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LKB1 and AMPK differentially regulate pancreatic beta-cell identity

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Title: LKB1 and AMPK differentially regulate pancreatic beta-cell identity
Authors: Kone, M
Sun, G
Ibberson, M
Martinez-Sanchez, A
Sayers, S
Marie-Sophie, N-T
Kantor, C
Swisa, A
Dor, Y
Gorman, T
Ferrer, J
Thorens, B
Reimann, F
Gribble, F
McGinty, JA
Chen, L
French, PM
Birzele, F
Hildebrandt, T
Uphues, I
Rutter, GA
Item Type: Journal Article
Abstract: Fully differentiated pancreatic b 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 b-cell identity of the tumor suppressor liver kinase B1 (LKB1/STK11) and the downstream fuel-sensitive kinase, AMP-activated protein kinase (AMPK). Highly b-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 b-cell “disallowed” genes (Slc16a1, Ldha, Mgst1, Pdgfra) 1.8- to 3.4-fold (E<0.01). Correspondingly, targeted promoters were enriched for neuronal (Zfp206; P51.3310233) and hypoxia-regulated (HIF1; P52.5310216) transcription factors. In summary, LKB1 and AMPK, through only partly overlapping mechanisms, maintain b-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 b-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 b-cell identity.
Issue Date: 1-Nov-2014
Date of Acceptance: 14-Jul-2014
URI: http://hdl.handle.net/10044/1/38932
DOI: https://dx.doi.org/10.1096/fj.14-257667
ISSN: 1530-6860
Publisher: Federation of American Society of Experimental Biology (FASEB)
Start Page: 4972
End Page: 4985
Journal / Book Title: Faseb Journal
Volume: 28
Issue: 11
Copyright Statement: This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Medical Research Council (MRC)
Wellcome Trust
Biotechnology and Biological Sciences Research Council (BBSRC)
Funder's Grant Number: MR/K001981/1
098424/Z/12/ZR
BB/J015873/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Biology
Cell Biology
Life Sciences & Biomedicine - Other Topics
islet
diabetes
insulin secretion
RNASeq
PROTEIN-KINASE
INSULIN-SECRETION
GLUCOSE-TOLERANCE
EXPRESSION
FAMILY
ISLET
MASS
TRANSCRIPTOMES
REPRESSION
MUTATIONS
AMP-Activated Protein Kinases
Animals
Diabetes Mellitus, Type 2
Insulin
Insulin-Secreting Cells
Mice, Inbred C57BL
Protein-Serine-Threonine Kinases
Signal Transduction
0601 Biochemistry And Cell Biology
0606 Physiology
1116 Medical Physiology
Publication Status: Published
Appears in Collections:Physics
Photonics
Department of Medicine
Faculty of Medicine
Faculty of Natural Sciences



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