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Open Access 10-03-2025 | Type 2 Diabetes | Article

Rare MTNR1B variants causing diminished MT2 signalling associate with elevated HbA_1c levels but not with type 2 diabetes

Authors: Kimmie V. Sørensen, Johanne M. Justesen, Lars Ängquist, Jette Bork-Jensen, Bolette Hartmann, Niklas R. Jørgensen, Jørgen Rungby, Henrik T. Sørensen, Allan Vaag, Jens S. Nielsen, Jens J. Holst, Oluf Pedersen, Allan Linneberg, Torben Hansen, Niels Grarup

Published in: Diabetologia

Abstract

Aims/hypothesis

An intronic variant (rs10830963) in MTNR1B (encoding the melatonin receptor type 2 [MT2]) has been shown to strongly associate with impaired glucose regulation and elevated type 2 diabetes prevalence. However, MTNR1B missense variants have shown conflicting results on type 2 diabetes. Thus, we aimed to gain further insights into the impact of MTNR1B coding variants on type 2 diabetes prevalence and related phenotypes.

Methods

We conducted a cross-sectional study, performing MTNR1B variant burden testing of glycaemic phenotypes (N=248,454, without diabetes), other cardiometabolic phenotypes (N=330,453) and type 2 diabetes prevalence (case–control study; N=263,739) in the UK Biobank. Similar burden testing with glycaemic phenotypes was performed in Danish Inter99 participants without diabetes (N=5711), and type 2 diabetes prevalence (DD2 cohort serving as cases [N=2930] and Inter99 serving as controls [N=4243]). Finally, we evaluated the effects of MTNR1B variants on the melatonin-induced glucose regulation response in a recall-by-genotype study of individuals without diabetes.

Results

In the UK Biobank, MTNR1B variants were not associated with cardiometabolic phenotypes, including type 2 diabetes prevalence, except that carriers of missense MTNR1B variants causing impaired MT2 signalling exhibited higher HbA_1c levels compared with non-carriers (effect size, β, 0.087 SD [95% CI 0.039, 0.135]). Similarly, no significant associations were observed with phenotypes associated with glycaemic phenotypes in the Inter99 population. However, carriers of variants impairing MT2 signalling demonstrated a nominally significant lower glucose-stimulated insulin response (β −0.47 SD [95% CI −0.82, −0.11]). A reduced insulin response was also observed in carriers of variants impairing MT2 signalling (β −476.0 [95% CI −928.6, −24.4]) or the rs10830963 variant (β −390.8 [95% CI −740.1, −41.6]) compared with non-carriers after melatonin treatment.

Conclusions/interpretation

The higher type 2 diabetes prevalence previously observed in carriers of missense MTNR1B variants causing impairment in MT2 signalling was not replicated in the UK Biobank, yet carriers had elevated HbA_1c levels.

Data availability

Data (Inter99 cohort and recall-by-genotype study) are available on reasonable request from the corresponding author. Requests for DD2 data are through the application form at https://dd2.dk/forskning/ansoeg-om-data. Access to UK Biobank data can be requested through the UK Biobank website (https://www.ukbiobank.ac.uk/enable-your-research).

Graphical Abstract

Available only for authorised users

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Title: Rare MTNR1B variants causing diminished MT2 signalling associate with elevated HbA1c levels but not with type 2 diabetes
Authors: Kimmie V. Sørensen
Johanne M. Justesen
Lars Ängquist
Jette Bork-Jensen
Bolette Hartmann
Niklas R. Jørgensen
Jørgen Rungby
Henrik T. Sørensen
Allan Vaag
Jens S. Nielsen
Jens J. Holst
Oluf Pedersen
Allan Linneberg
Torben Hansen
Niels Grarup
Publication date: 10-03-2025
Publisher: Springer Berlin Heidelberg
Keywords: Type 2 Diabetes
Insulins
Insulins
Published in: Diabetologia
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-025-06381-y

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