ArticleProceedings of the National Academy of Sciences of the United States of America2011
Elevated Hedgehog/Gli signaling causes beta-cell dedifferentiation in mice.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers, 1 of them a synthesis that pooled it.
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Who cites it
53 citing papers in PubMed, 1 synthesis or guideline pooled it, 77 citations in OpenAlex.
- Manipulation of Sonic Hedgehog Signaling Pathway in Maintenance, Differentiation, and Endocrine Activity of Insulin-Producing Cells: A Systematic Review.Iranian journal of medical sciences · 2024Pooled it
- Primary cilium as a sensory organelle and metabolic hub in health and diseases.Journal of biomedical science · 2026Review
- Cell differentiation-related signaling pathways: biological functions, diseases and therapeutic targets.Signal transduction and targeted therapy · 2026Review
- Disrupting Treg lineage stability elicits RORgT-mediated plasticity and enhances anti-tumor immunity.Cell death & disease · 2026Article
- Compartmentalized glycolysis powers ATP production in primary cilia and engages mitochondria via the phosphoenolpyruvate cycle.bioRxiv : the preprint server for biology · 2026Article
- PTPN2 deficiency amplifies inflammatory signalling and impairs functional maturation of human stem cell-derived islets.Stem cell research & therapy · 2026Article
- The stem cell within the vessel wall: multipotent pericytes modulating β-cell function and diabetic complications.Stem cell research & therapy · 2025Review
- Is orbital adipose tissue obesity-privileged? The relationship between small adipocyte size and metabolically healthy state from the view of orbital fat.Journal of endocrinological investigation · 2025Article
- Hes1 in malignant tumors: from molecular mechanism to therapeutic potential.Frontiers in immunology · 2025Review
- Keeping pace: the primary cilium as the conducting baton of the islet.Diabetologia · 2024Review
- Heterozygous missense variant in GLI2 impairs human endocrine pancreas development.Nature communications · 2024Article
- Beta cell dedifferentiation in type 1 diabetes: sacrificing function for survival?Frontiers in endocrinology · 2024Article
- Insulin Secretion Defect in Children and Adolescents with Obesity: Clinical and Molecular Genetic Characterization.Journal of diabetes research · 2024Article
- Rediscovering Primary Cilia in Pancreatic Islets.Diabetes & metabolism journal · 2023Review
- Impacts of MicroRNA-483 on Human Diseases.Non-coding RNA · 2023Review
- The β-cell primary cilium is an autonomous Ca2+ compartment for paracrine GABA signaling.The Journal of cell biology · 2023Article
- β-cell dynamics in type 2 diabetes and in dietary and exercise interventions.Journal of molecular cell biology · 2022Review
- Pancreatic β-Cell Development and Regeneration.Cold Spring Harbor perspectives in biology · 2022Review
- Primary Cilia in Pancreatic β- and α-Cells: Time to Revisit the Role of Insulin-Degrading Enzyme.Frontiers in endocrinology · 2022Review
- Therapeutic targets, novel drugs, and delivery systems for diabetes associated NAFLD and liver fibrosis.Advanced drug delivery reviews · 2021Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Although Hedgehog (Hh) signaling regulates cell differentiation during pancreas organogenesis, the consequences of pathway up-regulation in adult β-cells in vivo have not been investigated. Here, we elevate Hh signaling in β-cells by expressing an active version of the GLI2 transcription factor, a mediator of the Hh pathway, in β-cells that are also devoid of primary cilia, a critical regulator of Hh activity. We show that increased Hh signaling leads to impaired β-cell function and insulin secretion, resulting in glucose intolerance in transgenic mice. This phenotype was accompanied by reduced expression of both genes critical for β-cell function and transcription factors associated with their mature phenotype. Increased Hh signaling further correlated with increased expression of the precursor cell markers Hes1 and Sox9, both direct Hh targets that are normally excluded from β-cells. Over time, the majority of β-cells down-regulated GLI2 levels, thereby regaining the full differentiation state and restoring normoglycemia in transgenic mice. However, sustained high Hh levels in some insulin-producing cells further eroded the β-cell identity and eventually led to the development of undifferentiated pancreatic tumors. Summarily, our results indicate that deregulation of the Hh pathway impairs β-cell function by interfering with the mature β-cell differentiation state.
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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.