Background
Enteroendocrine 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 from
proglucagon-expressing cells leads to the generation of intestinal polyps but no change in
circulating GLP-1 levels. Here, we explore the role of the downstream kinase AMPactivated
protein kinase (AMPK) in these cells.
Method
Loss of AMPK from proglucagon-expressing cells was achieved using a preproglucagon
promoter-driven Cre (iGluCre) to catalyse recombination of floxed alleles of AMPKα1 and
α2. Oral and intraperitoneal glucose tolerance were measured using standard protocols.
L-cell mass was measured by immunocytochemistry. Hormone and peptide levels were
measured by electrochemical-based luminescence detection or radioimmunoassay.
Results
Recombination with iGluCre led to efficient deletion of AMPK from intestinal L- and pancreatic
alpha-cells. In contrast to mice rendered null for LKB1 using the same strategy, mice
deleted for AMPK displayed an increase (WT: 0.05 ± 0.01, KO: 0.09±0.02%, p<0.01) in Lcell
mass 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 insulin
and 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).
Conclusion
AMPK restricts L-cell growth and GLP-1 secretion to suppress glucose tolerance. Targeted
inhibition of AMPK in L-cells may thus provide a new therapeutic strategy in some forms of
type 2 diabetes.