ArticlePloS one2012
Agonism and antagonism at the insulin receptor.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
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Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it, 51 citations in OpenAlex.
- Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence.Breast cancer research : BCR · 2015Pooled it
- Post-translational MYC stabilization in association with IGF-1 signaling during corneal epithelial repair.Experimental eye research · 2026Article
- Structural basis of insulin receptor antagonism by bivalent site 1-site 2 ligands S961 and Ins-AC-S2.Nature communications · 2026Article
- Stabilization of a protein by a single halogen-based aromatic amplifier.Protein science : a publication of the Protein Society · 2025Article
- Functional profiling of synthetic camel milk-derived peptides with implication in glucose transport and diabetes.PloS one · 2025Article
- State of the Science on Brain Insulin Resistance and Cognitive Decline Due to Alzheimer's Disease.Aging and disease · 2024Review
- The liver-derived exosomes stimulate insulin gene expression in pancreatic beta cells under condition of insulin resistance.Frontiers in endocrinology · 2023Article
- The Insulin Receptor: An Important Target for the Development of Novel Medicines and Pesticides.International journal of molecular sciences · 2022Review
- Insulin facilitates corneal wound healing in the diabetic environment through the RTK-PI3K/Akt/mTOR axis in vitro.Molecular and cellular endocrinology · 2022Article
- Modulation of Glucose Production by Central Insulin Requires IGF-1 Receptors in AgRP Neurons.Diabetes · 2021Article
- Animal models of gestational diabetes: characteristics and consequences to the brain and behavior of the offspring.Metabolic brain disease · 2021Review
- Disrupting Insulin and IGF Receptor Function in Cancer.International journal of molecular sciences · 2021Review
- Ligand bias in receptor tyrosine kinase signaling.The Journal of biological chemistry · 2020Review
- Interplay of Dietary Fatty Acids and Cholesterol Impacts Brain Mitochondria and Insulin Action.Nutrients · 2020Article
- "Register-shift" insulin analogs uncover constraints of proteotoxicity in protein evolution.The Journal of biological chemistry · 2020Article
- Diabetes pharmacotherapy and effects on the musculoskeletal system.Diabetes/metabolism research and reviews · 2019Review
- Steady-State Differential Dose Response in Biological Systems.Biophysical journal · 2018Article
- An ultra-stable single-chain insulin analog resists thermal inactivation and exhibits biological signaling duration equivalent to the native protein.The Journal of biological chemistry · 2018Article
- E4orf1: A protein for enhancing glucose uptake despite impaired proximal insulin signaling.PloS one · 2018Article
- Insulin upregulates betatrophin expression via PI3K/Akt pathway.Scientific reports · 2017Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Insulin can trigger metabolic as well as mitogenic effects, the latter being pharmaceutically undesirable. An understanding of the structure/function relationships between insulin receptor (IR) binding and mitogenic/metabolic signalling would greatly facilitate the preclinical development of new insulin analogues. The occurrence of ligand agonism and antagonism is well described for G protein-coupled receptors (GPCRs) and other receptors but in general, with the exception of antibodies, not for receptor tyrosine kinases (RTKs). In the case of the IR, no natural ligand or insulin analogue has been shown to exhibit antagonistic properties, with the exception of a crosslinked insulin dimer (B29-B'29). However, synthetic monomeric or dimeric peptides targeting sites 1 or 2 of the IR were shown to be either agonists or antagonists. We found here that the S961 peptide, previously described to be an IR antagonist, exhibited partial agonistic effects in the 1-10 nM range, showing altogether a bell-shaped dose-response curve. Intriguingly, the agonistic effects of S961 were seen only on mitogenic endpoints ((3)H-thymidine incorporation), and not on metabolic endpoints ((14)C-glucose incorporation in adipocytes and muscle cells). The agonistic effects of S961 were observed in 3 independent cell lines, with complete concordance between mitogenicity ((3)H-thymidine incorporation) and phosphorylation of the IR and Akt. Together with the B29-B'29 crosslinked dimer, S961 is a rare example of a mixed agonist/antagonist for the human IR. A plausible mechanistic explanation based on the bivalent crosslinking model of IR activation is proposed.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.