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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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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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