GLP-1 enhances beta-cell response to protein ingestion and bariatric surgery amplifies it

Objective Protein ingestion stimulates β-cell secretion and alters glucose flux. Enhanced action of glucagon-like peptide 1 (GLP-1) and increased plasma glucose excursion contribute to prandial hyperinsulinemia after gastric bypass surgery (GB) and sleeve gastrectomy (SG). We examined the contribution of endogenous GLP-1 to glucose kinetics and β-cell response to protein ingestion under basal glucose concentrations in humans, and whether these responses are affected by rerouted gut after GB or SG. Design Glucose fluxes, insulin secretion rate (ISR), and incretin responses to a 50-gram oral protein load were compared between 10 non-diabetic individuals with GB, 9 matched subjects with SG and 7 non-operated controls (CN) with and without intravenous infusion of exendin-(9-39) [Ex-9), a specific GLP-1 receptor (GLP-1R) antagonist. Results Blocking GLP-1R increased the plasma glucose concentration before and after protein ingestion in all 3 groups (p<0.05) and decreased β-cell sensitivity to glucose in the first 30 minutes of protein ingestion (p<0.05). Reduction in the prandial ISR3h by Ex-9 infusion, however, only was observed in GB and SG (p<0.05 for interaction) and not in controls. Also, GLP-1R blockade increased post-protein insulin action in GB and SG, but not CN (p=0.09 for interaction). Endogenous glucose production ( EGP ) during the first 60 minutes after protein ingestion was increased in all 3 groups but EGP 3h only was accentuated in GB by Ex-9 infusion (p<0.05 for interaction). Conclusion These findings are consistent with both a pancreatic and extrapancreatic role for GLP-1 during protein ingestion in humans, and GLP-1 actions are exaggerated by bariatric surgery. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT02823665 ### Funding Statement This study was funded by grants from the National Institute of Health, DK105379 (MS), KL2 TR002646 (MR), and in part by National Center for Advancing Translational Sciences, National Institute of Health grant UL1 TR002645. A.G. acknowledges the financial support from the European Unions Horizon 2020 Research and Innovation Programme for the project Stratification of Obesity Phenotypes to Optimize Future Obesity Therapy (SOPHIA). SOPHIA has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 875534. This Joint Undertaking received support from the European Unions Horizon 2020 research and innovation program, EFPIA, T1D Exchange, JDRF, and Obesity Action Coalition. The communication reflects the authors view. Neither IMI nor the European Union, EFPIA, or any Associated Partners are responsible for any use that may be made of the information contained herein. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of University of Texas Health San Antonio gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.