LKB1 and AMPK differentially regulate pancreatic β-cell identity.

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Version: Final published version
Serval ID
serval:BIB_8F808B5B27DA
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
LKB1 and AMPK differentially regulate pancreatic β-cell identity.
Journal
FASEB Journal
Author(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
Publication state
Published
Issued date
2014
Volume
28
Number
11
Pages
4972-4985
Language
english
Abstract
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.
Keywords
islet, diabetes, insulin secretion, RNASeq
Pubmed
Web of science
Create date
04/12/2014 11:23
Last modification date
20/08/2019 14:53
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