström, J., Pesonen, A.-K., Martikainen, S., Räikkönen, K., Forsén, T., Hakaste, L., Almgren, P., Storm, P., Asplund, O., Shcherbina, L., Fex, M., Fadista, J., Tengholm, A., Wierup, N., Groop, L., & Mulder, H.
- Affiliations
- Lund University (SE)
- Uppsala University (SE)
- University of Helsinki (FI)
- Folkhälsans Forskningscentrum (FI)
- Corresponding author
- Mulder, Hindrik
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 23
- Issue
- 6
- Pages
- 1067-1077
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2367683267
- Cited by
- 262
- References
- 44
- Citations by year
- 2026: 17 · 2025: 27 · 2024: 20 · 2023: 17 · 2022: 17 · 2021: 28 · 2020: 29 · 2019: 27 · 2018: 36 · 2017: 30 · 2016: 13
- FWCI
- 39.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion, other-oa)
- Työväentutkimus Vuosikirja (submittedVersion, other-oa)
- Funders
- Helsingin ja Uudenmaan Sairaanhoitopiiri
- Finska Läkaresällskapet
- Folkhälsanin Tutkimussäätiö
- European Foundation for the Study of Diabetes
- Lunds Universitet (2009-1039)
- Novo Nordisk
- Signe ja Ane Gyllenbergin Säätiö
- Vetenskapsrådet (349-2006-237, 325‐2012‐6778, 2010-03490, 521-2012-2119, 2006–237, 2009-1039, 521-2010-3490)
- Samfundet Folkhälsan
- Sigrid Juséliuksen Säätiö
- Svenska Kulturfonden
- Paavo Nurmen Säätiö
- Novo Nordisk Fonden (NNF14OC0010995, NNF14OC0010363)
- Diabetestutkimussäätiö
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- type 2 diabetes, melatonin signaling, MTNR1B, insulin secretion, pancreatic islets, cyclic AMP, genetic risk variants, hyperglycemia, melatonin treatment
- MeSH terms
- Insulin Secretion, Cyclic AMP, Animals, Diabetes Mellitus, Type 2, Glucose, Heterozygote, Humans, Insulin, Melatonin, Risk Factors, Signal Transduction, Mice, Knockout, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Receptors, Melatonin, Insulin-Secreting Cells
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