Common type 2 diabetes risk variant in MTNR1B worsens the deleterious effect of melatonin on glucose tolerance in humans
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Aims The common MTNR1B genetic variant rs10830963 is associated with an increased risk of type 2 diabetes (T2D). To date, no experimental study has tested the effect of the MTNR1B variant on glucose metabolism in humans during exposure of the melatonin receptors to their ligand. The aim of this study was to investigate whether this MTNR1B variant influenced the effect of melatonin (5mg) on glucose tolerance assessed by an oral glucose tolerance test (OGTT; 75 g) at different times of the day (morning and evening) as compared to a placebo. Methods Seventeen normoglycemic women (24 ± 6 years; BMI 23.0 ± 3.3 kg/m(2)) completed the study (11 carriers of the risk allele [CG] and 6 noncarriers [CC]). Results The effect of melatonin on glucose tolerance depended on the genotype. In the morning, the effect of melatonin (melatonin-placebo) on the glucose area under the curve (AUC) above baseline differed significantly (P=0.036) between the carriers and noncarriers. This effect of melatonin in the carriers was six times as large as that in the noncarriers. The MTNR1B SNP explained over one-quarter (26%) of the inter-individual differences in the effect of melatonin on glucose AUC. However, in the evening, the effect of melatonin on glucose AUC of the carriers and noncarriers did not differ significantly (P>0.05). Conclusions MTNR1B rs10830963 risk variant worsens the effect of melatonin on glucose tolerance, suggesting the importance of genotyping and personalized recommendations, especially in people consuming food when melatonin levels are elevated. Large-scale studies in vulnerable populations are necessary to translate these results into real-world, clinically relevant recommendations.
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Earlier work shows that elevated melatonin-whether from exogenous administration or due to the endogenous evening rise-acutely impairs glucose tolerance, with stronger effects in MTNR1B risk allele carriers.
“The present results align with and extend our earlier work showing that elevated melatonin—whether from exogenous administration or due to the endogenous evening rise—acutely impairs glucose tolerance, with stronger effects in MTNR1B risk allele carriers (11–14).”
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 [11]
The Results report that administered melatonin worsened glucose tolerance, with a significantly stronger effect in MTNR1B risk-allele carriers in the morning; the genotype difference was not significant in the evening. The Discussion says future studies must test whether physiological nighttime melatonin has similar effects, so this paper does not establish the claim about the endogenous evening rise. Page numbers were not provided in our copy. (LLM, conf=0.89)
Experimental — accuracy not yet measuredThe mechanisms underlying the association between melatonin administration and glycemic control remain unclear.
“While a few other studies (9–14) have examined the effects of melatonin administration on glycemic control, the mechanisms underlying such association remain unclear (7).”
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 [11]
The Introduction says few human studies had tested melatonin exposure and glucose measures, and the Discussion identifies an MTNR1B variant that modifies melatonin’s effect on glucose tolerance. Neither section states that the mechanisms underlying the association remain unclear; the Discussion’s stated uncertainty concerns the receptor’s role in sleep and circadian effects, not glycemic control. (LLM, conf=0.70)
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- Authors
- Garaulet, M., Gómez-Abellán, P., Rubio-Sastre, P., Madrid, J. A., Saxena, R., & Scheer, F. A. J. L.
- Affiliations
- Instituto Murciano de Investigación Biosanitaria (ES)
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Garaulet, Marta
- Gómez-Abellán, Purificación
- Rubio-Sastre, Patricia
- Madrid, Juan A.
- Scheer, Frank A.J.L.
- Venue
- Metabolism
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 64
- Issue
- 12
- Pages
- 1650-1657
- ISSN
- 0026-0495 (ISSN-L)
- PMC
- PMC4856010
- OpenAlex
- W2166166135
- Semantic Scholar
- 85c64d101d83cda6f4ad22b2ffaeb12886264cbf
- Cited by
- 100
- References
- 25
- Citations by year
- 2026: 9 · 2025: 5 · 2024: 8 · 2023: 10 · 2022: 10 · 2021: 8 · 2020: 7 · 2019: 7 · 2018: 11 · 2017: 11 · 2016: 13 · 2014: 1
- FWCI
- 6.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK102696, R21DK089378)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- MTNR1B, rs10830963, melatonin, glucose tolerance, oral glucose tolerance test, melatonin receptors, genetic polymorphism, personalized medicine, circadian timing
- MeSH terms
- Adult, Blood Glucose, Diabetes Mellitus, Type 2, Female, Genotype, Glucose Tolerance Test, Humans, Melatonin, Polymorphism, Single Nucleotide, Receptor, Melatonin, MT2, Young Adult
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