Melatonin effects on glucose metabolism: time to unlock the controversy

Garaulet, Marta; Qian, Jingyi; Florez, Jose C.; Arendt, Josephine; Saxena, Richa; Scheer, Frank A.J.L.

doi:10.1016/j.tem.2019.11.011

Cited by 193Circadian rhythm and melatoninPancreatic function and diabetesDiabetes Treatment and Management

Melatonin effects on glucose metabolism: time to unlock the controversy

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Garaulet, Marta, Qian, Jingyi, Florez, Jose C., Arendt, Josephine, Saxena, Richa, Scheer, Frank A.J.L.·2020·Trends in Endocrinology & Metabolism

DOI 10.1016/j.tem.2019.11.011PMC PMC7349733

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Abstract

The past decade has witnessed a revival of interest in the hormone melatonin, partly attributable to the discovery that genetic variation in MTNR1B - the melatonin receptor gene - is a risk factor for impaired fasting glucose and type 2 diabetes (T2D). Despite intensive investigation, there is considerable confusion and seemingly conflicting data on the metabolic effects of melatonin and MTNR1B variation, and disagreement on whether melatonin is metabolically beneficial or deleterious, a crucial issue for melatonin agonist/antagonist drug development and dosing time. We provide a conceptual framework - anchored in the dimension of 'time' - to reconcile paradoxical findings in the literature. We propose that the relative timing between elevated melatonin concentrations and glycemic challenge should be considered to better understand the mechanisms and therapeutic opportunities of melatonin signaling in glycemic health and disease.

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The rs10830963 G variant in MTNR1B shows the strongest association among known single nucleotide polymorphisms with elevated fasting glucose and impaired insulin secretion.
“Notably, the common intronic gain-of-function variant rs10830963 G in MTNR1B shows the strongest association among known single nucleotide polymorphisms with elevated fasting glucose and impaired insulin secretion (6,7)”
From Melatonin Impairs Glucose Tolerance, First-Phase Insulin Secretion, and Insulin Feedback Inhibition; Interaction With MTNR1B Diabetes Risk Variant (2026) · cites this paper as [7]
In “Is melatonin deleterious for T2D?” (page not provided), the paper links rs10830963 to impaired fasting glucose and decreased insulin secretion. It says the common MTNR1B risk allele has *one of the strongest* effects among known T2D-risk SNPs on lowering the disposition index—not the single strongest association with both elevated fasting glucose and impaired insulin secretion. (LLM, conf=0.86)
Experimental — accuracy not yet measured
There exist conflicting data regarding the effects of melatonin and MTNR1B genotype on glucose control and disagreement on whether melatonin increases or decreases fasting glucose, glucose tolerance, and T2D risk.
“There exist conflicting data regarding the effects of melatonin and MTNR1B genotype on glucose control (12)(13)(14) and disagreement on whether melatonin increases or decreases fasting glucose, glucose tolerance, and T2D risk.”
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 [14]
The 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 MTNR1B Diabetes Risk Variant (2026) · cites this paper as [7]
The common MTNR1B variant increases risk of type 2 diabetes.
“The common melatonin receptor 1B gene (MTNR1B) variant increases risk of type 2 diabetes”
From Melatonin Impairs Glucose Tolerance, First-Phase Insulin Secretion, and Insulin Feedback Inhibition; Interaction With MTNR1B Diabetes Risk Variant (2026) · cites this paper as [7]

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Impact of Common Diabetes Risk Variant in MTNR1B on Sleep, Circadian, and Melatonin Physiology
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“Moreover, a genetic study together with a recent functional genomics study has reported that rare coding variants in the melatonin receptor gene MTNR1B, that inhibit melatonin binding or signaling, are collectively associated with increased risk of T2D [11, 12]; although recent well-powered analysis of coding variants…”
Background
Common genetic variants differentially influence the transition from clinically defined states of fasting glucose metabolism
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Authors: Garaulet, M., Qian, J., Florez, J. C., Arendt, J., Saxena, R., & Scheer, F. A. J. L.
Affiliations: Brigham and Women's Hospital (US)
Broad Institute (US)
Corresponding author: Saxena, Richa
Scheer, Frank A.J.L.
ORCID: Garaulet, Marta
Qian, Jingyi
Saxena, Richa
Scheer, Frank A.J.L.
Venue: Trends in Endocrinology & Metabolism
Publisher: Elsevier BV
Published: 2020-03
Volume: 31
Issue: 3
Pages: 192-204
ISSN: 1043-2760 (ISSN-L)
DOI: 10.1016/j.tem.2019.11.011
PMC: PMC7349733
OpenAlex: W2997273097
Cited by: 193
References: 94
Citations by year: 2026: 28 · 2025: 22 · 2024: 42 · 2023: 32 · 2022: 38 · 2021: 19 · 2020: 12
FWCI: 3.41
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Trends in Endocrinology and Metabolism (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: The Spanish Government of Investigation, Development and Innovation (SAF2017-84135-R)
NIH (R01DK105072, R01DK102696, R01DK107859, R01HL118601, R01DK099512, R01HL140574)
American Diabetes Association (1-17-PDF-103)
NIDDK (P30 DK057521, R01 DK105072, K24 DK110550)
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords: melatonin, glucose metabolism, MTNR1B, melatonin receptors, type 2 diabetes, impaired fasting glucose, genetic variation, melatonin receptor agonists, circadian rhythm, drug dosing
MeSH terms: Animals, Blood Glucose, Circadian Rhythm, Diabetes Mellitus, Type 2, Glucose, Humans, Insulin, Melatonin, Genetic Variation, Polymorphism, Single Nucleotide, Receptor, Melatonin, MT2, Carbohydrate Metabolism

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Melatonin effects on glucose metabolism: time to unlock the controversy

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