{"gene":"INSR","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2005,"finding":"Restoration of hepatic insulin receptor (Insr) expression and normal insulin-stimulated Akt phosphorylation in the liver of Insr knockout mice fails to normalize in vivo hepatic insulin action (glucose production remained ~2-fold elevated during euglycemic clamp), demonstrating that hepatic Insr signaling alone is insufficient for normal hepatic insulin action and implicating hypothalamic Insr loss as a key contributor.","method":"Euglycemic hyperinsulinemic clamp in transgenic Insr knockout rescue mice (L1) with tissue-specific Insr restoration; Western blot for Akt phosphorylation","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo physiological clamp experiment with molecular readouts, directly tested the sufficiency of hepatic Insr restoration","pmids":["15864351"],"is_preprint":false},{"year":2007,"finding":"Beta-cell-specific loss of Irs2 combined with Insr haploinsufficiency causes progressive beta-cell mass decline and diabetes (~70% penetrance); in early disease stages, beta-cells compensate for insulin resistance by increasing insulin secretion rather than mass, demonstrating separable functional and proliferative compensatory mechanisms.","method":"Compound Insr/Irs2 mutant mice; beta-cell mass quantification; circulating insulin measurements","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in double-mutant mouse model with quantitative beta-cell mass and secretion readouts","pmids":["17299086"],"is_preprint":false},{"year":2012,"finding":"Insulin receptor (InsR) signaling through FoxO1 controls hypothalamic POMC neuron number in a cell-autonomous manner: hypothalamus-wide Insr ablation increased POMC neuron number by ~25% in young adults, selective restoration of Insr in POMC neurons partially reversed this, and POMC-specific FoxO1 deletion decreased POMC neuron number by ~23%.","method":"Cre/lox conditional mouse knockouts; POMC neuron counting by in situ hybridization; selective POMC-Insr and POMC-FoxO1 deletion models","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional genetic models with convergent quantitative phenotype, cell-autonomous rescue experiment","pmids":["22319636"],"is_preprint":false},{"year":2015,"finding":"Insulin-InsR signaling in hematopoietic multipotent progenitors (MPPs) drives lymphoid lineage commitment; deletion of Insr in murine bone marrow causes skewed differentiation toward myeloid cells. Mechanistically, mTOR acts downstream of InsR to phosphorylate Stat3 at serine 727, which then binds the Ikaros promoter to initiate transcription.","method":"Bone marrow-specific Insr deletion in mice; lineage analysis; downstream signaling by Western blot; Stat3 ChIP at Ikaros promoter","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined phenotype, ChIP-validated pathway placement, two orthogonal methods (lineage tracing + ChIP)","pmids":["26573296"],"is_preprint":false},{"year":2017,"finding":"A novel p.V657F INSR missense mutation in the second fibronectin type III domain (FnIII-2) reduces proreceptor processing and impairs activation of downstream signaling cascades. Structural analysis of 82 INSR missense mutations shows that mutations predicted to severely disrupt FnIII domain hydrophobic core stability cause the more severe Donohue syndrome, while those causing only localized destabilization cause the milder Rabson-Mendenhall syndrome.","method":"Mutant INSR expression in CHO cells; insulin proreceptor processing assay; downstream signaling cascade assay; in silico structural analysis of mutation database","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — cell-based functional expression of mutant receptor with mechanistic readouts plus in silico structural analysis with genotype-phenotype validation across 82 mutations","pmids":["28765322"],"is_preprint":false},{"year":2022,"finding":"Beta-cell-specific deletion of Insr (using Ins1cre) promotes insulin hypersecretion and improves glucose tolerance in insulin-sensitive contexts (female mice and insulin-sensitive males), demonstrating that beta-cell Insr normally restrains insulin secretion. Female βInsrKO mice showed increased action potential and calcium oscillation frequencies, whereas male βInsrKO islets had reduced ATP-coupled oxygen consumption.","method":"Ins1cre-mediated beta-cell-specific Insr knockout; RNA-seq of purified beta-cells; ex vivo perifusion; hyperglycemic clamp; electrophysiology; Seahorse respirometry","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO with multiple orthogonal functional readouts including electrophysiology, clamp studies, and transcriptomics","pmids":["35136059"],"is_preprint":false},{"year":2022,"finding":"Super-resolution imaging revealed that insulin activation induces INSR clustering at the cell membrane and that insulin resistance inhibits this clustering. INSR was found to be highly co-localized with the cytoskeletal protein βII-spectrin; specific knockout of βII-spectrin inhibited INSR interaction with GLUT4 and impaired glucose metabolism.","method":"Super-resolution (single-molecule) imaging; βII-spectrin knockout; GLUT4 co-localization; glucose metabolism assay","journal":"Nanoscale","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — novel direct localization experiment with functional consequence (GLUT4 interaction, glucose metabolism), single lab","pmids":["35579582"],"is_preprint":false},{"year":2022,"finding":"Syndecan-3 (SDC3) interacts with INSR and limits downstream AKT/mTOR signal transduction in muscle stem cells (MuSCs), restraining their differentiation. Both INSR knockdown and AKT inhibition restored Sdc3-/- MuSC differentiation to wild-type levels, placing SDC3-mediated INSR inhibition upstream of AKT/mTOR in myogenic timing.","method":"Phosphoproteomics; SDC3/INSR co-immunoprecipitation; Sdc3 knockout MuSCs; INSR knockdown; AKT inhibition rescue experiments","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction validated by pulldown/Co-IP plus genetic epistasis rescue, phosphoproteomics, two orthogonal methods in single lab","pmids":["36152781"],"is_preprint":false},{"year":2012,"finding":"A novel homozygous p.Leu795Pro INSR mutation located in the extracellular portion of the β-subunit causes a severe post-binding defect with decreased insulin receptor autophosphorylation, as demonstrated in cultured fibroblasts from the patient.","method":"INSR gene sequencing; insulin receptor autophosphorylation assay in cultured patient fibroblasts","journal":"European journal of pediatrics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct functional assay (autophosphorylation) in patient-derived cells, single case/single lab","pmids":["23229189"],"is_preprint":false},{"year":2021,"finding":"A novel INSR variant c.749_751del [p.(Thr250del)] in the α-subunit reduced expression of mature INSR protein and severely impaired INSR function, whereas variant c.3670G>A [p.(Val1224Met)] in the β-subunit had no effect on protein expression or phosphorylation of INSR and Akt.","method":"In vitro functional assays in transfected cells; Western blot for INSR expression and phosphorylation; Akt phosphorylation","journal":"Frontiers in endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct in vitro functional characterization of specific INSR variants, single lab, two variants tested with divergent results","pmids":["33995269"],"is_preprint":false},{"year":2018,"finding":"A novel heterozygous p.Phe1213Leu INSR mutation severely impairs insulin receptor function by abolishing tyrosine kinase activity and blocking downstream insulin signaling, as shown by in vitro functional studies.","method":"INSR gene sequencing; in vitro kinase activity assay; downstream insulin signaling assay in mutant receptor","journal":"Pediatric diabetes","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — direct in vitro enzymatic/kinase activity characterization of specific INSR mutation, single case study","pmids":["29411486"],"is_preprint":false},{"year":2016,"finding":"miR-96, induced by saturated fatty acid palmitate, directly targets the 3'UTRs of INSR and IRS-1, repressing their expression at the post-transcriptional level in hepatocytes, thereby impairing insulin signaling and glycogen synthesis.","method":"3'UTR luciferase reporter assay; miR-96 overexpression in hepatocytes; Western blot for INSR and IRS-1; glycogen synthesis assay; HFD mouse model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — validated by 3'UTR reporter assay plus overexpression functional readout, two orthogonal methods in single lab","pmids":["28036389"],"is_preprint":false},{"year":2016,"finding":"miR-1271, induced by saturated fatty acid palmitate, directly targets the 3'UTRs of INSR and IRS-1 in hepatocytes, reducing their expression and impairing insulin signaling and glycogen metabolism.","method":"3'UTR luciferase reporter assay; miR-1271 overexpression; Western blot for INSR and IRS-1; glycogen metabolism assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — 3'UTR reporter plus functional overexpression readout, single lab, single paper","pmids":["27613089"],"is_preprint":false},{"year":2015,"finding":"miR-195 and miR-497 directly target Igf1r, Insr, Ccnd2, and Ccne1 in myoblasts, inhibiting proliferation. These miRNAs are negatively regulated by NF-κB, defining a NF-κB–miR-195/497–Igf1r/Insr–Ccnd2/Ccne1 signaling axis in myogenesis.","method":"Luciferase reporter assays for direct miRNA targeting; miRNA gain/loss-of-function in C2C12 cells; proliferation assay; NF-κB inhibition","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR reporter validation plus pathway placement by epistasis, two orthogonal methods","pmids":["26567220"],"is_preprint":false},{"year":2020,"finding":"miR-322 overexpression promotes dexamethasone-induced muscle atrophy by directly targeting IGF1R and INSR (validated by luciferase reporter assay), reducing their expression and contributing to atrophy in C2C12 myotubes and mouse gastrocnemius muscles.","method":"Luciferase reporter assay for miR-322 targeting of INSR 3'UTR; miR-322 mimic/inhibitor transfection; in vivo mouse gastrocnemius atrophy model","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — 3'UTR reporter validated plus in vivo functional rescue, single lab","pmids":["32046161"],"is_preprint":false},{"year":2020,"finding":"RNA-binding protein CUGBP1 controls differential INSR splicing (IR-A vs IR-B ratio) in breast cancer cells; knockdown or overexpression of CUGBP1 altered the IR-A:IR-B ratio through modulation of IR-A expression, reversing or enhancing insulin-induced oncogenic behavior, respectively.","method":"CUGBP1 knockdown/overexpression in breast cancer cell lines; RT-PCR for IR-A/IR-B ratio; oncogenic behavior assays","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain and loss of function for CUGBP1 with defined splicing and phenotypic readout, single lab","pmids":["31958132"],"is_preprint":false},{"year":2013,"finding":"Expression of the INSR-B splice variant in adipose tissue correlates negatively with fasting insulin levels, and increases after weight loss induced by bariatric surgery or very low calorie diet. The splicing factor HNRNPA1 expression correlates negatively with INSR-B expression, consistent with its known role as a regulator of INSR exon 11 splicing.","method":"PCR-capillary electrophoresis for INSR splice variant quantification in adipose tissue across three human cohort studies (n=189 total); correlation analysis; pre/post weight loss comparison","journal":"Diabetologia","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — observational human tissue data replicated across three independent cohorts, no direct manipulation of HNRNPA1","pmids":["24196191"],"is_preprint":false},{"year":2015,"finding":"Deletion of Insr in mouse bone marrow results in skewed myeloid differentiation of multipotent progenitors; mechanistically, mTOR acts as a downstream effector of InsR to activate Stat3 via serine 727 phosphorylation, which binds the Ikaros promoter to drive lymphoid lineage transcription.","method":"Bone marrow Insr deletion; mTOR inhibitor treatment; Stat3 phosphorylation analysis; ChIP at Ikaros promoter; lineage flow cytometry","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO plus ChIP epistasis, two orthogonal methods establishing pathway order","pmids":["26573296"],"is_preprint":false},{"year":2018,"finding":"C-myc directly binds to the INSR and IGF1R promoters and up-regulates their expression in tongue squamous cell carcinoma (TSCC) cells. Both INSR and IGF1R directly target p65 and activate the NF-κB pathway to promote tumorigenesis and metastasis.","method":"ChIP assay for C-myc binding to INSR promoter; luciferase reporter; INSR knockdown/overexpression; in vitro and in vivo tumor models; NF-κB pathway readouts","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP validates transcriptional regulation, pathway placement by KD with NF-κB readout, single lab","pmids":["29518496"],"is_preprint":false},{"year":2015,"finding":"Unsuppressed lipolysis in adipocytes of Insr(P1195L/+) mice on high-fat diet leads to enhanced gluconeogenesis from glycerol and decreased Cyp7a1 expression in liver; wild-type white adipose tissue transplantation rescued hyperglycemia, elevated G6pc expression, and reduced Cyp7a1 expression, placing adipose tissue Insr function upstream of hepatic gluconeogenic and bile acid pathways.","method":"Insr point-mutant mice on HFD; wild-type WAT transplantation; liver G6Pase/G6pc expression; Cyp7a1 expression; lipolysis assays; glycerol administration experiment","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue rescue experiment (WAT transplant) with defined mechanistic readouts, single lab","pmids":["26615883"],"is_preprint":false},{"year":2009,"finding":"INSR haploinsufficiency combined with haploinsufficiency for CHN2 (encoding beta-2 chimerin) causes both insulin resistance and growth deficiency in humans, implicating CHN2 as a component of proximal insulin signaling. Chromosome breakpoint mapping and sequencing confirmed disruption of both loci by a translocation t(7;19).","method":"FISH mapping of chromosome translocation breakpoints; gene sequencing; gene expression in patient-derived adipose tissue","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — natural human genetic experiment (translocation) with tissue-level gene expression validation, single family","pmids":["19720790"],"is_preprint":false},{"year":2025,"finding":"In C. elegans, DAF-2/INSR stability is regulated by CHIP (CHN-1)-dependent ubiquitination at multiple sites; disruption of chn-1/CHIP increases DAF-2/INSR abundance and IIS activity in adults and starved L1 larvae. A mutation at one ubiquitination site (daf-2(gk390525)) shows loss-of-function in larvae but gain-of-function in adults, demonstrating that the functionally relevant ubiquitination sites differ by developmental stage, temperature, and nutritional status.","method":"C. elegans genetics; daf-2 ubiquitination site mutant allele; chn-1/CHIP disruption; IIS activity assays; dauer formation assay; developmental phenotype comparison","journal":"G3 (Bethesda, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ortholog (C. elegans DAF-2/INSR) mechanistic study with multiple genetic alleles and conditions, single lab","pmids":["39837352"],"is_preprint":false},{"year":2024,"finding":"Genetic epistasis in mice showed that Grb10 and Insr act largely independently to regulate fetal growth; however, the disproportionate liver overgrowth and excess hepatic lipid storage seen in Grb10 KO neonates was rescued in Grb10:Insr double mutants to wild-type levels, establishing that Grb10's effect on liver growth is specifically mediated through Insr.","method":"Grb10/Insr double knockout mouse genetics; organ weight measurement; hepatocyte lipid staining; systematic comparison of single vs. double mutant phenotypes","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — classical genetic epistasis in mammalian double KO, multiple organ readouts, single lab","pmids":["38816743"],"is_preprint":false},{"year":2018,"finding":"Prenatal high estradiol exposure decreases hypothalamic INSR expression through elevated promoter methylation in male offspring, contributing to insulin resistance and increased food intake. Chronic food restriction reversed insulin resistance and rescued hypothalamic INSR expression by correcting the elevated promoter methylation.","method":"Mouse prenatal high-estradiol model; bisulfite sequencing of Insr promoter methylation; Western blot for hypothalamic INSR protein; food restriction rescue experiment; HOMA-IR measurement","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct epigenetic mechanism (methylation) at INSR promoter with functional rescue, single lab","pmids":["29155986"],"is_preprint":false},{"year":2020,"finding":"KLF4 transcriptionally activates INSR expression in chondrocytes (confirmed by dual luciferase reporter and CHIP assay), and INSR expression is also regulated by DNA methylation at its promoter. INSR inactivates the JAK2/STAT3 pathway in OA chondrocytes; its overexpression ameliorates OA progression in vitro and in vivo.","method":"Dual luciferase reporter assay; CHIP assay; KLF4/INSR overexpression/knockdown; MS-PCR for promoter methylation; JAK2/STAT3 Western blot; mouse ACLT OA model","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP + reporter validates transcriptional regulation; pathway placement by KD/OE with JAK2/STAT3 readout; in vivo validation","pmids":["33437372"],"is_preprint":false}],"current_model":"INSR encodes the insulin receptor, a receptor tyrosine kinase that undergoes autophosphorylation upon insulin binding and propagates signals through IRS-1/PI3K/AKT/mTOR and MAPK/ERK cascades; tissue-specific functions include restraining beta-cell insulin secretion, directing hematopoietic progenitor lymphoid commitment via mTOR-Stat3-Ikaros, curtailing hypothalamic POMC neuron number through FoxO1, controlling adipose lipolysis upstream of hepatic gluconeogenesis and bile acid metabolism, regulating myogenic timing through a SDC3-INSR-AKT/mTOR interaction, and undergoing context-dependent ubiquitination (CHIP/CHN-1) that modulates receptor stability and signaling output; its expression is transcriptionally regulated by KLF4, epigenetically by promoter methylation, and post-transcriptionally by miR-96, miR-1271, miR-195/497, and miR-322 targeting its 3'UTR, while alternative splicing of exon 11 generates IR-A (mitogenic, embryonic) and IR-B (metabolic, adult) isoforms controlled by CUGBP1 and HNRNPA1; loss-of-function mutations in its fibronectin type III or tyrosine kinase domains cause graded insulin resistance syndromes from Type A insulin resistance to Rabson-Mendenhall and Donohue syndrome."},"narrative":{"mechanistic_narrative":"INSR encodes the insulin receptor tyrosine kinase, whose ligand-induced autophosphorylation and downstream signaling integrate metabolic and developmental control across many tissues [PMID:23229189, PMID:29411486]. Activation triggers receptor clustering at the plasma membrane in concert with the cytoskeletal protein βII-spectrin, which couples INSR to GLUT4 and glucose uptake [PMID:35579582]. Canonical output flows through AKT/mTOR, and this axis is tuned by tissue-specific partners: syndecan-3 binds INSR and restrains AKT/mTOR to time muscle stem cell differentiation [PMID:36152781], while in hematopoietic progenitors mTOR acts downstream of INSR to phosphorylate Stat3 at Ser727, driving Ikaros transcription and lymphoid lineage commitment [PMID:26573296]. INSR signaling exhibits distinct, often restraining, physiological roles: it limits hypothalamic POMC neuron number via FoxO1 [PMID:22319636], normally suppresses beta-cell insulin secretion [PMID:35136059], and acts in adipose tissue upstream of hepatic gluconeogenesis and bile-acid (Cyp7a1) metabolism, with hypothalamic and adipose INSR being required for whole-body insulin action that hepatic INSR alone cannot supply [PMID:15864351, PMID:26615883]. INSR mediates the growth-regulatory effects of Grb10 on the liver [PMID:38816743] and, in cancer contexts, is transcriptionally driven by C-myc to activate NF-κB and promote tumorigenesis [PMID:29518496]. Expression and signaling are layered with regulation: transcriptional activation by KLF4 and silencing by promoter methylation [PMID:29155986, PMID:33437372], post-transcriptional repression by palmitate-induced miR-96/miR-1271 and by miR-195/497 and miR-322 in muscle [PMID:28036389, PMID:26567220, PMID:32046161], alternative exon-11 splicing into IR-A/IR-B isoforms controlled by CUGBP1 and correlating with HNRNPA1 [PMID:31958132, PMID:24196191], and CHIP/CHN-1-dependent ubiquitination that sets receptor abundance in a developmental-stage- and nutrition-dependent manner [PMID:39837352]. Loss-of-function mutations across the fibronectin type III and tyrosine kinase domains graded by their structural severity cause inherited insulin resistance syndromes from Type A insulin resistance to Rabson-Mendenhall and Donohue syndromes [PMID:28765322, PMID:23229189, PMID:29411486].","teleology":[{"year":2005,"claim":"Established that restoring INSR signaling in liver is by itself insufficient for normal hepatic insulin action, redirecting attention to non-hepatic (hypothalamic) INSR as a controller of glucose production.","evidence":"Euglycemic hyperinsulinemic clamp in tissue-specific Insr-rescue knockout mice with Akt phosphorylation readout","pmids":["15864351"],"confidence":"High","gaps":["Did not directly demonstrate the hypothalamic INSR contribution it implicated","Did not resolve which extrahepatic tissue accounts for the residual defect"]},{"year":2007,"claim":"Showed beta-cell INSR/IRS2 dose controls beta-cell mass and that functional (secretory) and proliferative compensation for insulin resistance are separable mechanisms.","evidence":"Compound Insr-haploinsufficient/Irs2-null mice with beta-cell mass and insulin secretion quantification","pmids":["17299086"],"confidence":"High","gaps":["Did not define the molecular switch between secretory and proliferative compensation","Combined two genes, leaving INSR-only contribution incompletely isolated"]},{"year":2012,"claim":"Defined a cell-autonomous INSR–FoxO1 circuit setting hypothalamic POMC neuron number, linking receptor signaling to developmental control of feeding circuitry.","evidence":"Conditional Insr and FoxO1 deletions and POMC-Insr re-expression with POMC neuron counting","pmids":["22319636"],"confidence":"High","gaps":["Did not connect altered neuron number to a defined metabolic phenotype","Partial-only rescue leaves additional pathways unaccounted"]},{"year":2012,"claim":"Demonstrated that beta-subunit extracellular mutations cause post-binding signaling defects, anchoring a structure-function basis for receptor activation failure.","evidence":"INSR sequencing and autophosphorylation assay in patient fibroblasts (p.Leu795Pro)","pmids":["23229189"],"confidence":"Medium","gaps":["Single case, single lab","Did not test downstream cascade or in vivo consequence"]},{"year":2015,"claim":"Placed INSR upstream of an mTOR–Stat3(S727)–Ikaros axis governing lymphoid versus myeloid commitment, extending INSR function into hematopoietic lineage decisions.","evidence":"Bone-marrow Insr deletion with lineage analysis, mTOR inhibition, and Stat3 ChIP at the Ikaros promoter","pmids":["26573296"],"confidence":"High","gaps":["Mechanism of mTOR-to-Stat3 serine phosphorylation not biochemically reconstituted","Relevance to human hematopoiesis not established"]},{"year":2015,"claim":"Identified miR-195/497 (under NF-κB control) as direct repressors of Insr/Igf1r limiting myoblast proliferation, establishing post-transcriptional INSR control in myogenesis.","evidence":"3'UTR luciferase reporters and miRNA gain/loss with proliferation and NF-κB inhibition in C2C12 cells","pmids":["26567220"],"confidence":"Medium","gaps":["INSR contribution not separated from co-targeted Igf1r/cyclins","In vivo myogenic relevance not tested"]},{"year":2015,"claim":"Showed adipose INSR acts upstream of hepatic gluconeogenesis and bile-acid metabolism, with adipose tissue transplant rescuing systemic phenotypes.","evidence":"Insr(P1195L/+) mice on HFD with wild-type WAT transplantation and hepatic G6pc/Cyp7a1 readouts","pmids":["26615883"],"confidence":"Medium","gaps":["Circulating mediator linking adipose lipolysis to liver not identified","Single point-mutant model"]},{"year":2016,"claim":"Established palmitate-induced miR-96 and miR-1271 as direct repressors of INSR and IRS-1 in hepatocytes, providing a lipid-driven post-transcriptional route to hepatic insulin resistance.","evidence":"3'UTR luciferase reporters, miRNA overexpression, INSR/IRS-1 Western blots and glycogen assays in hepatocytes","pmids":["28036389","27613089"],"confidence":"Medium","gaps":["Endogenous miRNA loss-of-function effects on INSR not fully demonstrated in vivo","Relative contribution of INSR vs IRS-1 repression unresolved"]},{"year":2017,"claim":"Linked the structural severity of fibronectin type III domain mutations to disease grade, converting genotype into a predictive structure-function map of INSR syndromes.","evidence":"CHO-cell expression and proreceptor processing/signaling assays for p.V657F plus in silico analysis of 82 mutations","pmids":["28765322"],"confidence":"High","gaps":["Structural predictions not all validated experimentally","Does not address kinase-domain mutation mechanism"]},{"year":2018,"claim":"Demonstrated kinase-domain mutations abolish INSR catalytic activity and downstream signaling, and that C-myc-driven INSR expression activates NF-κB to promote tumor growth.","evidence":"In vitro kinase assay of p.Phe1213Leu; ChIP/reporter for C-myc at INSR promoter with NF-κB tumor readouts","pmids":["29411486","29518496"],"confidence":"Medium","gaps":["Single case for the kinase-dead allele","INSR-to-p65/NF-κB coupling mechanism not biochemically defined"]},{"year":2018,"claim":"Identified promoter methylation as a reversible epigenetic determinant of hypothalamic INSR expression and insulin sensitivity set by prenatal hormone exposure.","evidence":"Prenatal high-estradiol mouse model with bisulfite sequencing and food-restriction rescue","pmids":["29155986"],"confidence":"Medium","gaps":["Methyltransferase/demethylase machinery not identified","Mechanism linking methylation reversal to behavior not defined"]},{"year":2020,"claim":"Showed CUGBP1 controls the IR-A:IR-B splice ratio with oncogenic consequences, and KLF4 transcriptionally activates INSR to suppress JAK2/STAT3 in chondrocytes — defining transcriptional and splicing layers of INSR control.","evidence":"CUGBP1 gain/loss with IR-A/IR-B RT-PCR in breast cancer cells; KLF4/INSR reporter, ChIP and OA models with JAK2/STAT3 readout","pmids":["31958132","33437372"],"confidence":"Medium","gaps":["Splice-factor binding sites on INSR pre-mRNA not mapped","Tissue specificity of KLF4 regulation not generalized"]},{"year":2020,"claim":"Established miR-322 as a direct INSR repressor driving glucocorticoid-induced muscle atrophy, extending miRNA control of INSR to catabolic muscle wasting.","evidence":"Luciferase reporter and miR-322 mimic/inhibitor in C2C12 with in vivo gastrocnemius atrophy model","pmids":["32046161"],"confidence":"Medium","gaps":["INSR repression not separated from co-targeted IGF1R","Endogenous miR-322 loss-of-function effect on atrophy not fully resolved"]},{"year":2022,"claim":"Resolved that beta-cell INSR normally restrains insulin secretion, reversing the assumption that beta-cell INSR is purely pro-secretory, with sex-specific electrophysiological and metabolic mechanisms.","evidence":"Ins1cre beta-cell Insr knockout with perifusion, hyperglycemic clamp, electrophysiology, respirometry and RNA-seq","pmids":["35136059"],"confidence":"High","gaps":["Molecular basis of sex-specific divergence unresolved","Long-term consequences for beta-cell mass not defined"]},{"year":2022,"claim":"Provided direct spatial mechanism by showing insulin induces INSR membrane clustering coupled to βII-spectrin and GLUT4, with insulin resistance disrupting clustering.","evidence":"Super-resolution single-molecule imaging with βII-spectrin knockout and GLUT4 co-localization/glucose assays","pmids":["35579582"],"confidence":"Medium","gaps":["Single lab, not independently replicated","Whether clustering is cause or consequence of signaling not established"]},{"year":2022,"claim":"Identified SDC3 as a direct INSR-binding inhibitor that restrains AKT/mTOR to time muscle stem cell differentiation, defining an extracellular brake on INSR signaling.","evidence":"Phosphoproteomics, reciprocal SDC3/INSR Co-IP, and Sdc3-KO MuSC rescue by INSR knockdown or AKT inhibition","pmids":["36152781"],"confidence":"High","gaps":["Structural basis of SDC3-INSR interaction unknown","Whether SDC3 alters insulin binding or only downstream coupling unresolved"]},{"year":2024,"claim":"Used genetic epistasis to show Grb10's growth-restraining effect on the liver is specifically routed through INSR, while their broader fetal growth roles are largely independent.","evidence":"Grb10:Insr double-knockout mice with organ-weight and hepatic lipid analysis","pmids":["38816743"],"confidence":"Medium","gaps":["Direct biochemical Grb10-INSR coupling in liver not shown here","Tissue-restricted contribution not dissected"]},{"year":2025,"claim":"Demonstrated that CHIP/CHN-1-dependent ubiquitination sets INSR (DAF-2) abundance and signaling output in a stage-, temperature-, and nutrition-dependent manner, adding post-translational control of receptor stability.","evidence":"C. elegans daf-2 ubiquitination-site mutants and chn-1/CHIP disruption with IIS and dauer assays","pmids":["39837352"],"confidence":"Medium","gaps":["Ortholog (C. elegans) system; conservation of specific sites in mammalian INSR not confirmed","Whether ubiquitination targets receptor for degradation or alters signaling not separated"]},{"year":null,"claim":"How the many tissue-specific INSR outputs (restraint of secretion, neuronal patterning, lineage commitment, lipolysis control) are determined by isoform, clustering, partner, and modification state at the single-receptor level remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking IR-A/IR-B isoform, clustering, ubiquitination, and partner binding to output","Mammalian validation of ubiquitination-based stability control lacking","Mechanism converting identical kinase activation into opposing tissue phenotypes unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[8,10]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[8,10]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,7,17]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,5,19]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,7,22]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,8,10]}],"complexes":[],"partners":["IRS2","SDC3","GRB10","CHN2","GLUT4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P06213","full_name":"Insulin receptor","aliases":[],"length_aa":1382,"mass_kda":156.3,"function":"Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosine residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin. 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25114673","citation_count":12,"is_preprint":false},{"pmid":"25927028","id":"PMC_25927028","title":"An Association Study between INSR/NsiI (rs2059806) and INSR/PmlI (rs1799817) SNPs in Women with Polycystic Ovary Syndrome from West Azerbaijan Province, Iran.","date":"2015","source":"Journal of reproduction & infertility","url":"https://pubmed.ncbi.nlm.nih.gov/25927028","citation_count":11,"is_preprint":false},{"pmid":"24947064","id":"PMC_24947064","title":"Family-based analysis of INSR polymorphisms in Chinese PCOS.","date":"2014","source":"Reproductive biomedicine online","url":"https://pubmed.ncbi.nlm.nih.gov/24947064","citation_count":10,"is_preprint":false},{"pmid":"28560459","id":"PMC_28560459","title":"σ-1 receptor stimulation protects against pressure-induced damage through InsR-MAPK signaling in human trabecular meshwork cells.","date":"2017","source":"Molecular medicine 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pigs.","date":"1992","source":"Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/1295851","citation_count":10,"is_preprint":false},{"pmid":"39089538","id":"PMC_39089538","title":"Theaflavins mitigate diabetic symptoms in GK rats by modulating the INSR/PI3K-Akt/GSK-3 pathway and intestinal microbiota.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39089538","citation_count":9,"is_preprint":false},{"pmid":"35368462","id":"PMC_35368462","title":"Molecular docking and mouse modeling suggest CMKLR1 and INSR as targets for improving PCOS phenotypes by minocycline.","date":"2022","source":"EXCLI journal","url":"https://pubmed.ncbi.nlm.nih.gov/35368462","citation_count":8,"is_preprint":false},{"pmid":"33040071","id":"PMC_33040071","title":"Unusual Glycemic Presentations in a Child with a Novel Heterozygous Intragenic INSR Deletion.","date":"2020","source":"Hormone research in paediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/33040071","citation_count":8,"is_preprint":false},{"pmid":"27172637","id":"PMC_27172637","title":"Four Single Nucleotide Polymorphisms in INSR, SLC6A14, TAS2R38, and OR2W3 Genes in Association with Idiopathic Infertility in Persian Men.","date":"2016","source":"The Journal of reproductive medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27172637","citation_count":8,"is_preprint":false},{"pmid":"21507380","id":"PMC_21507380","title":"Recovery of INS-R and ER-alpha expression in the salivary glands of diabetic mice submitted to hormone replacement therapy.","date":"2011","source":"Archives of oral biology","url":"https://pubmed.ncbi.nlm.nih.gov/21507380","citation_count":8,"is_preprint":false},{"pmid":"1923792","id":"PMC_1923792","title":"Microsatellite polymorphism in human insulin receptor gene (INSR) on chromosome 19.","date":"1991","source":"Nucleic acids 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zhi","url":"https://pubmed.ncbi.nlm.nih.gov/25608993","citation_count":7,"is_preprint":false},{"pmid":"29971619","id":"PMC_29971619","title":"Functional Polymorphism Located in the microRNA Binding Site of the Insulin Receptor (INSR) Gene Confers Risk for Type 2 Diabetes Mellitus in the Bangladeshi Population.","date":"2018","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29971619","citation_count":7,"is_preprint":false},{"pmid":"35000900","id":"PMC_35000900","title":"Monogenic diabetes due to an INSR mutation in a child with severe insulin resistance.","date":"2022","source":"Endocrinology, diabetes & metabolism case reports","url":"https://pubmed.ncbi.nlm.nih.gov/35000900","citation_count":6,"is_preprint":false},{"pmid":"38816743","id":"PMC_38816743","title":"Imprinted Grb10, encoding growth factor receptor bound protein 10, regulates fetal growth independently of the insulin-like growth factor type 1 receptor (Igf1r) and insulin receptor (Insr) genes.","date":"2024","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/38816743","citation_count":6,"is_preprint":false},{"pmid":"30903488","id":"PMC_30903488","title":"Changes in the Metastatic Properties of MDA-MB-231 Cells after IGFBP6 Gene Knockdown Is Associated with Increased Expression of miRNA Genes Controlling INSR, IGF1R, and CCND1 Genes.","date":"2019","source":"Bulletin of experimental biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30903488","citation_count":6,"is_preprint":false},{"pmid":"32775006","id":"PMC_32775006","title":"Associations of novel variants in PIK3C3, INSR and MAP3K4 of the ATM pathway genes with pancreatic cancer risk.","date":"2020","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/32775006","citation_count":6,"is_preprint":false},{"pmid":"29082893","id":"PMC_29082893","title":"One Novel 2.43Kb Deletion and One Single Nucleotide Mutation of the INSR Gene in a Chinese Neonate with Rabson-Mendenhall Syndrome.","date":"2017","source":"Journal of clinical research in pediatric endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/29082893","citation_count":6,"is_preprint":false},{"pmid":"2539148","id":"PMC_2539148","title":"Insulin receptor overexpression in a human pre-B acute lymphocytic leukemia cell line with a t(1;19) chromosome translocation near the INSR locus.","date":"1989","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/2539148","citation_count":6,"is_preprint":false},{"pmid":"7504518","id":"PMC_7504518","title":"Mapping of the 19p13 breakpoint in an ovarian carcinoma between the INSR and TCF3 loci.","date":"1993","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/7504518","citation_count":6,"is_preprint":false},{"pmid":"39837352","id":"PMC_39837352","title":"Developmental and conditional regulation of DAF-2/INSR ubiquitination in Caenorhabditis elegans.","date":"2025","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/39837352","citation_count":5,"is_preprint":false},{"pmid":"37993562","id":"PMC_37993562","title":"Metabolomics reveals that chronic restraint stress alleviates carbon tetrachloride-induced hepatic fibrosis through the INSR/PI3K/AKT/AMPK pathway.","date":"2023","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37993562","citation_count":5,"is_preprint":false},{"pmid":"36152781","id":"PMC_36152781","title":"The INSR/AKT/mTOR pathway regulates the pace of myogenesis in a syndecan-3-dependent manner.","date":"2022","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/36152781","citation_count":5,"is_preprint":false},{"pmid":"33728347","id":"PMC_33728347","title":"A New Mutation of the INSR Gene in a 13-Year-Old Girl with Severe Insulin Resistance Syndrome in China.","date":"2021","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/33728347","citation_count":5,"is_preprint":false},{"pmid":"28663160","id":"PMC_28663160","title":"A Mutation in INSR in a Child Presenting with Severe Acanthosis Nigricans.","date":"2017","source":"Journal of clinical research in pediatric endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/28663160","citation_count":5,"is_preprint":false},{"pmid":"28803747","id":"PMC_28803747","title":"Novel heterozygous mutations of the INSR gene in a familial case of Donohue syndrome.","date":"2017","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28803747","citation_count":5,"is_preprint":false},{"pmid":"30551378","id":"PMC_30551378","title":"A novel recombinant peptide INSR-IgG4Fc (Yiminsu) restores insulin sensitivity in experimental insulin resistance models.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/30551378","citation_count":5,"is_preprint":false},{"pmid":"38389245","id":"PMC_38389245","title":"The interaction between magnesium intake, the genetic variant INSR rs1799817 and colorectal cancer risk in a Korean population: a case-control study.","date":"2024","source":"International journal of food sciences and nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/38389245","citation_count":5,"is_preprint":false},{"pmid":"27160688","id":"PMC_27160688","title":"A comprehensive pharmacokinetic/pharmacodynamics analysis of the novel IGF1R/INSR inhibitor BI 893923 applying in vitro, in vivo and in silico modeling techniques.","date":"2016","source":"Cancer chemotherapy and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/27160688","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50492,"output_tokens":6318,"usd":0.123123,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15306,"output_tokens":5617,"usd":0.108478,"stage2_stop_reason":"end_turn"},"total_usd":0.231601,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"Restoration of hepatic insulin receptor (Insr) expression and normal insulin-stimulated Akt phosphorylation in the liver of Insr knockout mice fails to normalize in vivo hepatic insulin action (glucose production remained ~2-fold elevated during euglycemic clamp), demonstrating that hepatic Insr signaling alone is insufficient for normal hepatic insulin action and implicating hypothalamic Insr loss as a key contributor.\",\n      \"method\": \"Euglycemic hyperinsulinemic clamp in transgenic Insr knockout rescue mice (L1) with tissue-specific Insr restoration; Western blot for Akt phosphorylation\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo physiological clamp experiment with molecular readouts, directly tested the sufficiency of hepatic Insr restoration\",\n      \"pmids\": [\"15864351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Beta-cell-specific loss of Irs2 combined with Insr haploinsufficiency causes progressive beta-cell mass decline and diabetes (~70% penetrance); in early disease stages, beta-cells compensate for insulin resistance by increasing insulin secretion rather than mass, demonstrating separable functional and proliferative compensatory mechanisms.\",\n      \"method\": \"Compound Insr/Irs2 mutant mice; beta-cell mass quantification; circulating insulin measurements\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in double-mutant mouse model with quantitative beta-cell mass and secretion readouts\",\n      \"pmids\": [\"17299086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Insulin receptor (InsR) signaling through FoxO1 controls hypothalamic POMC neuron number in a cell-autonomous manner: hypothalamus-wide Insr ablation increased POMC neuron number by ~25% in young adults, selective restoration of Insr in POMC neurons partially reversed this, and POMC-specific FoxO1 deletion decreased POMC neuron number by ~23%.\",\n      \"method\": \"Cre/lox conditional mouse knockouts; POMC neuron counting by in situ hybridization; selective POMC-Insr and POMC-FoxO1 deletion models\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional genetic models with convergent quantitative phenotype, cell-autonomous rescue experiment\",\n      \"pmids\": [\"22319636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Insulin-InsR signaling in hematopoietic multipotent progenitors (MPPs) drives lymphoid lineage commitment; deletion of Insr in murine bone marrow causes skewed differentiation toward myeloid cells. Mechanistically, mTOR acts downstream of InsR to phosphorylate Stat3 at serine 727, which then binds the Ikaros promoter to initiate transcription.\",\n      \"method\": \"Bone marrow-specific Insr deletion in mice; lineage analysis; downstream signaling by Western blot; Stat3 ChIP at Ikaros promoter\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined phenotype, ChIP-validated pathway placement, two orthogonal methods (lineage tracing + ChIP)\",\n      \"pmids\": [\"26573296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A novel p.V657F INSR missense mutation in the second fibronectin type III domain (FnIII-2) reduces proreceptor processing and impairs activation of downstream signaling cascades. Structural analysis of 82 INSR missense mutations shows that mutations predicted to severely disrupt FnIII domain hydrophobic core stability cause the more severe Donohue syndrome, while those causing only localized destabilization cause the milder Rabson-Mendenhall syndrome.\",\n      \"method\": \"Mutant INSR expression in CHO cells; insulin proreceptor processing assay; downstream signaling cascade assay; in silico structural analysis of mutation database\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — cell-based functional expression of mutant receptor with mechanistic readouts plus in silico structural analysis with genotype-phenotype validation across 82 mutations\",\n      \"pmids\": [\"28765322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Beta-cell-specific deletion of Insr (using Ins1cre) promotes insulin hypersecretion and improves glucose tolerance in insulin-sensitive contexts (female mice and insulin-sensitive males), demonstrating that beta-cell Insr normally restrains insulin secretion. Female βInsrKO mice showed increased action potential and calcium oscillation frequencies, whereas male βInsrKO islets had reduced ATP-coupled oxygen consumption.\",\n      \"method\": \"Ins1cre-mediated beta-cell-specific Insr knockout; RNA-seq of purified beta-cells; ex vivo perifusion; hyperglycemic clamp; electrophysiology; Seahorse respirometry\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO with multiple orthogonal functional readouts including electrophysiology, clamp studies, and transcriptomics\",\n      \"pmids\": [\"35136059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Super-resolution imaging revealed that insulin activation induces INSR clustering at the cell membrane and that insulin resistance inhibits this clustering. INSR was found to be highly co-localized with the cytoskeletal protein βII-spectrin; specific knockout of βII-spectrin inhibited INSR interaction with GLUT4 and impaired glucose metabolism.\",\n      \"method\": \"Super-resolution (single-molecule) imaging; βII-spectrin knockout; GLUT4 co-localization; glucose metabolism assay\",\n      \"journal\": \"Nanoscale\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — novel direct localization experiment with functional consequence (GLUT4 interaction, glucose metabolism), single lab\",\n      \"pmids\": [\"35579582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Syndecan-3 (SDC3) interacts with INSR and limits downstream AKT/mTOR signal transduction in muscle stem cells (MuSCs), restraining their differentiation. Both INSR knockdown and AKT inhibition restored Sdc3-/- MuSC differentiation to wild-type levels, placing SDC3-mediated INSR inhibition upstream of AKT/mTOR in myogenic timing.\",\n      \"method\": \"Phosphoproteomics; SDC3/INSR co-immunoprecipitation; Sdc3 knockout MuSCs; INSR knockdown; AKT inhibition rescue experiments\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction validated by pulldown/Co-IP plus genetic epistasis rescue, phosphoproteomics, two orthogonal methods in single lab\",\n      \"pmids\": [\"36152781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A novel homozygous p.Leu795Pro INSR mutation located in the extracellular portion of the β-subunit causes a severe post-binding defect with decreased insulin receptor autophosphorylation, as demonstrated in cultured fibroblasts from the patient.\",\n      \"method\": \"INSR gene sequencing; insulin receptor autophosphorylation assay in cultured patient fibroblasts\",\n      \"journal\": \"European journal of pediatrics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct functional assay (autophosphorylation) in patient-derived cells, single case/single lab\",\n      \"pmids\": [\"23229189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A novel INSR variant c.749_751del [p.(Thr250del)] in the α-subunit reduced expression of mature INSR protein and severely impaired INSR function, whereas variant c.3670G>A [p.(Val1224Met)] in the β-subunit had no effect on protein expression or phosphorylation of INSR and Akt.\",\n      \"method\": \"In vitro functional assays in transfected cells; Western blot for INSR expression and phosphorylation; Akt phosphorylation\",\n      \"journal\": \"Frontiers in endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct in vitro functional characterization of specific INSR variants, single lab, two variants tested with divergent results\",\n      \"pmids\": [\"33995269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A novel heterozygous p.Phe1213Leu INSR mutation severely impairs insulin receptor function by abolishing tyrosine kinase activity and blocking downstream insulin signaling, as shown by in vitro functional studies.\",\n      \"method\": \"INSR gene sequencing; in vitro kinase activity assay; downstream insulin signaling assay in mutant receptor\",\n      \"journal\": \"Pediatric diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — direct in vitro enzymatic/kinase activity characterization of specific INSR mutation, single case study\",\n      \"pmids\": [\"29411486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-96, induced by saturated fatty acid palmitate, directly targets the 3'UTRs of INSR and IRS-1, repressing their expression at the post-transcriptional level in hepatocytes, thereby impairing insulin signaling and glycogen synthesis.\",\n      \"method\": \"3'UTR luciferase reporter assay; miR-96 overexpression in hepatocytes; Western blot for INSR and IRS-1; glycogen synthesis assay; HFD mouse model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — validated by 3'UTR reporter assay plus overexpression functional readout, two orthogonal methods in single lab\",\n      \"pmids\": [\"28036389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-1271, induced by saturated fatty acid palmitate, directly targets the 3'UTRs of INSR and IRS-1 in hepatocytes, reducing their expression and impairing insulin signaling and glycogen metabolism.\",\n      \"method\": \"3'UTR luciferase reporter assay; miR-1271 overexpression; Western blot for INSR and IRS-1; glycogen metabolism assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — 3'UTR reporter plus functional overexpression readout, single lab, single paper\",\n      \"pmids\": [\"27613089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"miR-195 and miR-497 directly target Igf1r, Insr, Ccnd2, and Ccne1 in myoblasts, inhibiting proliferation. These miRNAs are negatively regulated by NF-κB, defining a NF-κB–miR-195/497–Igf1r/Insr–Ccnd2/Ccne1 signaling axis in myogenesis.\",\n      \"method\": \"Luciferase reporter assays for direct miRNA targeting; miRNA gain/loss-of-function in C2C12 cells; proliferation assay; NF-κB inhibition\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR reporter validation plus pathway placement by epistasis, two orthogonal methods\",\n      \"pmids\": [\"26567220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-322 overexpression promotes dexamethasone-induced muscle atrophy by directly targeting IGF1R and INSR (validated by luciferase reporter assay), reducing their expression and contributing to atrophy in C2C12 myotubes and mouse gastrocnemius muscles.\",\n      \"method\": \"Luciferase reporter assay for miR-322 targeting of INSR 3'UTR; miR-322 mimic/inhibitor transfection; in vivo mouse gastrocnemius atrophy model\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 3'UTR reporter validated plus in vivo functional rescue, single lab\",\n      \"pmids\": [\"32046161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RNA-binding protein CUGBP1 controls differential INSR splicing (IR-A vs IR-B ratio) in breast cancer cells; knockdown or overexpression of CUGBP1 altered the IR-A:IR-B ratio through modulation of IR-A expression, reversing or enhancing insulin-induced oncogenic behavior, respectively.\",\n      \"method\": \"CUGBP1 knockdown/overexpression in breast cancer cell lines; RT-PCR for IR-A/IR-B ratio; oncogenic behavior assays\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss of function for CUGBP1 with defined splicing and phenotypic readout, single lab\",\n      \"pmids\": [\"31958132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Expression of the INSR-B splice variant in adipose tissue correlates negatively with fasting insulin levels, and increases after weight loss induced by bariatric surgery or very low calorie diet. The splicing factor HNRNPA1 expression correlates negatively with INSR-B expression, consistent with its known role as a regulator of INSR exon 11 splicing.\",\n      \"method\": \"PCR-capillary electrophoresis for INSR splice variant quantification in adipose tissue across three human cohort studies (n=189 total); correlation analysis; pre/post weight loss comparison\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — observational human tissue data replicated across three independent cohorts, no direct manipulation of HNRNPA1\",\n      \"pmids\": [\"24196191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Deletion of Insr in mouse bone marrow results in skewed myeloid differentiation of multipotent progenitors; mechanistically, mTOR acts as a downstream effector of InsR to activate Stat3 via serine 727 phosphorylation, which binds the Ikaros promoter to drive lymphoid lineage transcription.\",\n      \"method\": \"Bone marrow Insr deletion; mTOR inhibitor treatment; Stat3 phosphorylation analysis; ChIP at Ikaros promoter; lineage flow cytometry\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus ChIP epistasis, two orthogonal methods establishing pathway order\",\n      \"pmids\": [\"26573296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"C-myc directly binds to the INSR and IGF1R promoters and up-regulates their expression in tongue squamous cell carcinoma (TSCC) cells. Both INSR and IGF1R directly target p65 and activate the NF-κB pathway to promote tumorigenesis and metastasis.\",\n      \"method\": \"ChIP assay for C-myc binding to INSR promoter; luciferase reporter; INSR knockdown/overexpression; in vitro and in vivo tumor models; NF-κB pathway readouts\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP validates transcriptional regulation, pathway placement by KD with NF-κB readout, single lab\",\n      \"pmids\": [\"29518496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Unsuppressed lipolysis in adipocytes of Insr(P1195L/+) mice on high-fat diet leads to enhanced gluconeogenesis from glycerol and decreased Cyp7a1 expression in liver; wild-type white adipose tissue transplantation rescued hyperglycemia, elevated G6pc expression, and reduced Cyp7a1 expression, placing adipose tissue Insr function upstream of hepatic gluconeogenic and bile acid pathways.\",\n      \"method\": \"Insr point-mutant mice on HFD; wild-type WAT transplantation; liver G6Pase/G6pc expression; Cyp7a1 expression; lipolysis assays; glycerol administration experiment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue rescue experiment (WAT transplant) with defined mechanistic readouts, single lab\",\n      \"pmids\": [\"26615883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"INSR haploinsufficiency combined with haploinsufficiency for CHN2 (encoding beta-2 chimerin) causes both insulin resistance and growth deficiency in humans, implicating CHN2 as a component of proximal insulin signaling. Chromosome breakpoint mapping and sequencing confirmed disruption of both loci by a translocation t(7;19).\",\n      \"method\": \"FISH mapping of chromosome translocation breakpoints; gene sequencing; gene expression in patient-derived adipose tissue\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — natural human genetic experiment (translocation) with tissue-level gene expression validation, single family\",\n      \"pmids\": [\"19720790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In C. elegans, DAF-2/INSR stability is regulated by CHIP (CHN-1)-dependent ubiquitination at multiple sites; disruption of chn-1/CHIP increases DAF-2/INSR abundance and IIS activity in adults and starved L1 larvae. A mutation at one ubiquitination site (daf-2(gk390525)) shows loss-of-function in larvae but gain-of-function in adults, demonstrating that the functionally relevant ubiquitination sites differ by developmental stage, temperature, and nutritional status.\",\n      \"method\": \"C. elegans genetics; daf-2 ubiquitination site mutant allele; chn-1/CHIP disruption; IIS activity assays; dauer formation assay; developmental phenotype comparison\",\n      \"journal\": \"G3 (Bethesda, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ortholog (C. elegans DAF-2/INSR) mechanistic study with multiple genetic alleles and conditions, single lab\",\n      \"pmids\": [\"39837352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Genetic epistasis in mice showed that Grb10 and Insr act largely independently to regulate fetal growth; however, the disproportionate liver overgrowth and excess hepatic lipid storage seen in Grb10 KO neonates was rescued in Grb10:Insr double mutants to wild-type levels, establishing that Grb10's effect on liver growth is specifically mediated through Insr.\",\n      \"method\": \"Grb10/Insr double knockout mouse genetics; organ weight measurement; hepatocyte lipid staining; systematic comparison of single vs. double mutant phenotypes\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — classical genetic epistasis in mammalian double KO, multiple organ readouts, single lab\",\n      \"pmids\": [\"38816743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Prenatal high estradiol exposure decreases hypothalamic INSR expression through elevated promoter methylation in male offspring, contributing to insulin resistance and increased food intake. Chronic food restriction reversed insulin resistance and rescued hypothalamic INSR expression by correcting the elevated promoter methylation.\",\n      \"method\": \"Mouse prenatal high-estradiol model; bisulfite sequencing of Insr promoter methylation; Western blot for hypothalamic INSR protein; food restriction rescue experiment; HOMA-IR measurement\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct epigenetic mechanism (methylation) at INSR promoter with functional rescue, single lab\",\n      \"pmids\": [\"29155986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KLF4 transcriptionally activates INSR expression in chondrocytes (confirmed by dual luciferase reporter and CHIP assay), and INSR expression is also regulated by DNA methylation at its promoter. INSR inactivates the JAK2/STAT3 pathway in OA chondrocytes; its overexpression ameliorates OA progression in vitro and in vivo.\",\n      \"method\": \"Dual luciferase reporter assay; CHIP assay; KLF4/INSR overexpression/knockdown; MS-PCR for promoter methylation; JAK2/STAT3 Western blot; mouse ACLT OA model\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP + reporter validates transcriptional regulation; pathway placement by KD/OE with JAK2/STAT3 readout; in vivo validation\",\n      \"pmids\": [\"33437372\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INSR encodes the insulin receptor, a receptor tyrosine kinase that undergoes autophosphorylation upon insulin binding and propagates signals through IRS-1/PI3K/AKT/mTOR and MAPK/ERK cascades; tissue-specific functions include restraining beta-cell insulin secretion, directing hematopoietic progenitor lymphoid commitment via mTOR-Stat3-Ikaros, curtailing hypothalamic POMC neuron number through FoxO1, controlling adipose lipolysis upstream of hepatic gluconeogenesis and bile acid metabolism, regulating myogenic timing through a SDC3-INSR-AKT/mTOR interaction, and undergoing context-dependent ubiquitination (CHIP/CHN-1) that modulates receptor stability and signaling output; its expression is transcriptionally regulated by KLF4, epigenetically by promoter methylation, and post-transcriptionally by miR-96, miR-1271, miR-195/497, and miR-322 targeting its 3'UTR, while alternative splicing of exon 11 generates IR-A (mitogenic, embryonic) and IR-B (metabolic, adult) isoforms controlled by CUGBP1 and HNRNPA1; loss-of-function mutations in its fibronectin type III or tyrosine kinase domains cause graded insulin resistance syndromes from Type A insulin resistance to Rabson-Mendenhall and Donohue syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"INSR encodes the insulin receptor tyrosine kinase, whose ligand-induced autophosphorylation and downstream signaling integrate metabolic and developmental control across many tissues [#8, #10]. Activation triggers receptor clustering at the plasma membrane in concert with the cytoskeletal protein \\u03b2II-spectrin, which couples INSR to GLUT4 and glucose uptake [#6]. Canonical output flows through AKT/mTOR, and this axis is tuned by tissue-specific partners: syndecan-3 binds INSR and restrains AKT/mTOR to time muscle stem cell differentiation [#7], while in hematopoietic progenitors mTOR acts downstream of INSR to phosphorylate Stat3 at Ser727, driving Ikaros transcription and lymphoid lineage commitment [#3, #17]. INSR signaling exhibits distinct, often restraining, physiological roles: it limits hypothalamic POMC neuron number via FoxO1 [#2], normally suppresses beta-cell insulin secretion [#5], and acts in adipose tissue upstream of hepatic gluconeogenesis and bile-acid (Cyp7a1) metabolism, with hypothalamic and adipose INSR being required for whole-body insulin action that hepatic INSR alone cannot supply [#0, #19]. INSR mediates the growth-regulatory effects of Grb10 on the liver [#22] and, in cancer contexts, is transcriptionally driven by C-myc to activate NF-\\u03baB and promote tumorigenesis [#18]. Expression and signaling are layered with regulation: transcriptional activation by KLF4 and silencing by promoter methylation [#23, #24], post-transcriptional repression by palmitate-induced miR-96/miR-1271 and by miR-195/497 and miR-322 in muscle [#11, #13, #14], alternative exon-11 splicing into IR-A/IR-B isoforms controlled by CUGBP1 and correlating with HNRNPA1 [#15, #16], and CHIP/CHN-1-dependent ubiquitination that sets receptor abundance in a developmental-stage- and nutrition-dependent manner [#21]. Loss-of-function mutations across the fibronectin type III and tyrosine kinase domains graded by their structural severity cause inherited insulin resistance syndromes from Type A insulin resistance to Rabson-Mendenhall and Donohue syndromes [#4, #8, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that restoring INSR signaling in liver is by itself insufficient for normal hepatic insulin action, redirecting attention to non-hepatic (hypothalamic) INSR as a controller of glucose production.\",\n      \"evidence\": \"Euglycemic hyperinsulinemic clamp in tissue-specific Insr-rescue knockout mice with Akt phosphorylation readout\",\n      \"pmids\": [\"15864351\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not directly demonstrate the hypothalamic INSR contribution it implicated\", \"Did not resolve which extrahepatic tissue accounts for the residual defect\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed beta-cell INSR/IRS2 dose controls beta-cell mass and that functional (secretory) and proliferative compensation for insulin resistance are separable mechanisms.\",\n      \"evidence\": \"Compound Insr-haploinsufficient/Irs2-null mice with beta-cell mass and insulin secretion quantification\",\n      \"pmids\": [\"17299086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular switch between secretory and proliferative compensation\", \"Combined two genes, leaving INSR-only contribution incompletely isolated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined a cell-autonomous INSR\\u2013FoxO1 circuit setting hypothalamic POMC neuron number, linking receptor signaling to developmental control of feeding circuitry.\",\n      \"evidence\": \"Conditional Insr and FoxO1 deletions and POMC-Insr re-expression with POMC neuron counting\",\n      \"pmids\": [\"22319636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect altered neuron number to a defined metabolic phenotype\", \"Partial-only rescue leaves additional pathways unaccounted\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that beta-subunit extracellular mutations cause post-binding signaling defects, anchoring a structure-function basis for receptor activation failure.\",\n      \"evidence\": \"INSR sequencing and autophosphorylation assay in patient fibroblasts (p.Leu795Pro)\",\n      \"pmids\": [\"23229189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single case, single lab\", \"Did not test downstream cascade or in vivo consequence\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed INSR upstream of an mTOR\\u2013Stat3(S727)\\u2013Ikaros axis governing lymphoid versus myeloid commitment, extending INSR function into hematopoietic lineage decisions.\",\n      \"evidence\": \"Bone-marrow Insr deletion with lineage analysis, mTOR inhibition, and Stat3 ChIP at the Ikaros promoter\",\n      \"pmids\": [\"26573296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of mTOR-to-Stat3 serine phosphorylation not biochemically reconstituted\", \"Relevance to human hematopoiesis not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified miR-195/497 (under NF-\\u03baB control) as direct repressors of Insr/Igf1r limiting myoblast proliferation, establishing post-transcriptional INSR control in myogenesis.\",\n      \"evidence\": \"3'UTR luciferase reporters and miRNA gain/loss with proliferation and NF-\\u03baB inhibition in C2C12 cells\",\n      \"pmids\": [\"26567220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"INSR contribution not separated from co-targeted Igf1r/cyclins\", \"In vivo myogenic relevance not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed adipose INSR acts upstream of hepatic gluconeogenesis and bile-acid metabolism, with adipose tissue transplant rescuing systemic phenotypes.\",\n      \"evidence\": \"Insr(P1195L/+) mice on HFD with wild-type WAT transplantation and hepatic G6pc/Cyp7a1 readouts\",\n      \"pmids\": [\"26615883\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Circulating mediator linking adipose lipolysis to liver not identified\", \"Single point-mutant model\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established palmitate-induced miR-96 and miR-1271 as direct repressors of INSR and IRS-1 in hepatocytes, providing a lipid-driven post-transcriptional route to hepatic insulin resistance.\",\n      \"evidence\": \"3'UTR luciferase reporters, miRNA overexpression, INSR/IRS-1 Western blots and glycogen assays in hepatocytes\",\n      \"pmids\": [\"28036389\", \"27613089\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous miRNA loss-of-function effects on INSR not fully demonstrated in vivo\", \"Relative contribution of INSR vs IRS-1 repression unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked the structural severity of fibronectin type III domain mutations to disease grade, converting genotype into a predictive structure-function map of INSR syndromes.\",\n      \"evidence\": \"CHO-cell expression and proreceptor processing/signaling assays for p.V657F plus in silico analysis of 82 mutations\",\n      \"pmids\": [\"28765322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural predictions not all validated experimentally\", \"Does not address kinase-domain mutation mechanism\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated kinase-domain mutations abolish INSR catalytic activity and downstream signaling, and that C-myc-driven INSR expression activates NF-\\u03baB to promote tumor growth.\",\n      \"evidence\": \"In vitro kinase assay of p.Phe1213Leu; ChIP/reporter for C-myc at INSR promoter with NF-\\u03baB tumor readouts\",\n      \"pmids\": [\"29411486\", \"29518496\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single case for the kinase-dead allele\", \"INSR-to-p65/NF-\\u03baB coupling mechanism not biochemically defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified promoter methylation as a reversible epigenetic determinant of hypothalamic INSR expression and insulin sensitivity set by prenatal hormone exposure.\",\n      \"evidence\": \"Prenatal high-estradiol mouse model with bisulfite sequencing and food-restriction rescue\",\n      \"pmids\": [\"29155986\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Methyltransferase/demethylase machinery not identified\", \"Mechanism linking methylation reversal to behavior not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed CUGBP1 controls the IR-A:IR-B splice ratio with oncogenic consequences, and KLF4 transcriptionally activates INSR to suppress JAK2/STAT3 in chondrocytes — defining transcriptional and splicing layers of INSR control.\",\n      \"evidence\": \"CUGBP1 gain/loss with IR-A/IR-B RT-PCR in breast cancer cells; KLF4/INSR reporter, ChIP and OA models with JAK2/STAT3 readout\",\n      \"pmids\": [\"31958132\", \"33437372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Splice-factor binding sites on INSR pre-mRNA not mapped\", \"Tissue specificity of KLF4 regulation not generalized\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established miR-322 as a direct INSR repressor driving glucocorticoid-induced muscle atrophy, extending miRNA control of INSR to catabolic muscle wasting.\",\n      \"evidence\": \"Luciferase reporter and miR-322 mimic/inhibitor in C2C12 with in vivo gastrocnemius atrophy model\",\n      \"pmids\": [\"32046161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"INSR repression not separated from co-targeted IGF1R\", \"Endogenous miR-322 loss-of-function effect on atrophy not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved that beta-cell INSR normally restrains insulin secretion, reversing the assumption that beta-cell INSR is purely pro-secretory, with sex-specific electrophysiological and metabolic mechanisms.\",\n      \"evidence\": \"Ins1cre beta-cell Insr knockout with perifusion, hyperglycemic clamp, electrophysiology, respirometry and RNA-seq\",\n      \"pmids\": [\"35136059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of sex-specific divergence unresolved\", \"Long-term consequences for beta-cell mass not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided direct spatial mechanism by showing insulin induces INSR membrane clustering coupled to \\u03b2II-spectrin and GLUT4, with insulin resistance disrupting clustering.\",\n      \"evidence\": \"Super-resolution single-molecule imaging with \\u03b2II-spectrin knockout and GLUT4 co-localization/glucose assays\",\n      \"pmids\": [\"35579582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, not independently replicated\", \"Whether clustering is cause or consequence of signaling not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified SDC3 as a direct INSR-binding inhibitor that restrains AKT/mTOR to time muscle stem cell differentiation, defining an extracellular brake on INSR signaling.\",\n      \"evidence\": \"Phosphoproteomics, reciprocal SDC3/INSR Co-IP, and Sdc3-KO MuSC rescue by INSR knockdown or AKT inhibition\",\n      \"pmids\": [\"36152781\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of SDC3-INSR interaction unknown\", \"Whether SDC3 alters insulin binding or only downstream coupling unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Used genetic epistasis to show Grb10's growth-restraining effect on the liver is specifically routed through INSR, while their broader fetal growth roles are largely independent.\",\n      \"evidence\": \"Grb10:Insr double-knockout mice with organ-weight and hepatic lipid analysis\",\n      \"pmids\": [\"38816743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical Grb10-INSR coupling in liver not shown here\", \"Tissue-restricted contribution not dissected\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated that CHIP/CHN-1-dependent ubiquitination sets INSR (DAF-2) abundance and signaling output in a stage-, temperature-, and nutrition-dependent manner, adding post-translational control of receptor stability.\",\n      \"evidence\": \"C. elegans daf-2 ubiquitination-site mutants and chn-1/CHIP disruption with IIS and dauer assays\",\n      \"pmids\": [\"39837352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog (C. elegans) system; conservation of specific sites in mammalian INSR not confirmed\", \"Whether ubiquitination targets receptor for degradation or alters signaling not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many tissue-specific INSR outputs (restraint of secretion, neuronal patterning, lineage commitment, lipolysis control) are determined by isoform, clustering, partner, and modification state at the single-receptor level remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking IR-A/IR-B isoform, clustering, ubiquitination, and partner binding to output\", \"Mammalian validation of ubiquitination-based stability control lacking\", \"Mechanism converting identical kinase activation into opposing tissue phenotypes unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [8, 10]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [8, 10]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 7, 17]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 5, 19]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 7, 22]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 8, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IRS2\", \"SDC3\", \"GRB10\", \"CHN2\", \"GLUT4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}