rs10830963 — MTNR1B Intron C>G

MTNR1B — When You Eat Matters More Than What You Eat

The MTNR1B gene encodes melatonin receptor 1B¹¹ melatonin receptor 1B
One of two G-protein-coupled receptors for melatonin (MT1 and MT2). MT2 (MTNR1B) is expressed in the brain, retina, and — critically — in pancreatic beta cells (MT2), a receptor found not only in the brain but also on the insulin-producing beta cells of the pancreas. This dual role places MTNR1B at the crossroads of two fundamental biological systems: the circadian clock and glucose metabolism.

The rs10830963 variant sits in an intron of MTNR1B and is one of the strongest GWAS²² GWAS
Genome-wide association study: an approach that scans the entire genome of thousands of people to find genetic variants associated with a trait or disease hits for fasting glucose levels ever identified, reaching a significance of P = 3.2 x 10^-50 in the original discovery. The G allele — carried by roughly 28% of Europeans and up to 45% of East Asians — extends the duration of melatonin signaling in pancreatic beta cells, impairing their ability to release insulin in response to glucose. This makes it one of the most actionable chrono-nutrition³³ chrono-nutrition
The study of how the timing of food intake interacts with circadian biology to affect metabolic health SNPs: for G carriers, when you eat may matter as much as what you eat.

The Mechanism

Melatonin is the hormone of darkness — it rises in the evening, peaks during the night, and falls before dawn. When melatonin binds MT2 receptors on pancreatic beta cells, it activates inhibitory G-proteins⁴⁴ inhibitory G-proteins
Gi proteins that reduce intracellular cAMP levels, dampening the cell's ability to secrete insulin in response to glucose (Gi), reducing cAMP and suppressing glucose-stimulated insulin secretion. This is normally useful: it prevents insulin surges during sleep when you are not eating.

The rs10830963 G allele increases MTNR1B expression in beta cells. More MT2 receptors mean stronger melatonin-mediated suppression of insulin secretion, and Lane and colleagues⁵⁵ Lane and colleagues
Lane JM et al. Impact of Common Diabetes Risk Variant in MTNR1B on Sleep, Circadian, and Melatonin Physiology. Diabetes, 2016 showed that G carriers also have a 41-minute longer duration of elevated melatonin and a 1.37-hour delayed melatonin offset in the morning. The result is a wider window during which insulin secretion is suppressed — a window that overlaps with meal times if you eat late at night or early in the morning.

The Evidence

The original GWAS discovery⁶⁶ original GWAS discovery
Prokopenko I et al. Variants in MTNR1B influence fasting glucose levels. Nat Genet, 2009 across 36,610 individuals found each G allele raises fasting glucose by 0.07 mmol/L (P = 3.2 x 10^-50). A simultaneous study by Lyssenko and colleagues⁷⁷ Lyssenko and colleagues
Lyssenko V et al. Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat Genet, 2009 confirmed that the risk genotype impairs early insulin response to both oral and intravenous glucose, with MTNR1B expression elevated in islets of risk carriers.

A large replication study⁸⁸ large replication study
Sparsø T et al. G-allele of intronic rs10830963 in MTNR1B confers increased risk of impaired fasting glycemia and type 2 diabetes. Diabetes, 2009 of 19,605 Europeans found the G allele increases impaired fasting glycemia risk with OR 1.64 (P = 5.5 x 10^-11). In the UK Biobank⁹⁹ UK Biobank
Tan X et al. Associations between chronotype, MTNR1B genotype and risk of type 2 diabetes in UK Biobank. J Intern Med, 2020 analysis of 337,083 participants, CG carriers had OR 1.10 and GG carriers OR 1.21 for type 2 diabetes compared to CC.

The meal-timing dimension was demonstrated in a randomized crossover trial¹⁰¹⁰ randomized crossover trial
Garaulet M et al. Late dinner impairs glucose tolerance in MTNR1B risk allele carriers: a randomized, cross-over study. Clin Nutr, 2017: eating late (when melatonin is elevated) significantly impaired glucose tolerance in G carriers but not in CC individuals. A larger follow-up¹¹¹¹ larger follow-up
Lopez-Minguez J et al. Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion. Diabetes Care, 2022 with 845 participants confirmed that late dinner (1 hour before bed vs. 4 hours) produced 3.5-fold higher melatonin levels, 6.7% lower insulin area under the curve, and 8.3% higher glucose AUC — with significantly stronger effects in G carriers.

Practical Implications

This is one of the most actionable SNPs in the glucose-metabolism space because the intervention is simple: eat dinner earlier. For G carriers, the overlap of high melatonin and high glucose from a late meal is what drives the impairment — shifting the last meal to at least 3-4 hours before bedtime substantially reduces this effect.

Morning eating may also matter. Lane et al. found that the T2D risk in G carriers was amplified in early risers, likely because these individuals wake while melatonin is still elevated. Having breakfast 1-2 hours after waking (rather than immediately) may help avoid the melatonin-glucose collision for early-rising G carriers.

Weight management is also relevant: the POUNDS Lost trial¹²¹² POUNDS Lost trial
Huang T et al. A circadian rhythm-related MTNR1B genetic variant modulates the effect of weight-loss diets on changes in adiposity and body composition. Am J Clin Nutr, 2018 found that the G allele modulates the effect of diet composition on weight loss, with G carriers losing more weight on low-fat diets and gaining more body fat on high-fat diets.

Interactions

MTNR1B rs10830963 interacts with other type 2 diabetes risk loci. Carriers of the G allele here who also carry the TCF7L2 rs7903146 risk allele (T) face compounded diabetes risk through independent but converging pathways — MTNR1B impairing insulin secretion timing, TCF7L2 impairing beta cell development and incretin signaling. Both SNPs are independently actionable: meal timing for MTNR1B, dietary fat moderation for TCF7L2.

The CLOCK gene variant rs1801260 influences chronotype (morning vs. evening preference), which in turn affects when melatonin rises and falls. An evening chronotype combined with the MTNR1B G allele could extend the overlap between elevated melatonin and late eating, though direct evidence for this specific gene-gene interaction remains limited.