292: INS R6C signal-peptide defect reduces preproinsulin ER translocation in iPSC-derived βcells

Tong Y et al., EMBO Molecular Medicine, doi:10.1038/s44321-025-00362-9 - Patient data, population genetics and iPSC-derived βcell models show INS R6C impairs preproinsulin ER translocation and causes recessive insulin-deficient diabetes in homozygotes. Key terms: INS R6C, preproinsulin translocation, iPSC-derived beta cells, monogenic diabetes, population genetics.

Study Highlights:
The study integrates clinical pedigrees, large-scale population screens and patient-derived iPSC βcell models, plus in vivo transplantation and transcriptomics. AlphaFold 3 structural modeling suggested weakened SRP54 interaction and altered SEC61 orientation for the R6C signal peptide, and population data showed no enrichment of diabetes among heterozygotes. In homozygous R6C iPSC-βcells up to two-thirds of nascent preproinsulin failed to translocate, preproinsulin accumulated, and insulin content and secretion were reduced by roughly 50% with altered proinsulin processing. Functionally, homozygous R6C grafts produced minimal human C-peptide in mice and responded poorly to GLP-1 receptor agonists, while heterozygotes were largely compensated by a single wild-type allele.

Conclusion:
INS R6C is a recessive loss-of-function mutation that causes early-onset, insulin-deficient diabetes in homozygotes while heterozygous carriers show variable or absent glycemic phenotypes.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
A new form of diabetes caused by INS mutations defined by zygosity, stem cell and population data

First author:
Tong Y

Journal:
EMBO Molecular Medicine, doi:10.1038/s44321-025-00362-9

DOI:
10.1038/s44321-025-00362-9

Reference:
Tong Y, Becker M, Schierloh U, Natividade da Silva F, Haataja L, Cai Y, Patel KA, Kobaisi F, Mirshahi UL, Colclough K, Javed MS, Wakeling MN, Fantuzzi F, Lytrivi M, Sawatani T, Arroyo MN, Yi X, Vinci C, Montaser H, Pachera N, Otonkoski T, Igoillo-Esteve M, Scharfmann R, Hattersley AT, Arvan P, De Beaufort C, Cnop M. A new form of diabetes caused by INS mutations defined by zygosity, stem cell and population data. EMBO Molecular Medicine. 2026;18:620–645. https://doi.org/10.1038/s44321-025-00362-9

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-17.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the core scientific narrative conveyed in the transcript, focusing on: INS R6C zygosity-dependent diabetes; ER translocation defect caused by the signal peptide; SRP54 and SEC61 translocon involvement; heterozygous vs homozygous iPSC-derived β-cell phenotypes; population-genetic evidence; in vivo transplantatio
- transcript topics: INS R6C mutation and zygosity; ER translocation defect and signal peptide mechanism; SRP54 and SEC61 translocon interactions; iPSC-derived β-cell modeling (heterozygous and homozygous); In vivo transplantation and C-peptide outcomes; Population genetics data (UK Biobank, Geisinger) and penetrance

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4