ArticleeLife2019
Proinsulin misfolding is an early event in the progression to type 2 diabetes.
Article in eLife, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 101 papers.
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Who cites it
101 citing papers in PubMed, 152 citations in OpenAlex.
- Article
- JNK and p53 cause human and mouse β cell death during excessive unfolded protein response.The Journal of clinical investigation · 2026Article
- From Disposal to Display: Crinophagy as a β-Cell Source of Neoantigens in Type 1 Diabetes.Immunological reviews · 2026Review
- Coordinated expression and assembly of BiP, p58Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Proinsulin regulators identified with CRISPR screen and in vivo mouse QTL mapping.Nature communications · 2026Article
- A Real Time Quaking Induced Conversion (RT-QuIC) Assay for Detection of Misfolded Insulin Protein.bioRxiv : the preprint server for biology · 2026Article
- Unraveling C‑Peptide's Role in MIDY: A Structural Perspective.ACS omega · 2026Article
- Limiting ER-associated degradation capacity triggers acute and chronic effects on insulin biosynthesis.The Journal of clinical investigation · 2026Article
- Structural Communication Between C-Peptide and Insulin Within the Proinsulin Molecule.International journal of molecular sciences · 2026Article
- A microenvironment-driven HLA-II-associated insulin neoantigen elicits persistent memory T cell activation in diabetes.Nature immunology · 2026Article
- Phenotype of insulin-dependent diabetes in chronic undernutrition: beta cell stress and immune dysfunction-a rural sub-Saharan perspective on type 5 diabetes.Diabetologia · 2025Review
- On-demand insulin manufacturing using cell-free systems with an "on-column" conversion approach.New biotechnology · 2025Article
- A long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin secretion in mice.Science advances · 2025Article
- Metal-Responsive Up-Regulation of Bifunctional Disulfides for Suppressing Protein Misfolding and Promoting Oxidative Folding.Angewandte Chemie (International ed. in English) · 2025Article
- Diabetes mellitus and the key role of endoplasmic reticulum stress in pancreatic β cells.Nature reviews. Endocrinology · 2025Review
- LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes.Nature metabolism · 2025Article
- Pathophysiology of Prediabetes Hyperinsulinemia and Insulin Resistance in the Cardiovascular System.Biomedicines · 2025Review
- Trapα deficiency impairs the early events of insulin biosynthesis and glucose homeostasis.The Journal of clinical investigation · 2025Article
- Quantification of Folded and Misfolded Proinsulin Forms Using Nonreducing SDS-PAGE and Proinsulin-Specific Immunoblotting.Bio-protocol · 2025Article
- Renalase inhibition defends against acute and chronic β cell stress by regulating cell metabolism.Molecular metabolism · 2025Article
41 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
13 authors at 6 institutions in 5 countries.
Funding
Abstract
Biosynthesis of insulin - critical to metabolic homeostasis - begins with folding of the proinsulin precursor, including formation of three evolutionarily conserved intramolecular disulfide bonds. Remarkably, normal pancreatic islets contain a subset of proinsulin molecules bearing at least one free cysteine thiol. In human (or rodent) islets with a perturbed endoplasmic reticulum folding environment, non-native proinsulin enters intermolecular disulfide-linked complexes. In genetically obese mice with otherwise wild-type islets, disulfide-linked complexes of proinsulin are more abundant, and leptin receptor-deficient mice, the further increase of such complexes tracks with the onset of islet insulin deficiency and diabetes. Proinsulin-Cys(B19) and Cys(A20) are necessary and sufficient for the formation of proinsulin disulfide-linked complexes; indeed, proinsulin Cys(B19)-Cys(B19) covalent homodimers resist reductive dissociation, highlighting a structural basis for aberrant proinsulin complex formation. We conclude that increased proinsulin misfolding via disulfide-linked complexes is an early event associated with prediabetes that worsens with ß-cell dysfunction in type two diabetes.
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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.