ArticleDiabetes2012
Impaired cleavage of preproinsulin signal peptide linked to autosomal-dominant diabetes.
Article in Diabetes, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers, 1 of them a synthesis that pooled it.
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.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
49 citing papers in PubMed, 1 synthesis or guideline pooled it, 74 citations in OpenAlex.
- Insulin gene mutations and posttranslational and translocation defects: associations with diabetes.Endocrine · 2020Pooled it
- Metabolic regulation by tanycyte-derived extracellular vesicles through insulin precursor-mediated neuronal recognition and mTORC component delivery.Nature metabolism · 2026Article
- A new form of diabetes caused by INS mutations defined by zygosity, stem cell and population data.EMBO molecular medicine · 2026Article
- Structural Communication Between C-Peptide and Insulin Within the Proinsulin Molecule.International journal of molecular sciences · 2026Article
- Diabetes mellitus and the key role of endoplasmic reticulum stress in pancreatic β cells.Nature reviews. Endocrinology · 2025Review
- Maturity-Onset Diabetes of the Young 10 (MODY10): A Comprehensive Review of Genetics, Clinical Features, and Therapeutic Advances.International journal of molecular sciences · 2025Review
- Trapα deficiency impairs the early events of insulin biosynthesis and glucose homeostasis.The Journal of clinical investigation · 2025Article
- TanGIBLE: A selective probe for evaluating hydrophobicity-exposed defective proteins in live cells.The Journal of cell biology · 2025Article
- The role of mitochondrial function in the pathogenesis of diabetes.Frontiers in endocrinology · 2025Review
- Disrupted Endoplasmic Reticulum CaBiology · 2024Review
- Article
- TSignal: a transformer model for signal peptide prediction.Bioinformatics (Oxford, England) · 2023Article
- A Review of the Biosynthesis and Structural Implications of Insulin Gene Mutations Linked to Human Disease.Cells · 2023Review
- Understanding Insulin in the Age of Precision Medicine and Big Data: Under-Explored Nature of Genomics.Biomolecules · 2023Review
- IER3IP1 is critical for maintaining glucose homeostasis through regulating the endoplasmic reticulum function and survival of β cells.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- UDP-glucose, cereblon-dependent proinsulin degrader.Scientific reports · 2022Article
- The Role of TRAPγ/SSR3 in Preproinsulin Translocation Into the Endoplasmic Reticulum.Diabetes · 2022Article
- Peptide Model of the Mutant Proinsulin Syndrome. II. Nascent Structure and Biological Implications.Frontiers in endocrinology · 2022Article
- Article
- Inside the Insulin Secretory Granule.Metabolites · 2021Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
Abstract
Recently, missense mutations upstream of preproinsulin's signal peptide (SP) cleavage site were reported to cause mutant INS gene-induced diabetes of youth (MIDY). Our objective was to understand the molecular pathogenesis using metabolic labeling and assays of proinsulin export and insulin and C-peptide production to examine the earliest events of insulin biosynthesis, highlighting molecular mechanisms underlying β-cell failure plus a novel strategy that might ameliorate the MIDY syndrome. We find that whereas preproinsulin-A(SP23)S is efficiently cleaved, producing authentic proinsulin and insulin, preproinsulin-A(SP24)D is inefficiently cleaved at an improper site, producing two subpopulations of molecules. Both show impaired oxidative folding and are retained in the endoplasmic reticulum (ER). Preproinsulin-A(SP24)D also blocks ER exit of coexpressed wild-type proinsulin, accounting for its dominant-negative behavior. Upon increased expression of ER-oxidoreductin-1, preproinsulin-A(SP24)D remains blocked but oxidative folding of wild-type proinsulin improves, accelerating its ER export and increasing wild-type insulin production. We conclude that the efficiency of SP cleavage is linked to the oxidation of (pre)proinsulin. In turn, impaired (pre)proinsulin oxidation affects ER export of the mutant as well as that of coexpressed wild-type proinsulin. Improving oxidative folding of wild-type proinsulin may provide a feasible way to rescue insulin production in patients with MIDY.
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What OpenQuestion holds
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.