# Rare MTNR1B variants causing diminished MT2 signalling associate with elevated HbA1c levels but not with type 2 diabetes

## TL;DR

Rare MTNR1B gene variants linked to reduced melatonin receptor signaling are associated with higher HbA1c levels but not with type 2 diabetes.

## Contribution

Identifies rare MTNR1B variants that impair MT2 signaling and elevate HbA1c without increasing type 2 diabetes risk.

## Key findings

- Missense MTNR1B variants causing impaired MT2 signaling are associated with higher HbA1c levels.
- No significant association was found between MTNR1B variants and type 2 diabetes prevalence in the UK Biobank.
- Carriers of MT2-impairing variants showed a reduced glucose-stimulated insulin response after melatonin treatment.

## Abstract

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.

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.

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 HbA1c 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.

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 HbA1c levels.

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).

The online version of this article (10.1007/s00125-025-06381-y) contains peer-reviewed but unedited supplementary material.