Does the MTNR1B rs10830963 G allele raise fasting glucose and type 2 diabetes risk by reducing beta-cell insulin secretion, especially with late eating?

The MTNR1B rs10830963 G allele is a well-established genetic risk factor for impaired glucose regulation, specifically influencing fasting plasma glucose levels and the risk of developing type 2 diabetes (T2D).

Clinical and genetic evidence

Large-scale genome-wide association studies (GWAS) and meta-analyses consistently link the rs10830963 G allele to metabolic dysfunction. In European populations, each G allele is associated with a 0.06 to 0.08 mmol/L (1.1–1.4 mg/dL) increase in fasting glucose, with similar effects observed in East Asian and African-ancestry cohorts. The odds ratio (OR) for T2D risk ranges from 1.05 to 1.12 per risk allele. This genetic influence is characterized by a primary defect in early-phase insulin secretion rather than a change in insulin sensitivity.

Mechanistic pathways

The variant acts as a cis-expression quantitative trait locus (cis-eQTL) that increases the expression of MTNR1B (melatonin receptor 1B) in human pancreatic islets.

• Signaling: Melatonin receptors on beta-cells are Gi-coupled; overexpression in G-allele carriers enhances inhibitory signaling.
• Cellular effect: This leads to reduced intracellular cAMP levels, a secondary messenger essential for amplifying glucose-stimulated insulin secretion (GSIS).
• Result: The overactive melatonin signaling suppresses insulin granule exocytosis, resulting in lower beta-cell responsivity and a reduced Disposition Index.

Interaction with meal timing

The metabolic impact is significantly magnified by the timing of food intake relative to the circadian rhythm.

• Late eating: Consuming meals late in the evening (e.g., one hour before bedtime) coincides with endogenous melatonin levels that are approximately 3.5 times higher than in the early evening.
• Gene-environment interaction: Because G-allele carriers are more sensitive to melatonin’s inhibitory effects, late-night eating in these individuals results in an 8.3% increase in glucose area under the curve (AUC) and a 6.7% decrease in insulin AUC compared to earlier meal times.

Bottom line

The MTNR1B rs10830963 G allele increases type 2 diabetes risk by enhancing melatonin’s ability to suppress insulin secretion. For these individuals, avoiding late-night food intake is a critical behavioral strategy to mitigate impaired glucose tolerance.