ArticleDiabetologia2009
Paired box 6 (PAX6) regulates glucose metabolism via proinsulin processing mediated by prohormone convertase 1/3 (PC1/3).
Article in Diabetologia, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers, 1 of them a synthesis that pooled it.
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Who cites it
39 citing papers in PubMed, 1 synthesis or guideline pooled it.
- A common variant upstream of the PAX6 gene influences islet function in man.Diabetologia · 2012Pooled it
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- Epigenetic modulation of cell fate during pancreas development.Trends in developmental biology · 2023Article
- Whole-genome sequencing of multiple related individuals with type 2 diabetes reveals an atypical likely pathogenic mutation in the PAX6 gene.European journal of human genetics : EJHG · 2023Article
- Variants in PAX6, PITX3 and HSF4 causing autosomal dominant congenital cataracts.Eye (London, England) · 2022Article
- Experiment level curation of transcriptional regulatory interactions in neurodevelopment.PLoS computational biology · 2021Article
- Monogenic diabetes: a gateway to precision medicine in diabetes.The Journal of clinical investigation · 2021Review
- PAX6 mutation alters circadian rhythm and β cell function in mice without affecting glucose tolerance.Communications biology · 2020Article
- Liver-derived fibroblast growth factor 21 mediates effects of glucagon-like peptide-1 in attenuating hepatic glucose output.EBioMedicine · 2019Article
- Protecting Pax6 3' UTR from MicroRNA-7 Partially Restores PAX6 in Islets from an Aniridia Mouse Model.Molecular therapy. Nucleic acids · 2018Article
- Mapping the Pax6 3' untranslated region microRNA regulatory landscape.BMC genomics · 2018Article
- The transcription factorThe Journal of biological chemistry · 2017Article
- PAX6 maintains β cell identity by repressing genes of alternative islet cell types.The Journal of clinical investigation · 2017Article
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Authors and funding
13 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aims/hypothesisHuman patients with aniridia caused by heterozygous PAX6 mutations display abnormal glucose metabolism, but the underlying molecular mechanism is largely unknown. Disturbed islet architecture has been proposed as the reason why mice with complete inactivation of paired box 6 (PAX6) in the pancreas develop diabetes. This is not, however, the case in human aniridia patients with heterozygous PAX6 deficiency and no apparent defects in pancreatic development. We investigated the molecular mechanism underlying the development of abnormal glucose metabolism in these patients.
methodsA human aniridia pedigree with a PAX6 R240Stop mutation was examined for abnormal glucose metabolism using an OGTT. The underlying mechanism was further investigated using Pax6 R266Stop mutant small-eye mice, which also have abnormal glucose metabolism similar to that in PAX6 R240Stop mutation human aniridia patients.
resultsPaired box 6 (PAX6) deficiency, both in aniridia patients with a heterozygous PAX6 R240Stop mutation and in mice with a heterozygous Pax6 R266Stop mutation, causes defective proinsulin processing and abnormal glucose metabolism. PAX6 can bind to the promoter and directly upregulate production of prohormone convertase (PC)1/3, an enzyme essential for conversion of proinsulin to insulin. Pax6 mutations lead to PC1/3 deficiency, resulting in defective proinsulin processing and abnormal glucose metabolism. CONCLUSIONS/
interpretationThis study indicates a novel function for PAX6 in the regulation of proinsulin processing and glucose metabolism via modulation of PC1/3 production. It also provides an insight into the abnormal glucose metabolism caused by heterozygous PAX6 mutations in humans and mice.
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