ArticleDiabetologia2005
Suppression of Pdx-1 perturbs proinsulin processing, insulin secretion and GLP-1 signalling in INS-1 cells.
Article in Diabetologia, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 77 citations in OpenAlex.
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- p43, a Truncated Form of Thyroid Hormone Receptor α, Regulates Maturation of Pancreatic β Cells.International journal of molecular sciences · 2021Article
- Epigenetic Regulation of PDX-1 in Type 2 Diabetes Mellitus.Diabetes, metabolic syndrome and obesity : targets and therapy · 2021Review
- Actomyosin and the MRTF-SRF pathway downregulate FGFR1 in mesenchymal stromal cells.Communications biology · 2020Article
- Dissecting the Brain/Islet Axis in Metabesity.Genes · 2019Review
- Fibroblast growth factor receptor 5 (FGFR5) is a co-receptor for FGFR1 that is up-regulated in beta-cells by cytokine-induced inflammation.The Journal of biological chemistry · 2018Article
- Effects of Glucagon-Like Peptide-1 on Oxidative Stress and Nrf2 Signaling.International journal of molecular sciences · 2017Review
- Bioactivity of a modified human Glucagon-like peptide-1.PloS one · 2017Article
- An inhibitor of fibroblast growth factor receptor-1 (FGFR1) promotes late-stage terminal differentiation from NGN3+ pancreatic endocrine progenitors.Scientific reports · 2016Article
- Proper activation of MafA is required for optimal differentiation and maturation of pancreatic β-cells.Best practice & research. Clinical endocrinology & metabolism · 2015Review
- Article
- Pancreatic and duodenal homeobox protein 1 (Pdx-1) maintains endoplasmic reticulum calcium levels through transcriptional regulation of sarco-endoplasmic reticulum calcium ATPase 2b (SERCA2b) in the islet β cell.The Journal of biological chemistry · 2014Article
- Article
- Small molecule kaempferol modulates PDX-1 protein expression and subsequently promotes pancreatic β-cell survival and function via CREB.The Journal of nutritional biochemistry · 2013Article
- The transcriptional co-regulator HCF-1 is required for INS-1 β-cell glucose-stimulated insulin secretion.PloS one · 2013Article
- Decreased Expression and Induced Nucleocytoplasmic Translocation of Pancreatic and Duodenal Homeobox 1 in INS-1 Cells Exposed to High Glucose and Palmitate.Diabetes & metabolism journal · 2011Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aims/hypothesisMutations in genes encoding HNF-4alpha, HNF-1alpha and IPF-1/Pdx-1 are associated with, respectively, MODY subtypes-1, -3 and -4. Impaired glucose-stimulated insulin secretion is the common primary defect of these monogenic forms of diabetes. A regulatory circuit between these three transcription factors has also been suggested. We aimed to explore how Pdx-1 regulates beta cell function and gene expression patterns.
methodsWe studied two previously established INS-1 stable cell lines permitting inducible expression of, respectively, Pdx-1 and its dominant-negative mutant. We used HPLC for insulin processing, adenovirally encoded aequorin for cytosolic [Ca2+], and transient transfection of human growth hormone or patch-clamp capacitance recordings to monitor exocytosis.
resultsInduction of DN-Pdx-1 resulted in defective glucose-stimulated and K+-depolarisation-induced insulin secretion in INS-1 cells, while overexpression of Pdx-1 had no effect. We found that DN-Pdx-1 caused down-regulation of fibroblast growth factor receptor 1 (FGFR1), and consequently prohormone convertases (PC-1/3 and -2). As a result, DN-Pdx-1 severely impaired proinsulin processing. In addition, induction of Pdx-1 suppressed the expression of glucagon-like peptide 1 receptor (GLP-1R), which resulted in marked reduction of both basal and GLP-1 agonist exendin-4-stimulated cellular cAMP levels. Induction of DN-Pdx-1 did not affect glucokinase activity, glycolysis, mitochondrial metabolism or ATP generation. The K+-induced cytosolic [Ca2+] rise and Ca2+-evoked exocytosis (membrane capacitance) were not abrogated. CONCLUSIONS/
interpretationThe severely impaired proinsulin processing combined with decreased GLP-1R expression and cellular cAMP content, rather than metabolic defects or altered exocytosis, may contribute to the beta cell dysfunction induced by Pdx-1 deficiency.
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