Proglucagon Promoter Cre-Mediated AMPK Deletion in Mice Increases Circulating GLP-1 Levels and Oral Glucose Tolerance.

Abstract

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 AMP-activated 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 L-cell 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.

• Authors: Sophie R Sayers, Frank Reimann, Fiona M Gribble, Helen Parker, Sagen Zac-Varghese, Stephen R Bloom, Marc Foretz, Benoit Viollet, Guy A Rutter
• Journal: PloS one (PLoS One) Vol. 11 Issue 3 Pg. e0149549 ( 2016) ISSN: 1932-6203 [Electronic] United States
• PMID: 27010458 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Insulin
• Proglucagon
• Glucagon-Like Peptide 1
• AMP-Activated Protein Kinases
• Glucose

Topics

• AMP-Activated Protein Kinases (genetics)
• Animals
• Female
• Gene Deletion
• Glucagon-Like Peptide 1 (blood)
• Glucagon-Secreting Cells (cytology, metabolism)
• Glucose (metabolism)
• Glucose Tolerance Test
• Insulin (blood)
• Intestinal Mucosa (metabolism)
• Intestines (cytology)
• Male
• Mice
• Proglucagon (genetics)
• Promoter Regions, Genetic