Abstract
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 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.MethodLoss 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.ResultsRecombination 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).ConclusionAMPK 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.
Highlights
Release of hormones from enteroendocrine cells in response to food transit through the gut, and the consequent activation of insulin release beyond that prompted by the rise in blood glucose alone, is responsible for the incretin effect during feeding [1,2]
In contrast to mice rendered null for liver kinase B1 (LKB1) using the same strategy, mice deleted for AMPactivated protein kinase (AMPK) displayed an increase (WT: 0.05 ± 0.01, KO: 0.09±0.02%, p
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
Summary
Release of hormones from enteroendocrine cells in response to food transit through the gut, and the consequent activation of insulin release beyond that prompted by the rise in blood glucose alone, is responsible for the incretin effect during feeding [1,2]. L-cells are responsible for the synthesis and secretion of glucagon-like peptide-1 (GLP-1), GLP-2, peptide YY (PYY) and oxyntomodulin via the action of prohormone convertases (PC) 1/3 on proglucagon [5]. The mechanisms which trigger secretion from L-cells in response to nutrients are debated [6], roles for sodium-glucose cotransporters (SGLTs), ATP-sensitive K+ (KATP) channels and an array of G-protein-coupled receptors have all been implicated. Binding of GLP-1 to GLP1R on pancreatic beta-cells triggers cAMP synthesis and downstream signalling by Protein kinase A (PKA) and Exchange Protein Activated by cAMP-2 (EPAC2), to activate insulin secretion [8,9]. Enteroendocrine L-cells synthesise and release the gut hormone glucagon-like peptide-1 (GLP-1) in response to food transit. We explore the role of the downstream kinase AMPactivated protein kinase (AMPK) in these cells
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call