LKB1 and AMPK differentially regulate pancreatic β-cell identity.

Détails

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Etat: Public
Version: Final published version
ID Serval
serval:BIB_8F808B5B27DA
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
LKB1 and AMPK differentially regulate pancreatic β-cell identity.
Périodique
FASEB Journal
Auteur(s)
Kone M., Pullen T.J., Sun G., Ibberson M., Martinez-Sanchez A., Sayers S., Nguyen-Tu M.S., Kantor C., Swisa A., Dor Y., Gorman T., Ferrer J., Thorens B., Reimann F., Gribble F., McGinty J.A., Chen L., French P.M., Birzele F., Hildebrandt T., Uphues I., Rutter G.A.
ISSN
1530-6860 (Electronic)
ISSN-L
0892-6638
Statut éditorial
Publié
Date de publication
2014
Volume
28
Numéro
11
Pages
4972-4985
Langue
anglais
Résumé
Fully differentiated pancreatic β cells are essential for normal glucose homeostasis in mammals. Dedifferentiation of these cells has been suggested to occur in type 2 diabetes, impairing insulin production. Since chronic fuel excess ("glucotoxicity") is implicated in this process, we sought here to identify the potential roles in β-cell identity of the tumor suppressor liver kinase B1 (LKB1/STK11) and the downstream fuel-sensitive kinase, AMP-activated protein kinase (AMPK). Highly β-cell-restricted deletion of each kinase in mice, using an Ins1-controlled Cre, was therefore followed by physiological, morphometric, and massive parallel sequencing analysis. Loss of LKB1 strikingly (2.0-12-fold, E<0.01) increased the expression of subsets of hepatic (Alb, Iyd, Elovl2) and neuronal (Nptx2, Dlgap2, Cartpt, Pdyn) genes, enhancing glutamate signaling. These changes were partially recapitulated by the loss of AMPK, which also up-regulated β-cell "disallowed" genes (Slc16a1, Ldha, Mgst1, Pdgfra) 1.8- to 3.4-fold (E<0.01). Correspondingly, targeted promoters were enriched for neuronal (Zfp206; P=1.3×10(-33)) and hypoxia-regulated (HIF1; P=2.5×10(-16)) transcription factors. In summary, LKB1 and AMPK, through only partly overlapping mechanisms, maintain β-cell identity by suppressing alternate pathways leading to neuronal, hepatic, and other characteristics. Selective targeting of these enzymes may provide a new approach to maintaining β-cell function in some forms of diabetes.-Kone, M., Pullen, T. J., Sun, G., Ibberson, M., Martinez-Sanchez, A., Sayers, S., Nguyen-Tu, M.-S., Kantor, C., Swisa, A., Dor, Y., Gorman, T., Ferrer, J., Thorens, B., Reimann, F., Gribble, F., McGinty, J. A., Chen, L., French, P. M., Birzele, F., Hildebrandt, T., Uphues, I., Rutter, G. A. LKB1 and AMPK differentially regulate pancreatic β-cell identity.
Mots-clé
islet, diabetes, insulin secretion, RNASeq
Pubmed
Web of science
Création de la notice
04/12/2014 11:23
Dernière modification de la notice
20/08/2019 14:53
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