Affinage

INSR

Insulin receptor · UniProt P06213

Length
1382 aa
Mass
156.3 kDa
Annotated
2026-06-10
100 papers in source corpus 24 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2005 High

    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

    PMID:15864351

    Open questions at the time
    • Did not directly demonstrate the hypothalamic INSR contribution it implicated
    • Did not resolve which extrahepatic tissue accounts for the residual defect
  2. 2007 High

    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

    PMID:17299086

    Open questions at the time
    • Did not define the molecular switch between secretory and proliferative compensation
    • Combined two genes, leaving INSR-only contribution incompletely isolated
  3. 2012 High

    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

    PMID:22319636

    Open questions at the time
    • Did not connect altered neuron number to a defined metabolic phenotype
    • Partial-only rescue leaves additional pathways unaccounted
  4. 2012 Medium

    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)

    PMID:23229189

    Open questions at the time
    • Single case, single lab
    • Did not test downstream cascade or in vivo consequence
  5. 2015 High

    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

    PMID:26573296

    Open questions at the time
    • Mechanism of mTOR-to-Stat3 serine phosphorylation not biochemically reconstituted
    • Relevance to human hematopoiesis not established
  6. 2015 Medium

    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

    PMID:26567220

    Open questions at the time
    • INSR contribution not separated from co-targeted Igf1r/cyclins
    • In vivo myogenic relevance not tested
  7. 2015 Medium

    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

    PMID:26615883

    Open questions at the time
    • Circulating mediator linking adipose lipolysis to liver not identified
    • Single point-mutant model
  8. 2016 Medium

    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

    PMID:27613089 PMID:28036389

    Open questions at the time
    • Endogenous miRNA loss-of-function effects on INSR not fully demonstrated in vivo
    • Relative contribution of INSR vs IRS-1 repression unresolved
  9. 2017 High

    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

    PMID:28765322

    Open questions at the time
    • Structural predictions not all validated experimentally
    • Does not address kinase-domain mutation mechanism
  10. 2018 Medium

    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

    PMID:29411486 PMID:29518496

    Open questions at the time
    • Single case for the kinase-dead allele
    • INSR-to-p65/NF-κB coupling mechanism not biochemically defined
  11. 2018 Medium

    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

    PMID:29155986

    Open questions at the time
    • Methyltransferase/demethylase machinery not identified
    • Mechanism linking methylation reversal to behavior not defined
  12. 2020 Medium

    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

    PMID:31958132 PMID:33437372

    Open questions at the time
    • Splice-factor binding sites on INSR pre-mRNA not mapped
    • Tissue specificity of KLF4 regulation not generalized
  13. 2020 Medium

    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

    PMID:32046161

    Open questions at the time
    • INSR repression not separated from co-targeted IGF1R
    • Endogenous miR-322 loss-of-function effect on atrophy not fully resolved
  14. 2022 High

    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

    PMID:35136059

    Open questions at the time
    • Molecular basis of sex-specific divergence unresolved
    • Long-term consequences for beta-cell mass not defined
  15. 2022 Medium

    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

    PMID:35579582

    Open questions at the time
    • Single lab, not independently replicated
    • Whether clustering is cause or consequence of signaling not established
  16. 2022 High

    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

    PMID:36152781

    Open questions at the time
    • Structural basis of SDC3-INSR interaction unknown
    • Whether SDC3 alters insulin binding or only downstream coupling unresolved
  17. 2024 Medium

    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

    PMID:38816743

    Open questions at the time
    • Direct biochemical Grb10-INSR coupling in liver not shown here
    • Tissue-restricted contribution not dissected
  18. 2025 Medium

    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

    PMID:39837352

    Open questions at the time
    • Ortholog (C. elegans) system; conservation of specific sites in mammalian INSR not confirmed
    • Whether ubiquitination targets receptor for degradation or alters signaling not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0001618 virus receptor activity 1
Localization
GO:0005886 plasma membrane 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
CHN2GLUT4GRB10IRS2SDC3

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 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. Euglycemic hyperinsulinemic clamp in transgenic Insr knockout rescue mice (L1) with tissue-specific Insr restoration; Western blot for Akt phosphorylation The Journal of clinical investigation High 15864351
2007 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. Compound Insr/Irs2 mutant mice; beta-cell mass quantification; circulating insulin measurements American journal of physiology. Endocrinology and metabolism High 17299086
2012 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%. Cre/lox conditional mouse knockouts; POMC neuron counting by in situ hybridization; selective POMC-Insr and POMC-FoxO1 deletion models PloS one High 22319636
2015 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. Bone marrow-specific Insr deletion in mice; lineage analysis; downstream signaling by Western blot; Stat3 ChIP at Ikaros promoter The Journal of experimental medicine High 26573296
2017 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. Mutant INSR expression in CHO cells; insulin proreceptor processing assay; downstream signaling cascade assay; in silico structural analysis of mutation database Diabetes High 28765322
2022 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. Ins1cre-mediated beta-cell-specific Insr knockout; RNA-seq of purified beta-cells; ex vivo perifusion; hyperglycemic clamp; electrophysiology; Seahorse respirometry Nature communications High 35136059
2022 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. Super-resolution (single-molecule) imaging; βII-spectrin knockout; GLUT4 co-localization; glucose metabolism assay Nanoscale Medium 35579582
2022 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. Phosphoproteomics; SDC3/INSR co-immunoprecipitation; Sdc3 knockout MuSCs; INSR knockdown; AKT inhibition rescue experiments Matrix biology : journal of the International Society for Matrix Biology High 36152781
2012 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. INSR gene sequencing; insulin receptor autophosphorylation assay in cultured patient fibroblasts European journal of pediatrics Medium 23229189
2021 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. In vitro functional assays in transfected cells; Western blot for INSR expression and phosphorylation; Akt phosphorylation Frontiers in endocrinology Medium 33995269
2018 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. INSR gene sequencing; in vitro kinase activity assay; downstream insulin signaling assay in mutant receptor Pediatric diabetes Medium 29411486
2016 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. 3'UTR luciferase reporter assay; miR-96 overexpression in hepatocytes; Western blot for INSR and IRS-1; glycogen synthesis assay; HFD mouse model PloS one Medium 28036389
2016 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. 3'UTR luciferase reporter assay; miR-1271 overexpression; Western blot for INSR and IRS-1; glycogen metabolism assay Biochemical and biophysical research communications Medium 27613089
2015 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. Luciferase reporter assays for direct miRNA targeting; miRNA gain/loss-of-function in C2C12 cells; proliferation assay; NF-κB inhibition Journal of cell science Medium 26567220
2020 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. Luciferase reporter assay for miR-322 targeting of INSR 3'UTR; miR-322 mimic/inhibitor transfection; in vivo mouse gastrocnemius atrophy model International journal of molecular sciences Medium 32046161
2020 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. CUGBP1 knockdown/overexpression in breast cancer cell lines; RT-PCR for IR-A/IR-B ratio; oncogenic behavior assays Carcinogenesis Medium 31958132
2013 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. 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 Diabetologia Medium 24196191
2015 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. Bone marrow Insr deletion; mTOR inhibitor treatment; Stat3 phosphorylation analysis; ChIP at Ikaros promoter; lineage flow cytometry The Journal of experimental medicine High 26573296
2018 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. 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 Biochimica et biophysica acta. Molecular basis of disease Medium 29518496
2015 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. Insr point-mutant mice on HFD; wild-type WAT transplantation; liver G6Pase/G6pc expression; Cyp7a1 expression; lipolysis assays; glycerol administration experiment Scientific reports Medium 26615883
2009 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). FISH mapping of chromosome translocation breakpoints; gene sequencing; gene expression in patient-derived adipose tissue Diabetes Medium 19720790
2025 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. C. elegans genetics; daf-2 ubiquitination site mutant allele; chn-1/CHIP disruption; IIS activity assays; dauer formation assay; developmental phenotype comparison G3 (Bethesda, Md.) Medium 39837352
2024 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. Grb10/Insr double knockout mouse genetics; organ weight measurement; hepatocyte lipid staining; systematic comparison of single vs. double mutant phenotypes BMC biology Medium 38816743
2018 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. Mouse prenatal high-estradiol model; bisulfite sequencing of Insr promoter methylation; Western blot for hypothalamic INSR protein; food restriction rescue experiment; HOMA-IR measurement Endocrinology Medium 29155986
2020 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. Dual luciferase reporter assay; CHIP assay; KLF4/INSR overexpression/knockdown; MS-PCR for promoter methylation; JAK2/STAT3 Western blot; mouse ACLT OA model American journal of translational research Medium 33437372

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Genetic polymorphisms of FSHR, CYP17, CYP1A1, CAPN10, INSR, SERPINE1 genes in adolescent girls with polycystic ovary syndrome. Journal of assisted reproduction and genetics 94 19387820
2005 Restoration of liver insulin signaling in Insr knockout mice fails to normalize hepatic insulin action. The Journal of clinical investigation 93 15864351
2015 InsR/IGF1R Pathway Mediates Resistance to EGFR Inhibitors in Glioblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research 70 26561558
2009 Genetic variation in exon 17 of INSR is associated with insulin resistance and hyperandrogenemia among lean Indian women with polycystic ovary syndrome. European journal of endocrinology 69 19211708
2014 Oncogenic functions of IGF1R and INSR in prostate cancer include enhanced tumor growth, cell migration and angiogenesis. Oncotarget 67 24809298
2011 Dual IGF-1R/InsR inhibitor BMS-754807 synergizes with hormonal agents in treatment of estrogen-dependent breast cancer. Cancer research 65 22042792
2018 Loss of E-cadherin Enhances IGF1-IGF1R Pathway Activation and Sensitizes Breast Cancers to Anti-IGF1R/InsR Inhibitors. Clinical cancer research : an official journal of the American Association for Cancer Research 64 29941485
2014 Functional genetic approach identifies MET, HER3, IGF1R, INSR pathways as determinants of lapatinib unresponsiveness in HER2-positive gastric cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 62 24973425
2016 Induction of miR-96 by Dietary Saturated Fatty Acids Exacerbates Hepatic Insulin Resistance through the Suppression of INSR and IRS-1. PloS one 56 28036389
2019 Transcriptional Regulation of INSR, the Insulin Receptor Gene. Genes 54 31795422
2015 The NF-κB-modulated microRNAs miR-195 and miR-497 inhibit myoblast proliferation by targeting Igf1r, Insr and cyclin genes. Journal of cell science 48 26567220
2014 Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene. Molecular genetics and metabolism reports 48 27896077
2020 PCOS-GWAS Susceptibility Variants in THADA, INSR, TOX3, and DENND1A Are Associated With Metabolic Syndrome or Insulin Resistance in Women With PCOS. Frontiers in endocrinology 46 32425888
2010 Polymorphisms affecting micro-RNA regulation and associated with the risk of dietary-related cancers: a review from the literature and new evidence for a functional role of rs17281995 (CD86) and rs1051690 (INSR), previously associated with colorectal cancer. Mutation research 45 20971123
2007 A novel single nucleotide polymorphism of INSR gene for polycystic ovary syndrome. Fertility and sterility 43 17658524
2013 Adipose tissue INSR splicing in humans associates with fasting insulin level and is regulated by weight loss. Diabetologia 41 24196191
2022 Beta-cell specific Insr deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance. Nature communications 38 35136059
2011 Association study of single-nucleotide polymorphisms in FASLG, JMJDIA, LOC203413, TEX15, BRDT, OR2W3, INSR, and TAS2R38 genes with male infertility. Journal of andrology 37 22016351
2017 Structural Basis and Genotype-Phenotype Correlations of INSR Mutations Causing Severe Insulin Resistance. Diabetes 35 28765322
2007 Insulin pathway related genes and risk of colorectal cancer: INSR promoter polymorphism shows a protective effect. Endocrine-related cancer 34 17914103
1985 Rsa1 polymorphism at the insulin receptor locus (INSR) on chromosome 19. Nucleic acids research 33 3001646
2013 Alternative splicing of human insulin receptor gene (INSR) in type I and type II skeletal muscle fibers of patients with myotonic dystrophy type 1 and type 2. Molecular and cellular biochemistry 32 23666741
2006 A novel SNP at exon 17 of INSR is associated with decreased insulin sensitivity in Chinese women with PCOS. Molecular human reproduction 32 16510536
2018 Up-regulation of INSR/IGF1R by C-myc promotes TSCC tumorigenesis and metastasis through the NF-κB pathway. Biochimica et biophysica acta. Molecular basis of disease 31 29518496
2018 Bone marrow infiltrated Lnc-INSR induced suppressive immune microenvironment in pediatric acute lymphoblastic leukemia. Cell death & disease 30 30310051
2017 Single-nucleotide polymorphism of INS, INSR, IRS1, IRS2, PPAR-G and CAPN10 genes in the pathogenesis of polycystic ovary syndrome. Journal of genetics 28 28360393
2015 The association between polymorphism of INSR and polycystic ovary syndrome: a meta-analysis. International journal of molecular sciences 27 25622255
2012 Severe progressive obstructive cardiomyopathy and renal tubular dysfunction in Donohue syndrome with decreased insulin receptor autophosphorylation due to a novel INSR mutation. European journal of pediatrics 27 23229189
2023 Radix Rehmanniae Praeparata (Shu Dihuang) exerts neuroprotective effects on ICV-STZ-induced Alzheimer's disease mice through modulation of INSR/IRS-1/AKT/GSK-3β signaling pathway and intestinal microbiota. Frontiers in pharmacology 26 36843923
2017 The IGF1R/INSR Inhibitor BI 885578 Selectively Inhibits Growth of IGF2-Overexpressing Colorectal Cancer Tumors and Potentiates the Efficacy of Anti-VEGF Therapy. Molecular cancer therapeutics 26 28729397
2018 Prenatal High Estradiol Exposure Induces Sex-Specific and Dietarily Reversible Insulin Resistance Through Decreased Hypothalamic INSR. Endocrinology 25 29155986
2021 DNA methylation of AMHRII and INSR gene is associated with the pathogenesis of Polycystic Ovary Syndrome (PCOS). Technology and health care : official journal of the European Society for Engineering and Medicine 24 33682741
2016 MiR-1271 upregulated by saturated fatty acid palmitate provokes impaired insulin signaling by repressing INSR and IRS-1 expression in HepG2 cells. Biochemical and biophysical research communications 23 27613089
2015 Both IGF1R and INSR Knockdown Exert Antitumorigenic Effects in Prostate Cancer In Vitro and In Vivo. Molecular endocrinology (Baltimore, Md.) 23 26452103
2009 Severe insulin resistance and intrauterine growth deficiency associated with haploinsufficiency for INSR and CHN2: new insights into synergistic pathways involved in growth and metabolism. Diabetes 22 19720790
2019 Association of GWAS identified INSR variants (rs2059807 & rs1799817) with polycystic ovarian syndrome in Indian women. International journal of biological macromolecules 21 31837364
2022 Spermidine overrides INSR (insulin receptor)-IGF1R (insulin-like growth factor 1 receptor)-mediated inhibition of autophagy in the aging heart. Autophagy 20 35786404
2012 Association of His1085His INSR gene polymorphism with type 2 diabetes in South Indians. Diabetes technology & therapeutics 20 22775283
2019 Chronic heavy alcohol consumption influences the association between genetic variants of GCK or INSR and the development of diabetes in men: A 12-year follow-up study. Scientific reports 19 31882596
2018 Clinical characteristics of adolescent cases with Type A insulin resistance syndrome caused by heterozygous mutations in the β-subunit of the insulin receptor (INSR) gene. Journal of diabetes 19 29877041
2017 Polymorphisms of microRNA target genes IL12B, INSR, CCND1 and IL10 in gastric cancer. World journal of gastroenterology 19 28596683
2020 RNA-binding protein CUGBP1 controls the differential INSR splicing in molecular subtypes of breast cancer cells and affects cell aggressiveness. Carcinogenesis 18 31958132
2020 Heterozygous Insulin Receptor (INSR) Mutation Associated with Neonatal Hyperinsulinemic Hypoglycaemia and Familial Diabetes Mellitus: Case Series. Journal of clinical research in pediatric endocrinology 18 31989990
2020 MicroRNA 322 Aggravates Dexamethasone-Induced Muscle Atrophy by Targeting IGF1R and INSR. International journal of molecular sciences 18 32046161
2015 Tumor vessel up-regulation of INSR revealed by single-cell expression analysis of the tyrosine kinome and phosphatome in human cancers. The American journal of pathology 18 25864925
2015 Associations between INSR and MTOR polymorphisms in type 2 diabetes mellitus and diabetic nephropathy in a Northeast Chinese Han population. Genetics and molecular research : GMR 18 25867326
2015 Insulin-InsR signaling drives multipotent progenitor differentiation toward lymphoid lineages. The Journal of experimental medicine 18 26573296
2014 Insulin Receptor and the Kidney: Nephrocalcinosis in Patients with Recessive INSR Mutations. Nephron. Physiology 18 25358339
2011 Family association study between INSR gene polymorphisms and PCOS in Han Chinese. Reproductive biology and endocrinology : RB&E 18 21645371
2009 Effects of water extract and crude polysaccharides from Liriope spicata var. prolifera on InsR/IRS-1/PI3K pathway and glucose metabolism in mice. Journal of ethnopharmacology 18 19607904
2015 BI 885578, a Novel IGF1R/INSR Tyrosine Kinase Inhibitor with Pharmacokinetic Properties That Dissociate Antitumor Efficacy and Perturbation of Glucose Homeostasis. Molecular cancer therapeutics 17 26438154
2010 Alterations in hippocampal serotonergic and INSR function in streptozotocin induced diabetic rats exposed to stress: neuroprotective role of pyridoxine and Aegle marmelose. Journal of biomedical science 17 20868513
2015 Unsuppressed lipolysis in adipocytes is linked with enhanced gluconeogenesis and altered bile acid physiology in Insr(P1195L/+) mice fed high-fat-diet. Scientific reports 16 26615883
2013 Genetic polymorphisms of INS, INSR and IRS-1 genes are not associated with polycystic ovary syndrome in Croatian women. Collegium antropologicum 16 23697264
2013 Is there an association between variants in candidate insulin pathway genes IGF-I, IGFBP-3, INSR, and IRS2 and risk of colorectal cancer in the Iranian population? Asian Pacific journal of cancer prevention : APJCP 16 24175768
2020 RS1799817 in INSR associates with susceptibility to polycystic ovary syndrome. Journal of medical biochemistry 15 33033446
2019 Early-Life Exposure to the Chinese Famine Is Associated with Higher Methylation Level in the INSR Gene in Later Adulthood. Scientific reports 15 30833584
2007 Analysis of compensatory beta-cell response in mice with combined mutations of Insr and Irs2. American journal of physiology. Endocrinology and metabolism 15 17299086
2023 Insights into Vitamin E with Combined Oral Contraceptive on INSR Gene in PCOS by Integrating In Silico and In Vivo Approaches. Applied biochemistry and biotechnology 14 37610513
2021 Investigation of the FSHR, CYP11, and INSR Mutations and Polymorphisms in Iranian Infertile Women with Polycystic Ovary Syndrome (PCOS). Reports of biochemistry & molecular biology 14 33969141
2020 INSR mediated by transcription factor KLF4 and DNA methylation ameliorates osteoarthritis progression via inactivation of JAK2/STAT3 signaling pathway. American journal of translational research 14 33437372
2012 InsR/FoxO1 signaling curtails hypothalamic POMC neuron number. PloS one 14 22319636
1986 Three RFLPs for the insulin receptor gene INSR: EcoRI, Pst I, Hind III. Nucleic acids research 14 3018678
2023 Uterine inflammatory myofibroblastic tumor with THBS1-INSR fusion. Pathology, research and practice 13 37156213
2022 Mechanism of INSR clustering with insulin activation and resistance revealed by super-resolution imaging. Nanoscale 13 35579582
2020 DNA methylation of the INSR gene as a mediator of the association between prenatal exposure to famine and adulthood waist circumference. Scientific reports 13 32699300
2014 INSR gene variation is associated with decreased insulin sensitivity in Iraqi women with PCOs. Iranian journal of reproductive medicine 12 25114673
2005 No mutations detected in the INSR gene in a chromosome 19p13 linked migraine pedigree. European journal of medical genetics 12 16473310
2015 An Association Study between INSR/NsiI (rs2059806) and INSR/PmlI (rs1799817) SNPs in Women with Polycystic Ovary Syndrome from West Azerbaijan Province, Iran. Journal of reproduction & infertility 11 25927028
2021 Clinical and Functional Characterization of Novel INSR Variants in Two Families With Severe Insulin Resistance Syndrome. Frontiers in endocrinology 10 33995269
2018 Severe insulin resistance in disguise: A familial case of reactive hypoglycemia associated with a novel heterozygous INSR mutation. Pediatric diabetes 10 29411486
2017 σ-1 receptor stimulation protects against pressure-induced damage through InsR-MAPK signaling in human trabecular meshwork cells. Molecular medicine reports 10 28560459
2014 Family-based analysis of INSR polymorphisms in Chinese PCOS. Reproductive biomedicine online 10 24947064
1992 Chromosomal localization of the hormone sensitive lipase (LIPE) and insulin receptor (INSR) genes in pigs. Hereditas 10 1295851
2024 Theaflavins mitigate diabetic symptoms in GK rats by modulating the INSR/PI3K-Akt/GSK-3 pathway and intestinal microbiota. International journal of biological macromolecules 9 39089538
2022 Molecular docking and mouse modeling suggest CMKLR1 and INSR as targets for improving PCOS phenotypes by minocycline. EXCLI journal 8 35368462
2020 Unusual Glycemic Presentations in a Child with a Novel Heterozygous Intragenic INSR Deletion. Hormone research in paediatrics 8 33040071
2016 Four Single Nucleotide Polymorphisms in INSR, SLC6A14, TAS2R38, and OR2W3 Genes in Association with Idiopathic Infertility in Persian Men. The Journal of reproductive medicine 8 27172637
2011 Recovery of INS-R and ER-alpha expression in the salivary glands of diabetic mice submitted to hormone replacement therapy. Archives of oral biology 8 21507380
1991 Microsatellite polymorphism in human insulin receptor gene (INSR) on chromosome 19. Nucleic acids research 8 1923792
2023 INSR and ISR‑1 gene polymorphisms and the susceptibility of essential hypertension: A meta‑analysis. Experimental and therapeutic medicine 7 37153892
2021 Syndrome of Congenital Insulin Resistance Caused by a Novel INSR Gene Mutation. Journal of clinical research in pediatric endocrinology 7 34965699
2018 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. Biochemical genetics 7 29971619
2014 [Association between single nucleotide polymorphism of rs2252673 of INSR gene and polycystic ovarian syndrome]. Zhonghua fu chan ke za zhi 7 25608993
2024 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. BMC biology 6 38816743
2022 Monogenic diabetes due to an INSR mutation in a child with severe insulin resistance. Endocrinology, diabetes & metabolism case reports 6 35000900
2020 Associations of novel variants in PIK3C3, INSR and MAP3K4 of the ATM pathway genes with pancreatic cancer risk. American journal of cancer research 6 32775006
2019 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. Bulletin of experimental biology and medicine 6 30903488
2017 One Novel 2.43Kb Deletion and One Single Nucleotide Mutation of the INSR Gene in a Chinese Neonate with Rabson-Mendenhall Syndrome. Journal of clinical research in pediatric endocrinology 6 29082893
1993 Mapping of the 19p13 breakpoint in an ovarian carcinoma between the INSR and TCF3 loci. Genes, chromosomes & cancer 6 7504518
1989 Insulin receptor overexpression in a human pre-B acute lymphocytic leukemia cell line with a t(1;19) chromosome translocation near the INSR locus. Biochemical and biophysical research communications 6 2539148
2025 Developmental and conditional regulation of DAF-2/INSR ubiquitination in Caenorhabditis elegans. G3 (Bethesda, Md.) 5 39837352
2024 The interaction between magnesium intake, the genetic variant INSR rs1799817 and colorectal cancer risk in a Korean population: a case-control study. International journal of food sciences and nutrition 5 38389245
2023 Metabolomics reveals that chronic restraint stress alleviates carbon tetrachloride-induced hepatic fibrosis through the INSR/PI3K/AKT/AMPK pathway. Journal of molecular medicine (Berlin, Germany) 5 37993562
2022 The INSR/AKT/mTOR pathway regulates the pace of myogenesis in a syndecan-3-dependent manner. Matrix biology : journal of the International Society for Matrix Biology 5 36152781
2021 A New Mutation of the INSR Gene in a 13-Year-Old Girl with Severe Insulin Resistance Syndrome in China. BioMed research international 5 33728347
2018 A novel recombinant peptide INSR-IgG4Fc (Yiminsu) restores insulin sensitivity in experimental insulin resistance models. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 5 30551378
2017 A Mutation in INSR in a Child Presenting with Severe Acanthosis Nigricans. Journal of clinical research in pediatric endocrinology 5 28663160
2017 Novel heterozygous mutations of the INSR gene in a familial case of Donohue syndrome. Clinica chimica acta; international journal of clinical chemistry 5 28803747
2016 A comprehensive pharmacokinetic/pharmacodynamics analysis of the novel IGF1R/INSR inhibitor BI 893923 applying in vitro, in vivo and in silico modeling techniques. Cancer chemotherapy and pharmacology 5 27160688

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