ArticleThe Journal of clinical investigation1999
A mutation in the insulin 2 gene induces diabetes with severe pancreatic beta-cell dysfunction in the Mody mouse.
Article in The Journal of clinical investigation, 1999. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 310 papers.
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Who cites it
310 citing papers in PubMed, 568 citations in OpenAlex.
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- Mechanistic Role of Disulfidptosis in Type 2 Diabetes Mellitus.Molecular nutrition & food research · 2026Review
- A new form of diabetes caused by INS mutations defined by zygosity, stem cell and population data.EMBO molecular medicine · 2026Article
- One year of hyperglycemia in the Ins2Akita mouse does not impart changes in retinal vascular patterning.PloS one · 2026Article
- Research and advances in mouse models of diabetic nephropathy: a narrative review.BMC nephrology · 2025Review
- Trapα deficiency impairs the early events of insulin biosynthesis and glucose homeostasis.The Journal of clinical investigation · 2025Article
- Ryanodine Receptors in Islet Cell Function: Calcium Signaling, Hormone Secretion, and Diabetes.Cells · 2025Review
- The Role of Estrogen and ER Stress in Glycemic Regulation in the Sexually Dimorphic TALLYHO/JngJ Mouse Model of Diabetes.Journal of the Endocrine Society · 2025Article
- The B22 Dilemma: Structural Basis for Conformational Differences in Proinsulin B-Chain Arg22 Mutants.Biomolecules · 2025Article
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- Stress-Related LncRNAs and Their Roles in Diabetes and Diabetic Complications.International journal of molecular sciences · 2025Review
- A Novel Immunodeficient Hyperglycemic Mouse Carrying the Ins1 Akita Mutation for Xenogeneic Islet Cell Transplantation.Transplantation · 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
- Renal microcirculation and mechanisms in diabetic kidney disease.Frontiers in endocrinology · 2025Review
- A rare homozygousBMJ open diabetes research & care · 2024Article
250 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The mouse autosomal dominant mutation Mody develops hyperglycemia with notable pancreatic beta-cell dysfunction. This study demonstrates that one of the alleles of the gene for insulin 2 in Mody mice encodes a protein product that substitutes tyrosine for cysteine at the seventh amino acid of the A chain in its mature form. This mutation disrupts a disulfide bond between the A and B chains and can induce a drastic conformational change of this molecule. Although there was no gross defect in the transcription from the wild-type insulin 2 allele or two alleles of insulin 1, levels of proinsulin and insulin were profoundly diminished in the beta cells of Mody mice, suggesting that the number of wild-type (pro)insulin molecules was also decreased. Electron microscopy revealed a dramatic reduction of secretory granules and a remarkably enlarged lumen of the endoplasmic reticulum. Little proinsulin was processed to insulin, but high molecular weight forms of proinsulin existed with concomitant overexpression of BiP, a molecular chaperone in the endoplasmic reticulum. Furthermore, mutant proinsulin expressed in Chinese hamster ovary cells was inefficiently secreted, and its intracellular fraction formed complexes with BiP and was eventually degraded. These findings indicate that mutant proinsulin was trapped and accumulated in the endoplasmic reticulum, which could induce beta-cell dysfunction and account for the dominant phenotype of this mutation.
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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.