@article{Sayers:2016:10.1371/journal.pone.0149549,
author = {Sayers, SR and Reimann, F and Gribble, FM and Parker, H and Zac-Varghese, S and Bloom, SR and Foretz, M and Viollet, B and Rutter, GA},
doi = {10.1371/journal.pone.0149549},
journal = {PLOS One},
title = {Proglucagon Promoter Cre-Mediated AMPK Deletion in Mice Increases Circulating GLP-1 Levels and Oral Glucose Tolerance},
url = {http://dx.doi.org/10.1371/journal.pone.0149549},
volume = {11},
year = {2016}
}

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TY  - JOUR
AB  - BackgroundEnteroendocrine L-cells synthesise and release the gut hormone glucagon-like peptide-1(GLP-1) in response to food transit. Deletion of the tumour suppressor kinase LKB1 fromproglucagon-expressing cells leads to the generation of intestinal polyps but no change incirculating GLP-1 levels. Here, we explore the role of the downstream kinase AMPactivatedprotein kinase (AMPK) in these cells.MethodLoss of AMPK from proglucagon-expressing cells was achieved using a preproglucagonpromoter-driven Cre (iGluCre) to catalyse recombination of floxed alleles of AMPKα1 andα2. Oral and intraperitoneal glucose tolerance were measured using standard protocols.L-cell mass was measured by immunocytochemistry. Hormone and peptide levels weremeasured by electrochemical-based luminescence detection or radioimmunoassay.ResultsRecombination with iGluCre led to efficient deletion of AMPK from intestinal L- and pancreaticalpha-cells. In contrast to mice rendered null for LKB1 using the same strategy, micedeleted for AMPK displayed an increase (WT: 0.05 ± 0.01, KO: 0.09±0.02%, p<0.01) in Lcellmass and elevated plasma fasting (WT: 5.62 ± 0.800 pg/ml, KO: 14.5 ± 1.870, p<0.01)and fed (WT: 15.7 ± 1.48pg/ml, KO: 22.0 ± 6.62, p<0.01) GLP-1 levels. Oral, but not intraperitoneal,glucose tolerance was significantly improved by AMPK deletion, whilst insulinand glucagon levels were unchanged despite an increase in alpha to beta cell ratio (WT:0.23 ± 0.02, KO: 0.33 ± 0.03, p<0.01).ConclusionAMPK restricts L-cell growth and GLP-1 secretion to suppress glucose tolerance. Targetedinhibition of AMPK in L-cells may thus provide a new therapeutic strategy in some forms oftype 2 diabetes.
AU  - Sayers,SR
AU  - Reimann,F
AU  - Gribble,FM
AU  - Parker,H
AU  - Zac-Varghese,S
AU  - Bloom,SR
AU  - Foretz,M
AU  - Viollet,B
AU  - Rutter,GA
DO  - 10.1371/journal.pone.0149549
PY  - 2016///
SN  - 1932-6203
TI  - Proglucagon Promoter Cre-Mediated AMPK Deletion in Mice Increases Circulating GLP-1 Levels and Oral Glucose Tolerance
T2  - PLOS One
UR  - http://dx.doi.org/10.1371/journal.pone.0149549
UR  - http://hdl.handle.net/10044/1/34442
VL  - 11
ER  - 

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