Altered insulin receptor signalling and β-cell cycle dynamics in type 2 diabetes mellitus.

Détails

ID Serval
serval:BIB_F5270F674CEE
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Altered insulin receptor signalling and β-cell cycle dynamics in type 2 diabetes mellitus.
Périodique
Plos One
Auteur(s)
Folli F., Okada T., Perego C., Gunton J., Liew C.W., Akiyama M., D'Amico A., La Rosa S., Placidi C., Lupi R., Marchetti P., Sesti G., Hellerstein M., Perego L., Kulkarni R.N.
ISSN
1932-6203 (Electronic)
ISSN-L
1932-6203
Statut éditorial
Publié
Date de publication
2011
Peer-reviewed
Oui
Volume
6
Numéro
11
Pages
e28050
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Résumé
Insulin resistance, reduced β-cell mass, and hyperglucagonemia are consistent features in type 2 diabetes mellitus (T2DM). We used pancreas and islets from humans with T2DM to examine the regulation of insulin signaling and cell-cycle control of islet cells. We observed reduced β-cell mass and increased α-cell mass in the Type 2 diabetic pancreas. Confocal microscopy, real-time PCR and western blotting analyses revealed increased expression of PCNA and down-regulation of p27-Kip1 and altered expression of insulin receptors, insulin receptor substrate-2 and phosphorylated BAD. To investigate the mechanisms underlying these findings, we examined a mouse model of insulin resistance in β-cells--which also exhibits reduced β-cell mass, the β-cell-specific insulin receptor knockout (βIRKO). Freshly isolated islets and β-cell lines derived from βIRKO mice exhibited poor cell-cycle progression, nuclear restriction of FoxO1 and reduced expression of cell-cycle proteins favoring growth arrest. Re-expression of insulin receptors in βIRKO β-cells reversed the defects and promoted cell cycle progression and proliferation implying a role for insulin-signaling in β-cell growth. These data provide evidence that human β- and α-cells can enter the cell-cycle, but proliferation of β-cells in T2DM fails due to G1-to-S phase arrest secondary to defective insulin signaling. Activation of insulin signaling, FoxO1 and proteins in β-cell-cycle progression are attractive therapeutic targets to enhance β-cell regeneration in the treatment of T2DM.
Mots-clé
Aged, Aged, 80 and over, Animals, Cell Adhesion Molecules/metabolism, Cell Cycle Proteins/genetics, Cell Cycle Proteins/metabolism, Diabetes Mellitus, Type 2/metabolism, Diabetes Mellitus, Type 2/pathology, Female, G1 Phase/genetics, Gene Expression Regulation, Humans, Insulin/metabolism, Insulin-Secreting Cells/metabolism, Insulin-Secreting Cells/pathology, Male, Mice, Middle Aged, Models, Biological, Proliferating Cell Nuclear Antigen/metabolism, RNA, Messenger/genetics, RNA, Messenger/metabolism, Receptor, Insulin/deficiency, Receptor, Insulin/metabolism, S Phase/genetics, Signal Transduction/genetics, Tissue Donors
Pubmed
Web of science
Open Access
Oui
Création de la notice
06/09/2016 13:14
Dernière modification de la notice
20/08/2019 16:21
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