An engineered insulin analog with dual insulin and IGF-1 receptor agonism and distinct signaling.

Overview

1. Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo n. 2, 16000 Praha 6, Czech Republic
2. WEHI, 1G Royal Parade, Parkville, Victoria 3052, Australia
3. Department of Medical Biology, Faculty of Medicine, Dentistry, and Health Sciences, University of Melbourne, Parkville, Victoria, 3010, Australia
4. Department of Genetics and Microbiology, Faculty of Science, Charles University, 12840 Prague 2, Czech Republic
5. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
6. Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
7. Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA

Abstract

Insulin and insulin-like growth factors (IGF-1 and IGF-2) regulate metabolism, growth, and development via related receptors. In contexts such as brain function or fetal development, coordinated signaling by all three hormones is essential. We report the engineering of [GluB10, D-HisB24, GlyB31, TyrB32]-insulin (1Ins), an analog with high affinity for IR-A, IR-B, and especially IGF-1R. 1Ins binds IGF-1R ~1000-fold more strongly than native insulin, approaching IGF-1 levels. Cryo–electron microscopy structures reveal how minimal substitutions in 1Ins enable effective binding to both IR-A and IGF-1R. In neuronal cells, 1Ins robustly activates both IR and IGF-1R pathways, promotes survival, and exceeds native ligands in neuroprotective assays. In vivo, 1Ins regulates glucose effectively in mice and rats. Phosphoproteomic profiling confirms dual pathway activation and identifies targets specific to 1Ins. These findings demonstrate that rational design of dual-receptor agonists can yield potent, versatile ligands with therapeutic promise in metabolic control, neuroprotection, and regeneration.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

The paper's code and data availability statement is in the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none, so it has no map.

Data

Datasets cited

• ebi.ac.uk/emdb/emd-49260 — at EMBL-EBI; found in “Data, code, and materials availability:”
• ebi.ac.uk/emdb/emd-49261 — at EMBL-EBI; found in “Data, code, and materials availability:”
• rcsb.org/structure/9ncn — at PDB; found in “Data, code, and materials availability:”
• rcsb.org/structure/9nco — at PDB; found in “Data, code, and materials availability:”

Data, code, and materials availability

All data and code needed to evaluate and reproduce the results in the paper are present in the paper and/or the Supplementary Materials. The models and maps from cryo-EM are available under accession codes PDB 9NCN, EMDB-49260, and 9NCO, EMDB-49261 at https://rcsb.org/structure/9NCN, https://ebi.ac.uk/emdb/EMD-49260, https://rcsb.org/structure/9NCO, and https://ebi.ac.uk/emdb/EMD-49261, respectively. The mass spectrometry proteomics data were deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD067251 and are available at https://ebi.ac.uk/pride/archive/projects/PXD067251. The new insulin analogs described in this study are available from the corresponding author upon reasonable request, subject to applicable patent regulations. The insulin analogs can be provided by J.J. pending scientific review and a completed material transfer agreement through the Institute of Organic Chemistry and Biochemistry. Requests for the insulin analogues should be submitted to: .

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 14 authors, 11 MeSH terms, 4 funders, 109 references.

Cite

This paper

Selicharová, I., Kirk, N. S., Kertisová, A., Lubos, M., Mitrová, K., Ticháčková, T., Žáková, L., Chrudinová, M., Březinová, J., Harant, K., Voldřich, J., Hájek, M., Huffman, D. M., & Jiráček, J. (2026). An engineered insulin analog with dual insulin and IGF-1 receptor agonism and distinct signaling. Science advances, 12(20), eaeb7558. https://doi.org/10.1126/sciadv.aeb7558

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.1186/s12987-026-00825-2

Acute amyloid-β exposure disrupts insulin signaling in hCMEC/D3 blood-brain barrier endothelial cells.

Journal: Fluids and barriers of the CNS

In common: cellular / molecular, 2 references

[2] doi:10.1038/s41594-026-01857-w [code]

Protein thiol alterations drive pathologic liquid-liquid phase separation in the aging brain.

Journal: Nature structural & molecular biology

In common: mouse, cellular / molecular, 2 references

[3] doi:10.1038/s41467-026-71418-8 [code]

Deep visual proteomics uncovers nociceptor diversity and pain targets.

Journal: Nature communications

In common: mouse, cellular / molecular, 2 references

[4] doi:10.1038/s41420-026-03185-w [code]

An electrophysiological and proteomics roadmap for human induced glutamatergic neurons: fine-tuning of culture conditions for pathophysiological studies.

Journal: Cell death discovery

In common: 2 references

[5] doi:10.1242/dmm.052681

Transcriptomic and proteomic insights into progressive myoclonus epilepsy type 1.

Journal: Disease models & mechanisms

In common: mouse, 2 references

[6] doi:10.1038/s41586-026-10299-9 [code]

A µ-opioid receptor superagonist analgesic with minimal adverse effects.

Journal: Nature

In common: rat, mouse, cellular / molecular, 1 reference

[7] doi:10.1016/j.isci.2026.116085

Temporal multi-omic exploration of the ventral tegmental area in chronic pain and passive coping behaviors.

Journal: iScience

In common: cellular / molecular, 2 references

[8] doi:10.1186/s13293-026-00930-9

Early, sex-dependent and progressive proteomic imbalance in the amygdala during Alzheimer´s disease continuum.

Journal: Biology of sex differences

In common: 2 references

[9] doi:10.1186/s13024-026-00946-0

Insulin resistance alters cortical inhibitory neurons and microglia to exacerbate Alzheimer's knock-in mouse phenotypes.

Journal: Molecular neurodegeneration

In common: mouse, cellular / molecular, 1 reference

[10] doi:10.1371/journal.pone.0350674

Transcriptomic profile of the hippocampus of rat strains with contrasting nervous system excitability.

Journal: PloS one

In common: rat, cellular / molecular, 1 reference

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.

Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.