Introduction Hyperglucagonemia is a key pathophysiological driver of type 2 diabetes. Although Roux-en-Y gastric bypass (RYGB) is a highly effective treatment for diabetes, it is presently unclear how surgery alters glucagon physiology. The aim of this study was to characterize the behavior of proglucagon-derived peptide (glucagon, glucagon-like peptide-1 (GLP-1), oxyntomodulin, glicentin) secretion after RYGB surgery.
Research design and methods Prospective study of 19 patients with obesity and pre-diabetes/diabetes undergoing RYGB. We assessed the glucose, insulin, GLP-1, glucose-dependent insulinotropic peptide (GIP), oxyntomodulin, glicentin and glucagon responses to a mixed-meal test (MMT) before and 1, 3 and 12 months after surgery. Glucagon was measured using a Mercodia glucagon ELISA using the ‘Alternative’ improved specificity protocol, which was validated against a reference liquid chromatography combined with mass spectrometry method.
Results After RYGB, there were early improvements in fasting glucose and glucose tolerance and the insulin response to MMT was accelerated and amplified, in parallel to significant increases in postprandial GLP-1, oxyntomodulin and glicentin secretion. There was a significant decrease in fasting glucagon levels at the later time points of 3 and 12 months after surgery. Glucagon was secreted in response to the MMT preoperatively and postoperatively in all patients and there was no significant change in this postprandial secretion. There was no significant change in GIP secretion.
Conclusions There is a clear difference in the dynamics of secretion of proglucagon peptides after RYGB. The reduction in fasting glucagon secretion may be one of the mechanisms driving later improvements in glycemia after RYGB.
Trial registration number NCT01945840.
- glucagon-like peptide-1 (GLP-1)
- bariatric surgery
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BK and TM-MT are joint senior authors.
KA, JC and JH contributed equally.
Contributors TM-MT, BK and SRB contributed to study design, data collection, statistical analysis, data interpretation, and writing of the manuscript. KA and JC drafted the manuscript. KA, JC, II, AK, GT, PB and PRB contributed to the running of the study, sample analysis, data collection and data interpretation. JH, RW and MF performed LC/MS-MS assay development and analysis for glucagon. ARA and SP were the surgeons of the study. JJH and NJWA contributed to the analysis of samples and data interpretation. All authors contributed to critical review of the manuscript. TM-MT is the guarantor of this work and had full access to all the data in the study; she takes responsibility for the integrity of the data and the accuracy of the data analysis.
Funding This work was supported by a UK Medical Research Council (MRC) Experimental Challenge Grant (MR/K02115X/1) and UK National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation Grant (13/121/07). This work was also supported by the Imperial NIHR Clinical Research Facility at Imperial College Healthcare NHS Trust. The Department of Metabolism, Digestion and Reproduction is funded by grants from the MRC and Biotechnology and Biological Sciences Research Council and is supported by the NIHR Imperial Biomedical Research Centre (BRC) Funding Scheme. KA is supported by an NIHR Academic Clinical Lectureship and acknowledges support from the NIHR Imperial BRC. TM-MT and SRB are funded by the NIHR Imperial BRC. AK was funded by the NIHR Imperial BRC and a fellowship from the Royal College of Surgeons. II and JC are funded by the NIHR Imperial BRC. JJH is supported by the Novo Nordisk Foundation.
Disclaimer The views expressed are those of the authors and not necessarily those of the above-mentioned funders, the NHS, the NIHR, or the Department of Health.
Competing interests JJH is a member of advisory boards for Novo Nordisk.
Patient consent for publication Not required.
Ethics approval Ethical approval was obtained from the West London National Research Ethics Committee (reference number 13/LO/1510), and the studies were conducted according to the principles of the Declaration of Helsinki.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. The data sets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
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