ArticleDiabetes2016
Disulfide Mispairing During Proinsulin Folding in the Endoplasmic Reticulum.
Article in Diabetes, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
39 citing papers in PubMed, 63 citations in OpenAlex.
- Structural Communication Between C-Peptide and Insulin Within the Proinsulin Molecule.International journal of molecular sciences · 2026Article
- Neoepitopes at the crossroads of immunometabolism: metabolic remodeling of antigen presentation in type 1 diabetes.Frontiers in immunology · 2026Review
- 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
- Advanced glycation end product (AGE) crosslinking of a bacterial protein: Are AGE-modifications going undetected in our studies?Structural dynamics (Melville, N.Y.) · 2025Article
- The B22 Dilemma: Structural Basis for Conformational Differences in Proinsulin B-Chain Arg22 Mutants.Biomolecules · 2025Article
- An antireductant approach ameliorates misfolded proinsulin-induced hyperglycemia and glucose intolerance in male Akita mice.GeroScience · 2025Article
- Long-Term Administration of Antioxidant N-Acetyl-L-Cysteine Impacts Beta Cell Oxidative Stress, Insulin Secretion, and Intracellular Signaling Pathways in Aging Mice.Antioxidants (Basel, Switzerland) · 2025Article
- Exploring proinsulin proteostasis: insights into beta cell health and diabetes.Frontiers in molecular biosciences · 2025Review
- Synthetic studies of the mutant proinsulin syndrome demonstrate correlation between folding efficiency and age of diabetes onset.International journal of peptide research and therapeutics · 2025Article
- Functional expression of recombinant insulins in Saccharomyces cerevisiae.Microbial cell factories · 2024Article
- Proinsulin folding and trafficking defects trigger a common pathological disturbance of endoplasmic reticulum homeostasis.Protein science : a publication of the Protein Society · 2024Article
- Post-Translational Modifications and Diabetes.Biomolecules · 2024Review
- Article
- Insulin-degrading enzyme regulates insulin-directed cellular autoimmunity in murine type 1 diabetes.Frontiers in immunology · 2024Article
- Differentially Expressed Genes Regulating Glutathione Metabolism, Protein-Folding, and Unfolded Protein Response in Pancreatic β-Cells in Type 2 Diabetes Mellitus.International journal of molecular sciences · 2023Article
- Carbonyl Posttranslational Modification Associated With Early-Onset Type 1 Diabetes Autoimmunity.Diabetes · 2022Article
- Autoreactive antibodies control blood glucose by regulating insulin homeostasis.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Diabetes-Associated Mutations in Proinsulin Provide a "Molecular Rheostat" of Nascent Foldability.Current diabetes reports · 2022Review
- The Link between Type 2 Diabetes Mellitus and the Polymorphisms of Glutathione-Metabolizing Genes Suggests a New Hypothesis Explaining Disease Initiation and Progression.Life (Basel, Switzerland) · 2021Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Proinsulin folding within the endoplasmic reticulum (ER) remains incompletely understood, but it is clear that in mutant INS gene-induced diabetes of youth (MIDY), progression of the (three) native disulfide bonds of proinsulin becomes derailed, causing insulin deficiency, β-cell ER stress, and onset of diabetes. Herein, we have undertaken a molecular dissection of proinsulin disulfide bond formation, using bioengineered proinsulins that can form only two (or even only one) of the native proinsulin disulfide bonds. In the absence of preexisting proinsulin disulfide pairing, Cys(B19)-Cys(A20) (a major determinant of ER stress response activation and proinsulin stability) preferentially initiates B-A chain disulfide bond formation, whereas Cys(B7)-Cys(A7) can initiate only under oxidizing conditions beyond that existing within the ER of β-cells. Interestingly, formation of these two "interchain" disulfide bonds demonstrates cooperativity, and together, they are sufficient to confer intracellular transport competence to proinsulin. The three most common proinsulin disulfide mispairings in the ER appear to involve Cys(A11)-Cys(A20), Cys(A7)-Cys(A20), and Cys(B19)-Cys(A11), each disrupting the critical Cys(B19)-Cys(A20) pairing. MIDY mutations inhibit Cys(B19)-Cys(A20) formation, but treatment to force oxidation of this disulfide bond improves folding and results in a small but detectable increase of proinsulin export. These data suggest possible therapeutic avenues to ameliorate ER stress and 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.