MTNR1B

MTNR1B encodes the melatonin receptor 1B, a G protein-coupled receptor central to circadian regulation, metabolic function, and reproductive physiology. 

Genetic variants in MTNR1B, particularly rs10830963, are strongly associated with disrupted insulin secretion, increased risk of type 2 and gestational diabetes, and heightened vulnerability to circadian misalignment, making this gene a key target in precision medicine research.

What is MTNR1B (Melatonin Receptor 1B)?

MTNR1B is a protein-coding gene that encodes the melatonin receptor 1B (MT2), a G protein-coupled receptor (GPCR) primarily involved in melatonin signaling. 

Located on chromosome 11q14.3, this receptor spans 362 amino acids and is embedded in the cell membrane, with secondary localization to the cytosol, nucleus, and mitochondria. It binds melatonin with high affinity and regulates circadian rhythms, metabolic function, and reproductive processes.

MTNR1B: A Receptor for Melatonin with Metabolic Implications

MTNR1B plays a central role in circadian biology and glucose metabolism. 

While it is strongly expressed in the retina and brain (notably the suprachiasmatic nucleus), it also functions in pancreatic β-cells, where it inhibits insulin secretion through Gi/o protein signaling pathways. Its activation decreases cAMP and cGMP levels, affecting metabolic homeostasis. 

MTNR1B is also expressed in the placenta, where it regulates vascularization and fetal growth via the STAT3/VEGFR2/PI3K/AKT pathway.

When is MTNR1B Testing or Research Relevant?

MTNR1B is not yet routinely tested in clinical practice but is highly relevant in research settings, particularly for:

Type 2 Diabetes Mellitus (T2DM)

The rs10830963 (G allele) is strongly associated with elevated fasting glucose, impaired early insulin secretion, and increased T2DM risk.

The G allele is linked to a weaker response to diabetes medications that help the body release insulin and to poorer blood sugar control, especially when sleep and eating patterns are out of sync with the body's natural rhythm.

Gestational Diabetes Mellitus (GDM)

Variants such as rs10830963 and rs1387153 are linked to GDM, particularly in women with increased MTNR1B expression in the placenta. 

Additionally, the MTNR1B rs10830962 G allele may predispose women to GDM in pregnancy, as it is associated with higher fasting glucose levels in pregnancy.

Sleep Disorders

Altered melatonin signaling in MTNR1B variant carriers is linked to insomnia, delayed melatonin onset, and chronotype shifts.

Other Conditions

Emerging evidence implicates MTNR1B in cardiovascular disease, metabolic syndrome, and idiopathic scoliosis.

MTNR1B genotyping may inform personalized risk assessment and future therapeutic targeting.

MTNR1B Genetic Testing: Test Procedure and Interpretation

Testing for MTNR1B is performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for MTNR1B genetic testing are considered to be without mutations that can alter the activity of the MTNR1B proteins.

What Do Mutations/Variants in MTNR1B Mean?

MTNR1B mutations may have the following implications: 

Disrupted Melatonin Signaling

Variants can delay melatonin offset, prolong nocturnal secretion, and misalign circadian rhythms.

Metabolic Impact

The rs10830963 G allele impairs glucose regulation by decreasing insulin secretion and altering β-cell function, and may predict future type 2 diabetes.

Gestational Effects

In pregnancy, the G allele is associated with increased risk of gestational diabetes, placental dysfunction, fetal growth restriction, and increased offspring adiposity, especially when maternal gestational weight gain is high. 

rs10830962 has also been implicated in the connection between gestational weight gain and childhood obesity.

Gene–Environment Interaction

Carriers of MTNR1B risk alleles are more susceptible to metabolic dysregulation under conditions of circadian misalignment, such as irregular sleep or late-night meals.

What Does the Absence of Specific Studied MTNR1B Genetic Variations Mean?

A negative MTNR1B test (i.e., absence of rs10830963 or rs1387153 risk alleles) does not eliminate risk for metabolic or circadian-related disorders. T2DM, GDM, and sleep disorders are polygenic and multifactorial, influenced by other genes and lifestyle factors. 

Negative results should be interpreted in the broader clinical context, not in isolation.

Clinical Takeaways

MTNR1B encodes a melatonin receptor critical for regulating sleep and metabolism.

rs10830963 (G allele) is the most studied risk variant and is linked to:

• Elevated fasting glucose
• Increased risk of T2DM and GDM
• Impaired response to insulin secretagogues
• Prenatal and pediatric implications: In pregnant women, G allele carriage interacts with gestational weight gain to increase offspring obesity risk.

Potential interventions may include:

• Tailored metabolic screening in risk allele carriers
• Cautious use of melatonin supplements in G allele carriers
• Exploration of MTNR1B as a therapeutic target in GDM and IUGR

MTNR1B genotyping holds promise for precision medicine in metabolic, reproductive, and circadian disorders.

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