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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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Citations
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“A variant in the MTNR1B gene, rs10830963, was recently identified to be associated with altered melatonin rhythm and melatonin signaling (10, 11).”
BackgroundInfluentialTree Nut Consumption and Adipose Tissue Mass: Mechanisms of Action
Tindall, A. M., Petersen, K. S., Lamendella, R., Shearer, G. C., Murray‐Kolb, L. E., Proctor, D. N., & Kris‐Etherton, P. M. (2018) · Current Developments in Nutrition · doi:10.1093/cdn/nzy069 · Cited by 21
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“showed that a common (about 30%) human type 2 diabetes (T2D) risk variant of the melatonin receptor 1B gene affects insulin release [13]; this study demonstrated that melatonin treatment inhibits insulin secretion, with at-risk carriers exhibiting higher glucose levels.”
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ResultPilot GWAS of caries in African-Americans shows genetic heterogeneity
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BackgroundPharmacological Actions of Carbamate Insecticides at Mammalian Melatonin Receptors
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“Indeed, a study demonstrated that the increased mRNA expression of T2D-associated TCF7L2 gene in pancreatic islets from donors with T2D actually correlated with a strong decrease in TCF7L2 protein levels (Shu et al., 2009).”
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“In addition, G allele carriers are significantly more vulnerable due to increased melatonin signaling (5) and impaired early insulin secretion capacity, and the long-term regular need for insulin secretion due to early morning food intake could expose this group to a greater risk of developing glucose tolerance disord…”
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“In a study of 17 normoglycemic women, 5 mg of melatonin administered in the morning resulted in increased AUC glucose in response to OGTT, with the effects seen six times as large in those carrying MTNR1B genetic variant rs10830963 (known to be associated with type 2 diabetes risk) than in non-carriers (Garaulet et al…”
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Gkouskou, K. K., Grammatikopoulou, M. G., Lazou, E., Sanoudou, D., Goulis, D. G., & Eliopoulos, A. G. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.772243 · Cited by 18
“The patient was advised to avoid melatonin supplementation as prescription of melatonin to rs10830963 GG carriers is not linked to beneficial health outcomes (35, 36) (Table 3).”
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“Of note, another study reported that individuals with the rs10830963 G allele have higher MTNR1B expression in pancreatic β-cells, which is thus correlated with reduced insulin secretion, leading to the greater risk of T2D.27 Accordingly, one recent study demonstrated that rs10830963 was an expression quantitative tra…”
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“Tuomi et al. (2016) found that elevated melatonin levels may increase the risk of diabetes.”
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“MTNR1B expression is increased in human islets among carriers of the G allele of MTNR1B -rs10830963, which may account for a reduced insulin release [6–8].”
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Mondal, P., Prasad, A., & Girdhar, K. (2017) · Annales d Endocrinologie · doi:10.1016/j.ando.2016.11.002 · Cited by 7
Melatonin receptor 1B gene rs10830963 polymorphism, depressive symptoms and glycaemic traits
Haljas, K., Lahti, J. M. T., Tuomilehto, J., Isomaa, B., Eriksson, J. G., Groop, L., & Räikkönen, K. (2018) · Annals of Medicine · doi:10.1080/07853890.2018.1509118 · Cited by 9
“We have recently demonstrated that in the MTNR1B risk genotype carriers, the administration of 4mg/night of melatonin for three months was associated with impaired insulin secretion [34].”
Backgroundvan Faassen, M. H. J. R., van der Veen, A., van Ockenburg, S. L., de Jong, H., de Vries, E. G. E., & Kema, I. P. (2020) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm-2020-0455 · Cited by 7
Sorlí, J. V., Barragán, R., Coltell, Ó., Portolés, O., Pascual, E. C., Ortega‐Azorín, C., González, J. I., Estruch, R., Sáiz, C., Fidalgo, J. A. P., et al. (2020) · Nutrients · doi:10.3390/nu12113323 · Cited by 8
“This variant is relatively frequent and some functionality has been reported (compared with the C allele, the variant G allele was associated with increased MTNR1B transcript levels and gene expression in human islets) [42,43], which likely leads to a reduction in insulin release, increasing type-2 diabetes risk [43].”
BackgroundLauritzen, E. S., Støy, J., Bæch‐Laursen, C., Grarup, N., Jessen, N., Hansen, T. F., Møller, N., Hartmann, B., Holst, J. J., & Kampmann, U. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab521 · Cited by 8
de Luis, D. A., Izaola, O., Primo, D., & Aller, R. (2020) · Endocrinología Diabetes y Nutrición (English ed ) · doi:10.1016/j.endien.2019.12.004 · Cited by 8
Nunes, C. B., Borges, M. C., Freathy, R. M., Lawlor, D. A., Qvigstad, E., Evans, D. M., & Moen, G.-H. (2024) · Metabolites · doi:10.3390/metabo14090508 · Cited by 7
“The NEDD1 (Neural precursor cell expressed, developmentally down-regulated gene 1) gene encodes a protein that interacts with γ -tubulin and forms a complex that is targeted to the centrosome for spindle assembly and centriole duplication; hence, it is involved in mitosis [234–237].”
BackgroundRole of circadian rhythms in heart failure: insights from myocardial energy metabolism
Wang, P., Yu, B., Liu, L., Zhang, C., & Ai, S. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06828-1 · Cited by 7
“Melatonin inhibits cyclic adenosine monophosphate (cAMP) production by activating the MTNR1B receptor on β-cells, thereby reducing insulin secretion [94].”
Wang, B., Zeng, H., Yang, X., Zuo, X., Liang, L., Zhang, R., Deng, W., Ju, R., Wang, X., & Yuan, J. (2025) · Journal of Pineal Research · doi:10.1111/jpi.70076 · Cited by 7
Cell Signaling by Tryptophan Catabolism
Torrelli-Diljohn, A., Kulkarni, B., & Vitturi, D. A. (2026) · Biochemistry · doi:10.1021/acs.biochem.6c00179 · Cited by 7
Mazzoccoli, G., Dagostino, M. P., Paroni, G., Seripa, D., Ciccone, F., Addante, F., Favuzzi, G., Grandone, E., Avola, R., Mazza, T., et al. (2017) · Chronobiology International · doi:10.1080/07420528.2017.1340894 · Cited by 7
“…insulin secretion: (i) knockdown of MT2 receptor encoding gene enhanced insulin secretion in mice models; (ii) a human recall-by-genotype study showed broader decrease of insulin secretion and increase of glucose levels in risk G-allele carriers upon melatonin administration (Tuomi et al., 2016).”
BackgroundSocial jetlag, circadian disruption, and cardiometabolic disease risk
Malone, S. K., Mendoza, M. A., & Patterson, F. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-815373-4.00018-6 · Cited by 8
GPCR targets in type 2 diabetes
Atanes, P., & Persaud, S. J. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-816228-6.00018-0 · Cited by 7
Melatonin Receptor Gene Polymorphism in Bipolar-I Disorder
Mulayim, E., Karababa, İ. F., Akbaş, H., Bayazıt, H., & Selek, S. (2021) · Archives of Medical Research · doi:10.1016/j.arcmed.2021.01.002 · Cited by 7
Cold Exposure Alleviates T2DM Through Plasma-Derived Extracellular Vesicles
Li, F., Xu, F., Li, C., Lei, L.-M., Shan, S., Zheng, M.-H., Lin, X., Guo, B., Tang, K.-X., Duan, J.-Y., et al. (2024) · International Journal of Nanomedicine · doi:10.2147/ijn.s441847 · Cited by 7
Ocak, Ö., Sılan, F., & Şahi̇n, E. M. (2022) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.3573 · Cited by 6
Okano, S. (2016) · Journal of Diabetes Research · doi:10.1155/2016/3459246 · Cited by 7
“This trend is exemplified by recent reports: melatonin, a hormone that exhibits some relation to circadian rhythm [71], directly regulates insulin secretion of βcells [72].”
BackgroundTchio, C. I. M., Musani, S. K., Quarshie, A., & Tosini, G. (2021) · BMC Medical Genomics · doi:10.1186/s12920-021-00983-2 · Cited by 6
“Body Mass Index; MTNR1A:Melatonin Receptor Type 1 Gene; MTNR1B:Melatonin Receptor Type 2 Gene; FDR:False Discovery Rate; HWE:Hardy-Weinberg Equilibrium; JHS:Jackson Heart Study; LD:Linkage Disequilibrium; LCI:Lower Con dence Interval; MAF:Minor Allele Frequency; UCI:Upper Con dence Interval; SE:Standard Error; SNP:Sin…”
InfluentialSleep disruption in nonalcoholic fatty liver disease: What is the role of lifestyle and diet?
Akram, S., Ewy, M. W., & Said, A. (2021) · PubMed · doi:10.1097/meg.0000000000002049 · Cited by 5
Wang, B., Hou, J., Mao, Z., Chen, C., Wang, C., & Yu, S. (2024) · Journal of Diabetes & Metabolic Disorders · doi:10.1007/s40200-023-01382-3 · Cited by 5
“In addition, melatonin receptor 1 gene inhibited adenylate cyclase synthesis, which in turn inhibited insulin release [12].”
Bridging the variant-to-function gap in type 2 diabetes: advances and challenges
Maynard, A. G., Bhardwaj, R., Jones, T. R., & Claussnitzer, M. (2025) · Diabetologia · doi:10.1007/s00125-025-06600-6 · Cited by 7
“…human hepatoma cell line (derived from a liver tumour of a 57-year-old Asian man); RFX, regulatory factor X; U2OS, human osteosarcoma cell line (derived from a 15-year-old girl of European descent with bone cancer) [190] insulin secretion (a mechanism amplified by the MTNR1B risk allele) [54].”
Patel, R., Parmar, N. B., Palit, S. P., RATHWA, N. N., & Begum, R. (2023) · Journal of Endocrinological Investigation · doi:10.1007/s40618-023-02014-6 · Cited by 6
“The findings of melatonin regulating glucose metabolism via increased PI3KAkt activity [39, 40] support our findings.”
ResultWang, T., Wang, X., Lai, R., Ling, H., Zhang, F., Lü, Q., Lv, D., & Yin, X. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01318 · Cited by 4
The impact of circadian timing on energy balance: an extension of the energy balance model
Veronda, A. C., Kline, C. E., & Irish, L. A. (2021) · Health Psychology Review · doi:10.1080/17437199.2021.1968310 · Cited by 4
The promising oncostatic effects of melatonin against ovarian cancer
Das, N. K., & Samanta, S. (2021) · World Journal of Current Medical and Pharmaceutical Research · doi:10.37022/wjcmpr.v3i4.185 · Cited by 4
Meta-Analysis of the Genetic Factors that Predisposed Asian Women to Gestational Diabetes Mellitus
Bahktiar, S. N. S. M., Jamari, M. H., Noor, N. A. W., Fadzilah, R. A. A., Karim, M. Z. A., Halim, H. H. A., Abu, N. F., Kek, T. L., & Salleh, M. Z. (2021) · Malaysian Journal of Pharmaceutical Sciences · doi:10.21315/mjps2021.19.2.9 · Cited by 4
Xue, P., Tan, X. W., Wu, J., Tang, X., & Benedict, C. (2021) · Journal of Pineal Research · doi:10.1111/jpi.12785 · Cited by 4
Kakko, K., Pihlakoski, L., Keskinen, P., Salmelin, R. K., & Puura, K. (2019) · Acta Paediatrica · doi:10.1111/apa.14951 · Cited by 4
Vitale, A., & Minicozzi, V. (2019) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.9b00058 · Cited by 4
Kiba, T. (2025) · Cells · doi:10.3390/cells14171371 · Cited by 4
“It is well described that pancreatic alpha and beta cells express melatonin receptors MT1 and MT2 [152], and evidence shows that melatonin action on the pancreatic melatonin receptors modulates insulin secretion and glucagon release in a diurnal fashion [153].”
Thomsen, S. K., McCarthy, M. I., & Gloyn, A. L. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00112 · Cited by 3
“Fine-mapping efforts identified a single likely causal variant that overlaps active islet and liver enhancers, and a cis-eQTL for MTNR1B in islets (14, 15, 18, 19).”
BackgroundLandvreugd, A., Pool, R., Nivard, M. G., & Bartels, M. (2024) · Journal of Biological Rhythms · doi:10.1177/07487304241230577 · Cited by 4
“, 2016), such as insulin resistance (Tuomi et al., 2016).”
MTNR1B variants increase gestational diabetes mellitus risk in young Chinese pregnant women
Zeng, Q., Liu, X., Liu, J., Wu, Y., Zhang, Y., He, Z., Wei, Y., Zeng, G., Zou, D., & Guo, R. (2025) · Scientific Reports · doi:10.1038/s41598-025-02248-9 · Cited by 3
“This means that individuals carrying the G allele of this variant may have a stronger melatonin signal in the pancreas, which could affect the transcription and secretion of insulin, thereby influencing blood glucose levels 7 .”
Singh, T., Kalamajski, S., Cunha, J. G. D., Hladkou, S., Roberts, F. L., Gheibi, S., Soltanian, A., Farahmand, K. Y., Ekström, O., Mamidi, A., et al. (2025) · Journal of Pineal Research · doi:10.1111/jpi.70073 · Cited by 3
Huang, Y., Dou, X., He, M. C., Su, Y., Lin, H., & Yang, Y. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26167855 · Cited by 3
“MTNR1B is a G-protein-coupled receptor that mainly acts by interfering with the formation of cAMP through inhibitory G proteins, inhibiting adenylate cyclase, and subsequently inhibiting insulin release [25–27].”
de Luis, D. A., Pacheco, D., Jáuregui, O. I., & Martín, D. P. (2020) · Nutrición Hospitalaria · doi:10.20960/nh.03153 · Cited by 3
“It has been related to impaired melatonin rhythm and signaling (8).”
BackgroundMelatonin and glucose metabolism.
Watanabe, K., Katagiri, S., & Hattori, A. (2020) · doi:10.24659/gsr.7.1_105 · Cited by 3
Loss of melatonin signaling increases the risk of T2DM caused by metabolic disorders
Yan, L., Lv, D., Zhang, L., Gao, Y., Zhu, T., Ding, M., Yao, Y., Wu, H., Fu, Y., Li, G., et al. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02539-8 · Cited by 3
“More-over, the glucose tolerance-reducing property of melatonin in humans received considerable attention when the MTNR1B variant carrying the rs10830963 mutation (G allele) was found to become increasingly overexpressed in human β-cells, especially in homozygous carriers of the G allele [27, 28].”
Nocturnal melatonin secretion and risk of type 2 diabetes: a prospective cohort study
Smith, E. S., Franzén, A., Pihlsgård, M., Nilsson, P. M., Timpka, S., & Enhörning, S. (2025) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaf667 · Cited by 2
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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