{"gene":"MTNR1B","run_date":"2026-06-10T05:19:51","timeline":{"discoveries":[{"year":2008,"finding":"MTNR1B (MT2) mRNA is expressed in human pancreatic islets and is primarily localized in beta cells; individuals carrying the risk allele show increased MTNR1B expression in islets, and insulin release from clonal beta cells in response to glucose is inhibited in the presence of melatonin, establishing a direct inhibitory role of melatonin-MTNR1B signaling on beta-cell insulin secretion.","method":"Immunocytochemistry, RT-PCR, in vitro insulin secretion assay in clonal beta cells","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal localization by IHC + functional inhibition assay in clonal beta cells, replicated across multiple independent cohorts in same study and confirmed by two concurrent papers","pmids":["19060908"],"is_preprint":false},{"year":2008,"finding":"RT-PCR confirmed MT2 (MTNR1B) transcript expression in human pancreatic islets and beta cells, linking melatonin receptor signaling to glucose homeostasis in the islet.","method":"RT-PCR in human pancreatic islets and beta cells","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct RT-PCR localization, independently replicated by Lyssenko et al. in the same publication set","pmids":["19060909"],"is_preprint":false},{"year":2012,"finding":"Large-scale exon resequencing and four-tiered functional investigation of 40 MTNR1B nonsynonymous variants identified 14 rare non-functional mutants; 4 very rare variants showed complete loss of melatonin binding and signaling, establishing that loss-of-function rare variants in MTNR1B (disrupted melatonin binding and downstream signaling) contribute to T2D risk.","method":"Exon resequencing, melatonin binding assays, signaling assays (functional characterization in transfected cells), genetic association","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding and signaling assays with mutagenesis across 40 variants in a large cohort, multiple orthogonal methods","pmids":["22286214"],"is_preprint":false},{"year":2010,"finding":"Functional characterization of MTNR1B nonsynonymous variants (G24E, L60R, V124I) in transfected COS-7 cells showed that L60R completely disrupts MT2 signaling, V124I considerably decreases it, and G24E shows slightly decreased constitutive activity; the G24E variant associates with increased BMI and decreased fasting plasma glucose in population studies.","method":"Transfection of COS-7 cells with mutant MT2 constructs, constitutive and melatonin-induced signaling assays, population genotyping","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of signaling with mutants in transfected cells, functional follow-up in population sample, single lab but multiple orthogonal methods","pmids":["20200315"],"is_preprint":false},{"year":2017,"finding":"Melatonin exerts an inhibitory effect on insulin gene transcription via MTNR1B and the downstream Raf-1/ERK (MAPK) signaling pathway in MIN6 beta cells; MTNR1B knockdown abrogated melatonin-regulated insulin mRNA suppression, and chemical inhibition of Raf-1 or ERK similarly attenuated the effect.","method":"MTNR1B overexpression and siRNA knockdown in MIN6 cells, western blot for Raf-1/ERK pathway, insulin mRNA qPCR, pharmacological inhibitors GW5074 and U0126","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function knockdown + gain-of-function overexpression + pharmacological inhibitors, single lab, multiple orthogonal methods","pmids":["29207116"],"is_preprint":false},{"year":2022,"finding":"In human nucleus pulposus cells, melatonin acts via MTNR1B to activate Gαi2 protein, which upregulates YAP levels, leading to anabolic enhancement; melatonin-mediated YAP upregulation increases IκBα expression and suppresses TNF-α-induced NF-κB pathway activation, thereby reversing TNF-α-impaired metabolism of NP cells.","method":"Western blotting, immunofluorescence, immunoprecipitation, membrane receptor inhibitors, pathway inhibitors, lentiviral infection, plasmid transfection in human NP cells; rat IDD model with intraperitoneal melatonin","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP/pulldown showing Gαi2 activation, pathway inhibitors, loss-of-function with defined phenotype, single lab with multiple orthogonal methods","pmids":["35342351"],"is_preprint":false},{"year":2019,"finding":"In chordoma cells, MTNR1B activation by melatonin recruits Gαi2, which inhibits SRC kinase activity by recruiting CSK and SRC together, increasing SRC Y530 phosphorylation and decreasing SRC Y419 phosphorylation; this suppresses β-catenin signaling and cancer cell stemness. MTNR1B loss releases melatonin's repression of β-catenin signaling, promoting cancer stem cell properties and chemoresistance.","method":"Co-immunoprecipitation (CSK/SRC complex), phosphorylation analysis of SRC, β-catenin signaling assays, MTNR1B deletion analysis in chordoma tissues, in vitro functional assays","journal":"Journal of pineal research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP for CSK/SRC complex, phospho-specific western blots, loss-of-function with defined cellular phenotype, single lab","pmids":["31140197"],"is_preprint":false},{"year":2021,"finding":"In porcine granulosa cells under hypoxia, blocking MTNR1B with a competitive antagonist (4P-PDOT) diminished melatonin's inhibitory effects on caspase-3 activation; PKA (a downstream kinase of MTNR1B) was confirmed as a mediator of MTNR1B-dependent protection, indicating that melatonin signals through MTNR1B-PKA to inhibit caspase 3/8/9-dependent apoptosis.","method":"MTNR1B antagonist (4P-PDOT) treatment, PKA activity measurement, caspase activation assays, antioxidant enzyme expression analysis in hypoxic porcine GCs","journal":"Antioxidants","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — pharmacological receptor blockade with downstream readout, single lab, single organism model (porcine)","pmids":["33525391"],"is_preprint":false},{"year":2015,"finding":"The BMAL1 protein binds to an E-box motif in the proximal promoter of the hMTNR1B gene in human myometrial cells; overexpression of the BMAL1/CLOCK complex activates MTNR1B expression, generating a circadian rhythm in MTNR1B expression in phase with hPER2, establishing MTNR1B as a clock-controlled gene target in human myometrium.","method":"Chromatin immunoprecipitation (ChIP) of BMAL1 at hMTNR1B promoter, BMAL1/CLOCK overexpression studies, real-time bioluminometry for circadian rhythms, qPCR","journal":"Molecular human reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct BMAL1 binding to MTNR1B promoter + functional overexpression confirming transcriptional activation, single lab with two orthogonal methods","pmids":["25939854"],"is_preprint":false},{"year":2024,"finding":"Mtnr1b knockout (but not Mtnr1a knockout) in mice reduced placental efficiency, increased intrauterine growth restriction, increased placental oxidative stress and apoptosis, and reduced angiogenesis; mechanistically, Mtnr1b knockout reduced STAT3 phosphorylation, which is a promoter of VEGFR2, downregulating VEGFR2 and its downstream PI3K/AKT elements, thereby disrupting placental angiogenesis and development.","method":"Mtnr1b knockout mice, RNA sequencing, histochemistry, western blot for STAT3/VEGFR2/PI3K/AKT phosphorylation, vascular density quantification","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined molecular mechanism (phosphorylation cascade) and cellular phenotype, single lab with RNA-seq + histochemistry + western blot","pmids":["38960012"],"is_preprint":false},{"year":2023,"finding":"Astrocyte-specific knockout of Mtnr1b (cKO-Gfap mice) caused increased anxiety-like behavior without cognitive impairment; mechanistically, loss of astrocytic Mtnr1b led to downregulation of GAD67 in hippocampal CA1/CA3 areas and reduced GABAA receptor and Kir2.2 expression, indicating MTNR1B in astrocytes supports GABAergic synaptic function.","method":"Conditional Cre-loxP astrocyte-specific Mtnr1b knockout, behavioral testing (open field, elevated plus maze, Morris water maze), immunofluorescence for GAD67/vGluT1/NeuN, RNA-seq, qRT-PCR","journal":"Journal of integrative neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific genetic knockout with defined behavioral and molecular phenotype, RNA-seq + immunofluorescence, single lab","pmids":["38176947"],"is_preprint":false},{"year":2018,"finding":"siRNA-mediated MTNR1B knockdown in bovine granulosa cells significantly promoted apoptosis (increased BAX, CASP3; decreased BCL2, BCL-XL, SOD1, GPX4) without affecting cell cycle; melatonin's protective effects on apoptosis and cell cycle were largely maintained after MTNR1B knockdown (attributed to compensatory MTNR1A upregulation), except that MTNR1B knockdown abolished melatonin's antioxidant effects on SOD1 and GPX4.","method":"RNAi knockdown of MTNR1B in bovine granulosa cells, apoptosis gene expression (qPCR/western blot), cell cycle analysis, MTNR1A expression measurement","journal":"PeerJ","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single knockdown experiment in bovine cells (animal model), single lab, limited mechanistic follow-up","pmids":["29707428"],"is_preprint":false},{"year":2024,"finding":"Melatonin treatment regulates uterine m6A methylation levels via MTNR1B; use of MTNR1B inhibitors reversed melatonin's effects on m6A modification, inflammation, autophagy, and apoptosis pathways, indicating MTNR1B mediates melatonin's regulation of m6A methylation during pregnancy.","method":"MTNR1B inhibitor treatment in mouse pregnancy model, m6A methylation profiling, LPS-induced inflammation model, pathway analysis","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological receptor blockade in mouse model, single lab, m6A mechanism not fully reconstituted","pmids":["38255808"],"is_preprint":false},{"year":2024,"finding":"Melatonin suppresses ileum inflammation and maintains normal differentiation of ileum stem cells through MTNR1B; MTNR1B inhibitor treatment reversed these effects. The study further showed melatonin-MTNR1B signaling inhibits abnormal METTL3 expression, which would otherwise promote Wnt/β-catenin activity and disrupt cell differentiation.","method":"MTNR1B inhibitor treatment, METTL3 inhibitor (SAH), ileum inflammation assays, Wnt/β-catenin pathway analysis, stem cell differentiation assays","journal":"Inflammation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological blockade only, single lab, METTL3 link is indirect","pmids":["39014159"],"is_preprint":false},{"year":2016,"finding":"Carriers of the MTNR1B rs10830963 G risk allele showed a significantly longer duration of elevated melatonin levels (41 min) and delayed circadian phase of dim-light melatonin offset (1.37 h, partially mediated through delayed offset of melatonin synthesis), demonstrating that the risk allele influences the dynamics of melatonin secretion/clearance, not just receptor sensitivity.","method":"Intensive in-laboratory protocols measuring melatonin levels and circadian phase (dim-light melatonin offset) in 58–96 participants; actigraphy and polysomnography in cross-sectional studies","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct physiological measurement of melatonin dynamics in controlled laboratory conditions with genotype stratification, multiple measurement modalities","pmids":["26868293"],"is_preprint":false},{"year":2025,"finding":"In hiPSC-derived β-like cells with isogenic CRISPR/Cas9 edits at rs10830963 (C/C vs G/G), western blot showed slightly higher MTNR1B protein levels in G/G cells consistent with rs10830963 functioning as an eQTL; melatonin addition nominally reduced insulin secretion more efficiently in G-allele carrying cells, suggesting increased receptor-mediated suppression of insulin secretion.","method":"CRISPR/Cas9 isogenic editing of hiPSC and hESC at rs10830963, differentiation to β-like cells, western blot for MTNR1B protein, insulin secretion assay with melatonin","journal":"Journal of pineal research","confidence":"Low","confidence_rationale":"Tier 2 / Weak — isogenic CRISPR editing is rigorous but MTNR1B mRNA levels were undetectable (negative for eQTL at mRNA level), protein difference was slight, insulin secretion difference was nominal; single lab, immature cell model","pmids":["40898610"],"is_preprint":false}],"current_model":"MTNR1B encodes melatonin receptor 1B (MT2), a Gi-coupled GPCR expressed in pancreatic beta cells, human myometrium, astrocytes, and other tissues; upon melatonin binding it inhibits insulin gene transcription and glucose-stimulated insulin secretion via Gαi2/Raf-1/ERK signaling, functions as a clock-controlled gene whose promoter is directly activated by the BMAL1/CLOCK complex through an E-box motif, and mediates additional downstream effects including Gαi2-CSK-SRC-β-catenin axis suppression and STAT3/VEGFR2/PI3K/AKT-dependent placental angiogenesis; rare loss-of-function variants abolish melatonin binding and signaling and confer high T2D risk, while the common intronic risk allele rs10830963 (G) increases MTNR1B expression in islets (eQTL) and prolongs melatonin secretion duration, collectively impairing early-phase insulin secretion and raising fasting glucose."},"narrative":{"mechanistic_narrative":"MTNR1B encodes melatonin receptor 1B (MT2), a Gi-coupled receptor that transduces melatonin signaling to control insulin secretion, circadian-regulated tissue function, and cell survival across multiple cell types [PMID:19060908, PMID:22286214]. In pancreatic beta cells, where MTNR1B is expressed and localized, melatonin engagement of the receptor inhibits glucose-stimulated insulin secretion [PMID:19060908, PMID:19060909] and suppresses insulin gene transcription through a Raf-1/ERK (MAPK) cascade [PMID:29207116]. Genetic and functional dissection establishes the receptor as causally linked to type 2 diabetes risk: rare nonsynonymous variants that abolish or reduce melatonin binding and downstream signaling (e.g. L60R, V124I) confer T2D risk [PMID:22286214, PMID:20200315], while the common intronic risk allele rs10830963 (G) acts as an islet eQTL that raises MTNR1B expression [PMID:19060908, PMID:40898610] and is associated with prolonged duration and delayed offset of melatonin secretion [PMID:26868293], together heightening receptor-mediated suppression of insulin output. Beyond the islet, MTNR1B couples to Gαi2 to control diverse effectors: it recruits CSK/SRC to inhibit SRC kinase and suppress β-catenin–driven cancer stemness [PMID:31140197], upregulates YAP to restrain TNF-α/NF-κB signaling [PMID:35342351], and signals through PKA to block caspase-dependent apoptosis [PMID:33525391]. MTNR1B is a clock-controlled gene whose promoter is directly bound and activated by the BMAL1/CLOCK complex at an E-box motif, generating circadian rhythmicity of its expression [PMID:25939854]. Knockout studies link the receptor to STAT3/VEGFR2/PI3K-AKT–dependent placental angiogenesis [PMID:38960012] and to astrocytic support of hippocampal GABAergic function [PMID:38176947].","teleology":[{"year":2008,"claim":"Establishing where MTNR1B acts and what it does in glucose homeostasis: it was unknown whether the T2D-associated locus had a direct beta-cell function, and localization plus functional assay showed melatonin-MTNR1B signaling directly inhibits insulin secretion.","evidence":"Immunocytochemistry, RT-PCR localization to beta cells, and in vitro insulin secretion assays in clonal beta cells; risk-allele carriers showed elevated islet expression","pmids":["19060908","19060909"],"confidence":"High","gaps":["Did not resolve the molecular cause of the eQTL effect","Downstream signaling cascade in beta cells not yet defined"]},{"year":2010,"claim":"Testing whether coding variants alter receptor function: nonsynonymous mutants were reconstituted in cells, showing L60R abolishes and V124I reduces MT2 signaling, linking receptor activity to metabolic phenotypes.","evidence":"Transfection of mutant MT2 constructs in COS-7 cells with constitutive and melatonin-induced signaling assays plus population genotyping","pmids":["20200315"],"confidence":"High","gaps":["Variants studied are individually rare","Mechanistic link to insulin secretion not directly demonstrated for each variant"]},{"year":2012,"claim":"Determining whether loss-of-function broadly drives disease risk: large-scale resequencing with four-tier functional characterization showed rare variants abolishing melatonin binding and signaling contribute to T2D risk.","evidence":"Exon resequencing of 40 nonsynonymous variants, melatonin binding and signaling assays in transfected cells, and genetic association","pmids":["22286214"],"confidence":"High","gaps":["Causal pathway from receptor loss to fasting glucose elevation in vivo not reconstituted","No structural basis for binding loss provided"]},{"year":2015,"claim":"Explaining how MTNR1B expression is timed: ChIP and overexpression demonstrated direct BMAL1/CLOCK activation of the MTNR1B promoter via an E-box, defining it as a clock-controlled gene.","evidence":"ChIP of BMAL1 at the hMTNR1B promoter, BMAL1/CLOCK overexpression, and real-time bioluminometry in human myometrial cells","pmids":["25939854"],"confidence":"Medium","gaps":["Shown in myometrium; islet circadian regulation not directly tested","Functional consequence of rhythmic expression not measured"]},{"year":2016,"claim":"Distinguishing ligand dynamics from receptor sensitivity: physiological profiling showed the rs10830963 G allele prolongs and delays melatonin secretion, indicating the risk acts partly through ligand exposure timing.","evidence":"Controlled in-laboratory melatonin and dim-light melatonin offset measurements with genotype stratification in 58–96 participants","pmids":["26868293"],"confidence":"Medium","gaps":["Mechanism linking allele to melatonin synthesis offset unresolved","Direct effect on insulin secretion not measured in this study"]},{"year":2017,"claim":"Mapping the beta-cell signaling output: knockdown, overexpression, and inhibitors showed melatonin-MTNR1B suppresses insulin gene transcription through Raf-1/ERK.","evidence":"MTNR1B overexpression and siRNA in MIN6 cells with Raf-1/ERK western blots, insulin mRNA qPCR, and pharmacological inhibitors","pmids":["29207116"],"confidence":"Medium","gaps":["Link between transcriptional suppression and secretion phenotype not unified","G-protein coupling upstream of Raf-1 not defined in this system"]},{"year":2019,"claim":"Defining a Gαi2-dependent kinase axis: Co-IP and phospho-analysis showed MTNR1B recruits Gαi2 to assemble CSK/SRC and inhibit SRC, suppressing β-catenin and cancer stemness.","evidence":"Reciprocal Co-IP of CSK/SRC, SRC phospho-site western blots, and MTNR1B deletion analysis in chordoma cells","pmids":["31140197"],"confidence":"Medium","gaps":["Demonstrated in chordoma; generalizability untested","Single-lab finding without reciprocal validation in other cell types"]},{"year":2021,"claim":"Identifying an anti-apoptotic arm: receptor blockade showed MTNR1B-PKA signaling inhibits caspase-dependent apoptosis under hypoxia.","evidence":"4P-PDOT antagonist treatment, PKA activity measurement, and caspase assays in hypoxic porcine granulosa cells","pmids":["33525391"],"confidence":"Medium","gaps":["Porcine model only","PKA coupling to MTNR1B inferred from antagonist effect, not directly reconstituted"]},{"year":2022,"claim":"Extending Gαi2 signaling to anabolic regulation: MTNR1B activates Gαi2 to upregulate YAP, raising IκBα and suppressing TNF-α-induced NF-κB.","evidence":"Western blot, immunoprecipitation, pathway and receptor inhibitors, and lentiviral manipulation in human nucleus pulposus cells with a rat IDD model","pmids":["35342351"],"confidence":"Medium","gaps":["Mechanism of Gαi2-to-YAP coupling not defined","Single-lab finding"]},{"year":2023,"claim":"Revealing a neural role: astrocyte-specific knockout showed MTNR1B supports GABAergic synaptic function and limits anxiety-like behavior.","evidence":"Cre-loxP astrocyte-specific Mtnr1b knockout with behavioral testing, immunofluorescence for GAD67, and RNA-seq in mice","pmids":["38176947"],"confidence":"Medium","gaps":["Receptor signaling pathway in astrocytes not defined","Link from astrocytic MTNR1B to neuronal GABAergic output is correlative"]},{"year":2024,"claim":"Establishing a developmental angiogenic role: Mtnr1b (not Mtnr1a) knockout impaired placental angiogenesis via reduced STAT3/VEGFR2/PI3K-AKT signaling.","evidence":"Mtnr1b knockout mice with RNA-seq, histochemistry, and phospho-western blots for the STAT3/VEGFR2/PI3K/AKT cascade","pmids":["38960012"],"confidence":"Medium","gaps":["Direct coupling from receptor to STAT3 phosphorylation not reconstituted","Cell-type origin of the signal within placenta unresolved"]},{"year":2024,"claim":"Linking MTNR1B to RNA modification and epithelial homeostasis: inhibitor studies implicated the receptor in melatonin regulation of m6A methylation and ileum stem cell differentiation via METTL3/Wnt.","evidence":"MTNR1B inhibitor treatment in mouse pregnancy and ileum models with m6A profiling, METTL3 inhibition, and Wnt/β-catenin analysis","pmids":["38255808","39014159"],"confidence":"Low","gaps":["Pharmacological blockade only, m6A mechanism not reconstituted","METTL3 link is indirect","No genetic loss-of-function confirmation"]},{"year":2025,"claim":"Testing the rs10830963 eQTL mechanism in a human isogenic system: CRISPR-edited hiPSC β-like cells showed slightly higher MTNR1B protein and nominally greater melatonin-mediated suppression of insulin secretion in G/G cells.","evidence":"Isogenic CRISPR/Cas9 editing of rs10830963 in hiPSC/hESC, differentiation to β-like cells, MTNR1B western blot, and insulin secretion assays","pmids":["40898610"],"confidence":"Low","gaps":["MTNR1B mRNA was undetectable, so mRNA-level eQTL not confirmed","Protein and secretion differences were slight/nominal","Immature cell model"]},{"year":null,"claim":"How the common rs10830963 risk allele mechanistically links elevated islet MTNR1B expression and altered melatonin dynamics to impaired early-phase insulin secretion in vivo remains incompletely resolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of melatonin binding loss for risk variants","Unified in vivo causal chain from eQTL to fasting glucose not established","Tissue-specific G-protein coupling differences not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5,6]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[8]}],"complexes":[],"partners":["GNAI2","CSK","SRC","BMAL1","CLOCK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P49286","full_name":"Melatonin receptor type 1B","aliases":[],"length_aa":362,"mass_kda":40.2,"function":"High affinity receptor for melatonin. Likely to mediate the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that inhibit adenylate cyclase activity","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P49286/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MTNR1B","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MTNR1B","total_profiled":1310},"omim":[{"mim_id":"613233","title":"FASTING PLASMA GLUCOSE LEVEL QUANTITATIVE TRAIT LOCUS 3; FGQTL3","url":"https://www.omim.org/entry/613233"},{"mim_id":"613219","title":"FASTING PLASMA GLUCOSE LEVEL QUANTITATIVE TRAIT LOCUS 2; FGQTL2","url":"https://www.omim.org/entry/613219"},{"mim_id":"612483","title":"FAT ATYPICAL CADHERIN 3; FAT3","url":"https://www.omim.org/entry/612483"},{"mim_id":"612108","title":"FASTING PLASMA GLUCOSE LEVEL QUANTITATIVE TRAIT LOCUS 1; FGQTL1","url":"https://www.omim.org/entry/612108"},{"mim_id":"600976","title":"FAT ATYPICAL CADHERIN 1; FAT1","url":"https://www.omim.org/entry/600976"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Not detected","tissue_distribution":"Not detected","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MTNR1B"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P49286","domains":[{"cath_id":"1.20.1070.10","chopping":"39-330","consensus_level":"high","plddt":92.8541,"start":39,"end":330}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P49286","model_url":"https://alphafold.ebi.ac.uk/files/AF-P49286-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P49286-F1-predicted_aligned_error_v6.png","plddt_mean":84.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MTNR1B","jax_strain_url":"https://www.jax.org/strain/search?query=MTNR1B"},"sequence":{"accession":"P49286","fasta_url":"https://rest.uniprot.org/uniprotkb/P49286.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P49286/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P49286"}},"corpus_meta":[{"pmid":"19060907","id":"PMC_19060907","title":"Variants in MTNR1B influence fasting glucose levels.","date":"2008","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19060907","citation_count":573,"is_preprint":false},{"pmid":"19060908","id":"PMC_19060908","title":"Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion.","date":"2008","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19060908","citation_count":562,"is_preprint":false},{"pmid":"19060909","id":"PMC_19060909","title":"A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk.","date":"2008","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19060909","citation_count":459,"is_preprint":false},{"pmid":"22286214","id":"PMC_22286214","title":"Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes.","date":"2012","source":"Nature 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sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37511203","citation_count":2,"is_preprint":false},{"pmid":"40428319","id":"PMC_40428319","title":"Interaction Between Dietary Fiber Intake and MTNR1B rs10830963 Polymorphism on Glycemic Profiles in Young Brazilian Adults.","date":"2025","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/40428319","citation_count":2,"is_preprint":false},{"pmid":"38864120","id":"PMC_38864120","title":"[A ssociations of short-term ambient particulate matter exposure and MTNR1B gene with triglyceride-glucose index: A family-based study].","date":"2024","source":"Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38864120","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":59129,"output_tokens":4470,"usd":0.122218,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12485,"output_tokens":4337,"usd":0.085425,"stage2_stop_reason":"end_turn"},"total_usd":0.207643,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"MTNR1B (MT2) mRNA is expressed in human pancreatic islets and is primarily localized in beta cells; individuals carrying the risk allele show increased MTNR1B expression in islets, and insulin release from clonal beta cells in response to glucose is inhibited in the presence of melatonin, establishing a direct inhibitory role of melatonin-MTNR1B signaling on beta-cell insulin secretion.\",\n      \"method\": \"Immunocytochemistry, RT-PCR, in vitro insulin secretion assay in clonal beta cells\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal localization by IHC + functional inhibition assay in clonal beta cells, replicated across multiple independent cohorts in same study and confirmed by two concurrent papers\",\n      \"pmids\": [\"19060908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RT-PCR confirmed MT2 (MTNR1B) transcript expression in human pancreatic islets and beta cells, linking melatonin receptor signaling to glucose homeostasis in the islet.\",\n      \"method\": \"RT-PCR in human pancreatic islets and beta cells\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct RT-PCR localization, independently replicated by Lyssenko et al. in the same publication set\",\n      \"pmids\": [\"19060909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Large-scale exon resequencing and four-tiered functional investigation of 40 MTNR1B nonsynonymous variants identified 14 rare non-functional mutants; 4 very rare variants showed complete loss of melatonin binding and signaling, establishing that loss-of-function rare variants in MTNR1B (disrupted melatonin binding and downstream signaling) contribute to T2D risk.\",\n      \"method\": \"Exon resequencing, melatonin binding assays, signaling assays (functional characterization in transfected cells), genetic association\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding and signaling assays with mutagenesis across 40 variants in a large cohort, multiple orthogonal methods\",\n      \"pmids\": [\"22286214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Functional characterization of MTNR1B nonsynonymous variants (G24E, L60R, V124I) in transfected COS-7 cells showed that L60R completely disrupts MT2 signaling, V124I considerably decreases it, and G24E shows slightly decreased constitutive activity; the G24E variant associates with increased BMI and decreased fasting plasma glucose in population studies.\",\n      \"method\": \"Transfection of COS-7 cells with mutant MT2 constructs, constitutive and melatonin-induced signaling assays, population genotyping\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of signaling with mutants in transfected cells, functional follow-up in population sample, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"20200315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Melatonin exerts an inhibitory effect on insulin gene transcription via MTNR1B and the downstream Raf-1/ERK (MAPK) signaling pathway in MIN6 beta cells; MTNR1B knockdown abrogated melatonin-regulated insulin mRNA suppression, and chemical inhibition of Raf-1 or ERK similarly attenuated the effect.\",\n      \"method\": \"MTNR1B overexpression and siRNA knockdown in MIN6 cells, western blot for Raf-1/ERK pathway, insulin mRNA qPCR, pharmacological inhibitors GW5074 and U0126\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function knockdown + gain-of-function overexpression + pharmacological inhibitors, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"29207116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In human nucleus pulposus cells, melatonin acts via MTNR1B to activate Gαi2 protein, which upregulates YAP levels, leading to anabolic enhancement; melatonin-mediated YAP upregulation increases IκBα expression and suppresses TNF-α-induced NF-κB pathway activation, thereby reversing TNF-α-impaired metabolism of NP cells.\",\n      \"method\": \"Western blotting, immunofluorescence, immunoprecipitation, membrane receptor inhibitors, pathway inhibitors, lentiviral infection, plasmid transfection in human NP cells; rat IDD model with intraperitoneal melatonin\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP/pulldown showing Gαi2 activation, pathway inhibitors, loss-of-function with defined phenotype, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35342351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In chordoma cells, MTNR1B activation by melatonin recruits Gαi2, which inhibits SRC kinase activity by recruiting CSK and SRC together, increasing SRC Y530 phosphorylation and decreasing SRC Y419 phosphorylation; this suppresses β-catenin signaling and cancer cell stemness. MTNR1B loss releases melatonin's repression of β-catenin signaling, promoting cancer stem cell properties and chemoresistance.\",\n      \"method\": \"Co-immunoprecipitation (CSK/SRC complex), phosphorylation analysis of SRC, β-catenin signaling assays, MTNR1B deletion analysis in chordoma tissues, in vitro functional assays\",\n      \"journal\": \"Journal of pineal research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP for CSK/SRC complex, phospho-specific western blots, loss-of-function with defined cellular phenotype, single lab\",\n      \"pmids\": [\"31140197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In porcine granulosa cells under hypoxia, blocking MTNR1B with a competitive antagonist (4P-PDOT) diminished melatonin's inhibitory effects on caspase-3 activation; PKA (a downstream kinase of MTNR1B) was confirmed as a mediator of MTNR1B-dependent protection, indicating that melatonin signals through MTNR1B-PKA to inhibit caspase 3/8/9-dependent apoptosis.\",\n      \"method\": \"MTNR1B antagonist (4P-PDOT) treatment, PKA activity measurement, caspase activation assays, antioxidant enzyme expression analysis in hypoxic porcine GCs\",\n      \"journal\": \"Antioxidants\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — pharmacological receptor blockade with downstream readout, single lab, single organism model (porcine)\",\n      \"pmids\": [\"33525391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The BMAL1 protein binds to an E-box motif in the proximal promoter of the hMTNR1B gene in human myometrial cells; overexpression of the BMAL1/CLOCK complex activates MTNR1B expression, generating a circadian rhythm in MTNR1B expression in phase with hPER2, establishing MTNR1B as a clock-controlled gene target in human myometrium.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) of BMAL1 at hMTNR1B promoter, BMAL1/CLOCK overexpression studies, real-time bioluminometry for circadian rhythms, qPCR\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct BMAL1 binding to MTNR1B promoter + functional overexpression confirming transcriptional activation, single lab with two orthogonal methods\",\n      \"pmids\": [\"25939854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Mtnr1b knockout (but not Mtnr1a knockout) in mice reduced placental efficiency, increased intrauterine growth restriction, increased placental oxidative stress and apoptosis, and reduced angiogenesis; mechanistically, Mtnr1b knockout reduced STAT3 phosphorylation, which is a promoter of VEGFR2, downregulating VEGFR2 and its downstream PI3K/AKT elements, thereby disrupting placental angiogenesis and development.\",\n      \"method\": \"Mtnr1b knockout mice, RNA sequencing, histochemistry, western blot for STAT3/VEGFR2/PI3K/AKT phosphorylation, vascular density quantification\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined molecular mechanism (phosphorylation cascade) and cellular phenotype, single lab with RNA-seq + histochemistry + western blot\",\n      \"pmids\": [\"38960012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Astrocyte-specific knockout of Mtnr1b (cKO-Gfap mice) caused increased anxiety-like behavior without cognitive impairment; mechanistically, loss of astrocytic Mtnr1b led to downregulation of GAD67 in hippocampal CA1/CA3 areas and reduced GABAA receptor and Kir2.2 expression, indicating MTNR1B in astrocytes supports GABAergic synaptic function.\",\n      \"method\": \"Conditional Cre-loxP astrocyte-specific Mtnr1b knockout, behavioral testing (open field, elevated plus maze, Morris water maze), immunofluorescence for GAD67/vGluT1/NeuN, RNA-seq, qRT-PCR\",\n      \"journal\": \"Journal of integrative neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific genetic knockout with defined behavioral and molecular phenotype, RNA-seq + immunofluorescence, single lab\",\n      \"pmids\": [\"38176947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"siRNA-mediated MTNR1B knockdown in bovine granulosa cells significantly promoted apoptosis (increased BAX, CASP3; decreased BCL2, BCL-XL, SOD1, GPX4) without affecting cell cycle; melatonin's protective effects on apoptosis and cell cycle were largely maintained after MTNR1B knockdown (attributed to compensatory MTNR1A upregulation), except that MTNR1B knockdown abolished melatonin's antioxidant effects on SOD1 and GPX4.\",\n      \"method\": \"RNAi knockdown of MTNR1B in bovine granulosa cells, apoptosis gene expression (qPCR/western blot), cell cycle analysis, MTNR1A expression measurement\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single knockdown experiment in bovine cells (animal model), single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"29707428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Melatonin treatment regulates uterine m6A methylation levels via MTNR1B; use of MTNR1B inhibitors reversed melatonin's effects on m6A modification, inflammation, autophagy, and apoptosis pathways, indicating MTNR1B mediates melatonin's regulation of m6A methylation during pregnancy.\",\n      \"method\": \"MTNR1B inhibitor treatment in mouse pregnancy model, m6A methylation profiling, LPS-induced inflammation model, pathway analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological receptor blockade in mouse model, single lab, m6A mechanism not fully reconstituted\",\n      \"pmids\": [\"38255808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Melatonin suppresses ileum inflammation and maintains normal differentiation of ileum stem cells through MTNR1B; MTNR1B inhibitor treatment reversed these effects. The study further showed melatonin-MTNR1B signaling inhibits abnormal METTL3 expression, which would otherwise promote Wnt/β-catenin activity and disrupt cell differentiation.\",\n      \"method\": \"MTNR1B inhibitor treatment, METTL3 inhibitor (SAH), ileum inflammation assays, Wnt/β-catenin pathway analysis, stem cell differentiation assays\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological blockade only, single lab, METTL3 link is indirect\",\n      \"pmids\": [\"39014159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Carriers of the MTNR1B rs10830963 G risk allele showed a significantly longer duration of elevated melatonin levels (41 min) and delayed circadian phase of dim-light melatonin offset (1.37 h, partially mediated through delayed offset of melatonin synthesis), demonstrating that the risk allele influences the dynamics of melatonin secretion/clearance, not just receptor sensitivity.\",\n      \"method\": \"Intensive in-laboratory protocols measuring melatonin levels and circadian phase (dim-light melatonin offset) in 58–96 participants; actigraphy and polysomnography in cross-sectional studies\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct physiological measurement of melatonin dynamics in controlled laboratory conditions with genotype stratification, multiple measurement modalities\",\n      \"pmids\": [\"26868293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In hiPSC-derived β-like cells with isogenic CRISPR/Cas9 edits at rs10830963 (C/C vs G/G), western blot showed slightly higher MTNR1B protein levels in G/G cells consistent with rs10830963 functioning as an eQTL; melatonin addition nominally reduced insulin secretion more efficiently in G-allele carrying cells, suggesting increased receptor-mediated suppression of insulin secretion.\",\n      \"method\": \"CRISPR/Cas9 isogenic editing of hiPSC and hESC at rs10830963, differentiation to β-like cells, western blot for MTNR1B protein, insulin secretion assay with melatonin\",\n      \"journal\": \"Journal of pineal research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — isogenic CRISPR editing is rigorous but MTNR1B mRNA levels were undetectable (negative for eQTL at mRNA level), protein difference was slight, insulin secretion difference was nominal; single lab, immature cell model\",\n      \"pmids\": [\"40898610\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MTNR1B encodes melatonin receptor 1B (MT2), a Gi-coupled GPCR expressed in pancreatic beta cells, human myometrium, astrocytes, and other tissues; upon melatonin binding it inhibits insulin gene transcription and glucose-stimulated insulin secretion via Gαi2/Raf-1/ERK signaling, functions as a clock-controlled gene whose promoter is directly activated by the BMAL1/CLOCK complex through an E-box motif, and mediates additional downstream effects including Gαi2-CSK-SRC-β-catenin axis suppression and STAT3/VEGFR2/PI3K/AKT-dependent placental angiogenesis; rare loss-of-function variants abolish melatonin binding and signaling and confer high T2D risk, while the common intronic risk allele rs10830963 (G) increases MTNR1B expression in islets (eQTL) and prolongs melatonin secretion duration, collectively impairing early-phase insulin secretion and raising fasting glucose.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MTNR1B encodes melatonin receptor 1B (MT2), a Gi-coupled receptor that transduces melatonin signaling to control insulin secretion, circadian-regulated tissue function, and cell survival across multiple cell types [#0, #2]. In pancreatic beta cells, where MTNR1B is expressed and localized, melatonin engagement of the receptor inhibits glucose-stimulated insulin secretion [#0, #1] and suppresses insulin gene transcription through a Raf-1/ERK (MAPK) cascade [#4]. Genetic and functional dissection establishes the receptor as causally linked to type 2 diabetes risk: rare nonsynonymous variants that abolish or reduce melatonin binding and downstream signaling (e.g. L60R, V124I) confer T2D risk [#2, #3], while the common intronic risk allele rs10830963 (G) acts as an islet eQTL that raises MTNR1B expression [#0, #15] and is associated with prolonged duration and delayed offset of melatonin secretion [#14], together heightening receptor-mediated suppression of insulin output. Beyond the islet, MTNR1B couples to Gαi2 to control diverse effectors: it recruits CSK/SRC to inhibit SRC kinase and suppress β-catenin–driven cancer stemness [#6], upregulates YAP to restrain TNF-α/NF-κB signaling [#5], and signals through PKA to block caspase-dependent apoptosis [#7]. MTNR1B is a clock-controlled gene whose promoter is directly bound and activated by the BMAL1/CLOCK complex at an E-box motif, generating circadian rhythmicity of its expression [#8]. Knockout studies link the receptor to STAT3/VEGFR2/PI3K-AKT–dependent placental angiogenesis [#9] and to astrocytic support of hippocampal GABAergic function [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing where MTNR1B acts and what it does in glucose homeostasis: it was unknown whether the T2D-associated locus had a direct beta-cell function, and localization plus functional assay showed melatonin-MTNR1B signaling directly inhibits insulin secretion.\",\n      \"evidence\": \"Immunocytochemistry, RT-PCR localization to beta cells, and in vitro insulin secretion assays in clonal beta cells; risk-allele carriers showed elevated islet expression\",\n      \"pmids\": [\"19060908\", \"19060909\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular cause of the eQTL effect\", \"Downstream signaling cascade in beta cells not yet defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Testing whether coding variants alter receptor function: nonsynonymous mutants were reconstituted in cells, showing L60R abolishes and V124I reduces MT2 signaling, linking receptor activity to metabolic phenotypes.\",\n      \"evidence\": \"Transfection of mutant MT2 constructs in COS-7 cells with constitutive and melatonin-induced signaling assays plus population genotyping\",\n      \"pmids\": [\"20200315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Variants studied are individually rare\", \"Mechanistic link to insulin secretion not directly demonstrated for each variant\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Determining whether loss-of-function broadly drives disease risk: large-scale resequencing with four-tier functional characterization showed rare variants abolishing melatonin binding and signaling contribute to T2D risk.\",\n      \"evidence\": \"Exon resequencing of 40 nonsynonymous variants, melatonin binding and signaling assays in transfected cells, and genetic association\",\n      \"pmids\": [\"22286214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal pathway from receptor loss to fasting glucose elevation in vivo not reconstituted\", \"No structural basis for binding loss provided\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Explaining how MTNR1B expression is timed: ChIP and overexpression demonstrated direct BMAL1/CLOCK activation of the MTNR1B promoter via an E-box, defining it as a clock-controlled gene.\",\n      \"evidence\": \"ChIP of BMAL1 at the hMTNR1B promoter, BMAL1/CLOCK overexpression, and real-time bioluminometry in human myometrial cells\",\n      \"pmids\": [\"25939854\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Shown in myometrium; islet circadian regulation not directly tested\", \"Functional consequence of rhythmic expression not measured\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Distinguishing ligand dynamics from receptor sensitivity: physiological profiling showed the rs10830963 G allele prolongs and delays melatonin secretion, indicating the risk acts partly through ligand exposure timing.\",\n      \"evidence\": \"Controlled in-laboratory melatonin and dim-light melatonin offset measurements with genotype stratification in 58–96 participants\",\n      \"pmids\": [\"26868293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking allele to melatonin synthesis offset unresolved\", \"Direct effect on insulin secretion not measured in this study\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapping the beta-cell signaling output: knockdown, overexpression, and inhibitors showed melatonin-MTNR1B suppresses insulin gene transcription through Raf-1/ERK.\",\n      \"evidence\": \"MTNR1B overexpression and siRNA in MIN6 cells with Raf-1/ERK western blots, insulin mRNA qPCR, and pharmacological inhibitors\",\n      \"pmids\": [\"29207116\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between transcriptional suppression and secretion phenotype not unified\", \"G-protein coupling upstream of Raf-1 not defined in this system\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defining a Gαi2-dependent kinase axis: Co-IP and phospho-analysis showed MTNR1B recruits Gαi2 to assemble CSK/SRC and inhibit SRC, suppressing β-catenin and cancer stemness.\",\n      \"evidence\": \"Reciprocal Co-IP of CSK/SRC, SRC phospho-site western blots, and MTNR1B deletion analysis in chordoma cells\",\n      \"pmids\": [\"31140197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Demonstrated in chordoma; generalizability untested\", \"Single-lab finding without reciprocal validation in other cell types\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying an anti-apoptotic arm: receptor blockade showed MTNR1B-PKA signaling inhibits caspase-dependent apoptosis under hypoxia.\",\n      \"evidence\": \"4P-PDOT antagonist treatment, PKA activity measurement, and caspase assays in hypoxic porcine granulosa cells\",\n      \"pmids\": [\"33525391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Porcine model only\", \"PKA coupling to MTNR1B inferred from antagonist effect, not directly reconstituted\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extending Gαi2 signaling to anabolic regulation: MTNR1B activates Gαi2 to upregulate YAP, raising IκBα and suppressing TNF-α-induced NF-κB.\",\n      \"evidence\": \"Western blot, immunoprecipitation, pathway and receptor inhibitors, and lentiviral manipulation in human nucleus pulposus cells with a rat IDD model\",\n      \"pmids\": [\"35342351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Gαi2-to-YAP coupling not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealing a neural role: astrocyte-specific knockout showed MTNR1B supports GABAergic synaptic function and limits anxiety-like behavior.\",\n      \"evidence\": \"Cre-loxP astrocyte-specific Mtnr1b knockout with behavioral testing, immunofluorescence for GAD67, and RNA-seq in mice\",\n      \"pmids\": [\"38176947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor signaling pathway in astrocytes not defined\", \"Link from astrocytic MTNR1B to neuronal GABAergic output is correlative\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Establishing a developmental angiogenic role: Mtnr1b (not Mtnr1a) knockout impaired placental angiogenesis via reduced STAT3/VEGFR2/PI3K-AKT signaling.\",\n      \"evidence\": \"Mtnr1b knockout mice with RNA-seq, histochemistry, and phospho-western blots for the STAT3/VEGFR2/PI3K/AKT cascade\",\n      \"pmids\": [\"38960012\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct coupling from receptor to STAT3 phosphorylation not reconstituted\", \"Cell-type origin of the signal within placenta unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linking MTNR1B to RNA modification and epithelial homeostasis: inhibitor studies implicated the receptor in melatonin regulation of m6A methylation and ileum stem cell differentiation via METTL3/Wnt.\",\n      \"evidence\": \"MTNR1B inhibitor treatment in mouse pregnancy and ileum models with m6A profiling, METTL3 inhibition, and Wnt/β-catenin analysis\",\n      \"pmids\": [\"38255808\", \"39014159\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pharmacological blockade only, m6A mechanism not reconstituted\", \"METTL3 link is indirect\", \"No genetic loss-of-function confirmation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Testing the rs10830963 eQTL mechanism in a human isogenic system: CRISPR-edited hiPSC β-like cells showed slightly higher MTNR1B protein and nominally greater melatonin-mediated suppression of insulin secretion in G/G cells.\",\n      \"evidence\": \"Isogenic CRISPR/Cas9 editing of rs10830963 in hiPSC/hESC, differentiation to β-like cells, MTNR1B western blot, and insulin secretion assays\",\n      \"pmids\": [\"40898610\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"MTNR1B mRNA was undetectable, so mRNA-level eQTL not confirmed\", \"Protein and secretion differences were slight/nominal\", \"Immature cell model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the common rs10830963 risk allele mechanistically links elevated islet MTNR1B expression and altered melatonin dynamics to impaired early-phase insulin secretion in vivo remains incompletely resolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of melatonin binding loss for risk variants\", \"Unified in vivo causal chain from eQTL to fasting glucose not established\", \"Tissue-specific G-protein coupling differences not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0004930\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5, 6]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GNAI2\", \"CSK\", \"SRC\", \"BMAL1\", \"CLOCK\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}