Gastrectomy with Roux-en-Y reconstruction as a lean model of bariatric surgery

Geoffrey P Roberts, Richard G Kay, James Howard, Richard H Hardwick, Frank Reimann, Fiona M Gribble, Geoffrey P Roberts, Richard G Kay, James Howard, Richard H Hardwick, Frank Reimann, Fiona M Gribble

Abstract

Background: Altered enteroendocrine hormone responses are widely believed to underlie the beneficial effects of bariatric surgery in type 2 diabetes. While elevated postprandial glucagon-like peptide-1 (GLP-1) is considered one of the mediators, increased postprandial glucagon levels have recently been implicated.

Objectives: We investigated hormonal responses in lean patients after prophylactic total gastrectomy (PTG), as a model of Roux-en-Y gastric bypass without the confounding effects of obesity or massive weight loss.

Setting: University hospital, United Kingdom.

Methods: Ten participants after PTG and 9 healthy volunteers were recruited for oral glucose tolerance tests. Plasma glucose, insulin, GLP-1, peptide YY, glucose-dependent insulinotropic-polypeptide, glucagon, oxyntomodulin, glucagon(1-61), and glicentin levels were assessed using immunoassays and/or mass spectrometry.

Results: PTG participants exhibited accelerated plasma glucose appearance, followed, in 3 of 10 cases, by hypoglycemia (<3 mM glucose). Plasma GLP-1, peptide YY, glucose-dependent insulinotropic-polypeptide, glicentin, and oxyntomodulin responses were elevated, and glucagon appeared to rise in PTG participants when measured with a glucagon-specific enzyme-linked immunosorbent assay. We revisited the specificity of this assay, and demonstrated significant cross-reactivity with glicentin and oxyntomodulin at concentrations observed in PTG plasma. Reassessment of glucagon with the same assay using a modified protocol, and by liquid chromatography-mass spectrometry, demonstrated suppression of glucagon secretion after oral glucose tolerance tests in both PTG and control cohorts.

Conclusions: Care should be taken when assessing glucagon levels in the presence of elevated plasma levels of other proglucagon products. Substantial elevation of GLP-1 and insulin responses after PTG likely contribute to the observed hypoglycemia, and mirror similar hormone levels and complications observed in bariatric weight loss patients.

Keywords: Bariatric surgery; Roux-en-Y gastric bypass; gastrectomy; glucagon, glucagon-like peptide-1 (GLP-1); hypoglycemia.

Copyright © 2018 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1
Fig. 1
Postoperative intestinal anatomy. Schematic representation of gastrointestinal anatomy before surgery and after sleeve gastrectomy, Roux-en-Y gastric bypass, or total gastrectomy with Roux-en-Y reconstruction.
Fig. 2
Fig. 2
Oral glucose tolerance test results. (a–f) Plasma glucose, insulin, glucagon-like peptide-1, peptide YY, glucose-dependent insulinotropic peptide, and “standard” glucagon concentrations after oral glucose tolerance test in 10 postgastrectomy participants (red/dashed) and 9 healthy controls (blue/solid). All values are mean ± standard error.
Fig. 3
Fig. 3
Proglucagon-derived peptide secretion. (a) Schematic of posttranslational products of the glucagon gene. (b, c) Plasma glicentin and glucagon(1-61) concentrations at 0 and 30 minutes after oral glucose tolerance test (mean ± standard error). (d, e) Correlation between 30-minute plasma glucagon and glucagon-like peptide-1 (d) and glicentin (e) concentrations (blue control, red prophylactic total gastrectomy).
Fig. 4
Fig. 4
Glucagon results with liquid chromotography/mass spectrometry and high specificity assay protocol. (a) Glucagon measured using “standard” protocol (black), “specific” protocol (dark gray) and liquid chromotography/mass spectrometry (light gray), fasting and 30 minutes after an oral glucose tolerance test results in controls and PTG patients (mean ± standard error). (b) Thirty-minute plasma glucagon results using standard assay (black/right column) and summed “specific” glucagon concentration (dark gray) and predicted cross reactivity based on measured oxyntomodulin (middle gray) and glicentin (light gray). All values are the mean of prophylactic total gastrectomy participants.

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