Phenotype of entero‐endocrine L cells becomes restricted during development

Grigoryan, Marine; Kedees, Mamdouh H.; Guz, Yelena; Teitelman, Gladys

doi:10.1002/dvdy.23875

Cited by 4 publications

(1 citation statement)

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“…Thus, this gluco-incretin-dependent methylation of the Fxyd3 promoter takes place in the perinatal period and is fully established in the adult animals. With respect to the timing of this methylation events, it is interesting to note that intestinal GLP-1 and GIP producing cells appear first at embryonic day 15 (E15), rapidly increase in number at E17, with both peptides being often co-expressed in the same cells [40]. In addition, GLP-1 receptor has an intrinsic signaling activity even in the absence of ligand [41].…”

Section: Discussionmentioning

confidence: 99%

Gluco-Incretins Regulate Beta-Cell Glucose Competence by Epigenetic Silencing of Fxyd3 Expression

et al. 2014

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Background/AimsGluco-incretin hormones increase the glucose competence of pancreatic beta-cells by incompletely characterized mechanisms.MethodsWe searched for genes that were differentially expressed in islets from control and Glp1r−/−; Gipr−/− (dKO) mice, which show reduced glucose competence. Overexpression and knockdown studies; insulin secretion analysis; analysis of gene expression in islets from control and diabetic mice and humans as well as gene methylation and transcriptional analysis were performed.Results Fxyd3 was the most up-regulated gene in glucose incompetent islets from dKO mice. When overexpressed in beta-cells Fxyd3 reduced glucose-induced insulin secretion by acting downstream of plasma membrane depolarization and Ca++ influx. Fxyd3 expression was not acutely regulated by cAMP raising agents in either control or dKO adult islets. Instead, expression of Fxyd3 was controlled by methylation of CpGs present in its proximal promoter region. Increased promoter methylation reduced Fxyd3 transcription as assessed by lower abundance of H3K4me3 at the transcriptional start site and in transcription reporter assays. This epigenetic imprinting was initiated perinatally and fully established in adult islets. Glucose incompetent islets from diabetic mice and humans showed increased expression of Fxyd3 and reduced promoter methylation.Conclusions/InterpretationBecause gluco-incretin secretion depends on feeding the epigenetic regulation of Fxyd3 expression may link nutrition in early life to establishment of adult beta-cell glucose competence; this epigenetic control is, however, lost in diabetes possibly as a result of gluco-incretin resistance and/or de-differentiation of beta-cells that are associated with the development of type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%