Important Role of the GLP-1 Axis for Glucose Homeostasis after Bariatric Surgery

Pierre Larraufie, Geoffrey P Roberts, Anne K McGavigan, Richard G Kay, Joyce Li, Andrew Leiter, Audrey Melvin, Emma K Biggs, Peter Ravn, Kathleen Davy, David C Hornigold, Giles S H Yeo, Richard H Hardwick, Frank Reimann, Fiona M Gribble, Pierre Larraufie, Geoffrey P Roberts, Anne K McGavigan, Richard G Kay, Joyce Li, Andrew Leiter, Audrey Melvin, Emma K Biggs, Peter Ravn, Kathleen Davy, David C Hornigold, Giles S H Yeo, Richard H Hardwick, Frank Reimann, Fiona M Gribble

Abstract

Bariatric surgery is widely used to treat obesity and improves type 2 diabetes beyond expectations from the degree of weight loss. Elevated post-prandial concentrations of glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and insulin are widely reported, but the importance of GLP-1 in post-bariatric physiology remains debated. Here, we show that GLP-1 is a major driver of insulin secretion after bariatric surgery, as demonstrated by blocking GLP-1 receptors (GLP1Rs) post-gastrectomy in lean humans using Exendin-9 or in mice using an anti-GLP1R antibody. Transcriptomics and peptidomics analyses revealed that human and mouse enteroendocrine cells were unaltered post-surgery; instead, we found that elevated plasma GLP-1 and PYY correlated with increased nutrient delivery to the distal gut in mice. We conclude that increased GLP-1 secretion after bariatric surgery arises from rapid nutrient delivery to the distal gut and is a key driver of enhanced insulin secretion.

Keywords: GLP-1; bariatric surgery; enteroendocrine cells; gut hormones; intestinal transit; mass spectrometry; peptidomics; transcriptomics.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Exendin-9 Infusion in Post-gastrectomy Participants Receiving a 50 g OGTT Plasma parameters from 5 post-gastrectomy participants receiving either Exendin-9 or placebo in a cross-over design and challenged with a 50 g OGTT at time = 0. (A) Plasma glucose levels on placebo infusion (solid lines) or Exendin-9 infusion (dotted lines). Colors indicate individual participants. (B) Nadir glucose concentrations, taken from data shown in (A). (C) Plasma insulin concentrations for gastrectomy patients given placebo (light blue) or Exendin-9 (dark blue) or control patients (red, control data from previous study) (Roberts et al., 2018b). (D) Incremental area under the curve of insulin levels over 120 min. Colors represent individuals. (E) Correlation between log insulin secretion rate (ISR) and log glucose concentration using all measured time points after the OGTT during placebo (dark blue) or Exendin-9 (light blue) infusion. (F) Delta plasma glucagon concentrations between 0 and 30 min after the OGTT in either placebo- or Exendin-9-infused post-gastrectomy patients. Individuals are paired. (G–L) Total GLP-1 (G), PYY (I), and GIP (J) concentrations and hunger (K) and fullness (L) ratings in placebo-infused (dark blue) or Exendin-9-infused (light blue) gastrectomy patients. Data are represented as mean ± SD. Areas under the curve between placebo and Exendin-9 are statistically different for GLP-1, PYY, and GIP, with p ∗ indicates that the two groups are statistically different with p < 0.05 using paired Student’s t test.
Figure 2
Figure 2
GLP1R Blockade in VSG-Operated Mice (A and D) Weight relative to surgery day (A) and cumulative energy intake (D) over time of vertical sleeve gastrectomy (VSG)-operated mice treated with control antibody (n = 4, dark blue) or GLP1R antibody (n = 6, light blue) and sham-operated mice treated with control antibody (n = 5, dark red) or GLP1R antibody (n = 5, pink). Data are mean ± SD. (B and E) Weight change (B) and cumulative energy intake (E) relative to the surgery day after 28 days of liquid diet. (C and F) Weight change (C) and cumulative energy intake (F) relative to the day of diet change from liquid to high fat after 28 days on high-fat diet. Data are median and individual values; significant differences between groups are assessed by Kruskal-Wallis followed by Dunn’s test; groups differing significantly with p ∗, $, and # indicate a difference with p < 0.05 between the VSG control antibody group and the VSG GLP1R-Ab, sham control-Ab, and sham GLP1R-Ab, respectively. Statistical differences between groups for the OGTT samples were assessed using a linear mixed model taking into account the repeated measures.
Figure 3
Figure 3
Effect of Bariatric Surgery on Tissue Peptide Content (A–C) Human jejunal peptidomics. (A) Principal-component analysis of the peptide content of human jejunal biopsies from patients before (n = 7, red) and after (n = 4, blue) gastrectomy surgery. Individual samples are plotted on the first two components representing all peptides measured in (B) and (C). (B and C) Peptide quantification for gut hormone peptides and granin-derived peptides for individual samples taken during (red) or after (blue) surgery. Data are normalized by tissue weight and internal standard for individual samples, and the medians are indicated. (D–K) Mouse peptidomics. (D and E) PCA of intestinal peptides measured in 3 VSG and 4 sham-operated mice in the stomach and every 5 cm along the gastrointestinal (GI) tract. Individual samples are color coded for their region of origin, and shape indicates the surgery type (D). Eigen vectors of each quantified peptide on the first two principal components (E). (F–K) Quantification of secretin (F), GIP (G), the N-terminal part of proCCK (H), SST28 (I), GLP-1 (J), and PYY1-36 (K) along the different regions of the GI tract, represented as median and individual samples from sham-operated (red) and VSG-operated (blue) mice. Differences between groups were assessed in each tissue for each peptide using a Mann-Whitney U test. Sto, stomach; Duo: duodenum; Jej, jejunum; Il, ileum; Col, colon; Rec, rectum; p, proximal; i, intermediate; d, distal; GHRL, ghrelin; proGAST, N terminus of proGastrin; NEUK_A, neurokinin A; SUB_P, substance P; SST14/28, somatostatin 14/28; GIP, glucose-dependent insulinotropic polypeptide; proCCK, N-terminal part of proCCK; SECR, secretin; NEUT, neurotensin; GRPP, glicentin-related peptide; OXM, oxyntomodulin; GLP1/2, glucagon-like peptide 1/2; PYY1-36/3-36, peptide YY1-36/3-36; INSL5 Nter, N-terminal part of INSL5 C-chain; INSL5 B-chain, B-chain of INSL5 (after reduction alkylation).
Figure 4
Figure 4
Transcriptomics of Human and Murine EECs after Gastrectomy Surgery (A) PCA of the 200 most variable genes significantly enriched in human jejunal EEC cells. Dots represent individual samples, color coded for before (red) or after (blue) gastrectomy and plotted on the first 2 principal components. (B) MA plot of post- versus pre-operative human samples representing, for each gene, the estimated log2 fold change between condition and mean normalized expression using a DESeq2 model. Genes that are differently expressed (padj ad libitum (red), sham weight-matched (green), and VSG-operated (blue) mice and shape coded for the tissue of origin on the first two principal components (Δ, top 5 cm of small intestine; ∗, bottom 15 cm of the small intestine; @, colon and rectum). (D) MA plot of VSG versus sham ad libitum samples representing the estimated log2 fold change between conditions across all 3 regions and the mean normalized expression of each gene using the DESeq2 model with interaction between surgery groups and regions. Genes that are differently expressed are annotated in red (adjusted p value [padj] < 0.05). (E–H) Heatmaps representing log2 normalized expression of the top variable EEC-enriched genes annotated as encoding hormones (E and G) or GPCRs (F and H) in human (E and F) and murine (G and H) samples. Samples and genes are clustered by Euclidean distance without scaling.
Figure 5
Figure 5
Intestinal Transit in VSG-Operated Mice (A) Ratio of fluorescence in each region of the GI tract (1, stomach; 2–9, small intestine (proximal to distal); 10, caecum; 11 and 12 colon and rectum) harvested 7 min after gavage. Dotted lines are individual mice, and solid lines are the median of each group (VSG-control antibody: blue, n = 4; VSG-GLP1R antibody: cyan, n = 6; sham-control antibody: red, n = 5; sham-GLP1R antibody: pink, n = 5). (B) Intestinal transit (IT) score measured as the weighted mean of the relative fluorescence by the tissue number. Data are individual and median. Significance between groups was assessed by Dunn’s test; groups differing significantly with p 

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