LKB1 and AMPK differentially regulate pancreatic beta-cell identity
File(s)
Published version
Author(s)
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.
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.
Date Issued
2014-11-01
Date Acceptance
2014-07-14
Citation
Faseb Journal, 2014, 28 (11), pp.4972-4985
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.
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.
License URL
Sponsor
Medical Research Council (MRC)
Wellcome Trust
Biotechnology and Biological Sciences Research Council (BBSRC)
Grant Number
MR/K001981/1
098424/Z/12/ZR
BB/J015873/1
Subjects
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
Publication Status
Published