Studies to develop a glucagon sensitivity test in humans: The GLUSENTIC study protocol

Introduction A physiological feedback system exists between hepatocytes and the alpha cells termed the liver-alpha cell axis and signifies the role between amino acid-stimulated glucagon secretion and glucagon-stimulated amino acid catabolism. Several reports indicate that metabolic diseases such as non-alcoholic fatty liver disease (NAFLD) disrupts this feedback system, because of impaired glucagon receptor (GCGR) signaling (glucagon resistance). However, no experimental test exists to assess glucagon resistance in humans. Objective To develop and evaluate a test for measuring glucagon sensitivity towards amino acid and glucose metabolism in humans. Methods and analysis The study protocol is based on several pilot studies presented in this paper. The study will include 65 participants including 20 individuals with a BMI 18.6-25 kg/m2, 30 individuals with a BMI ≥25-40 kg/m2, and 15 individuals with type 1 diabetes with a BMI between 18.6-40 kg/m2. Participants will be grouped according to their percentage of hepatic steatosis measured by whole-liver magnetic resonance imaging (MRI). The primary outcome measure will be differences in a novel ‘glucagon sensitivity’ index between individuals with and without hepatic steatosis (<5.6 % vs ≥5.6 %) without diabetes. Secondary outcomes include between-group differences regarding the glucagon-alanine-index, incremental and decremental area under the curve (AUC) and association analyses between hepatic steatosis and glucagon sensitivity. This report describes the design of the cross-sectional study currently taking place at Copenhagen University hospital Bispebjerg and Frederiksberg. Results These data will be published in peer-reviewed scientific journals and presented at scientific conferences. Ethics and dissemination The study was approved by the scientific-ethical committee of the Capital region of Denmark (H-20023717) and registered with Danish Data protection Agency (P-2021-39) and [ClinicalTrials.gov][1] ([NCT04907721][2]). Written and oral consent will be obtained from all participants, and the study will adhere to the principles of the Declaration of Helsinki. Strengths and limitations of this study ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT04907721 ### Funding Statement The study was funded by EFSD Future Leader Award (NNF21SA0072746) and DFF Sapere Aude (1052-00003B). ### 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: The study was approved by the scientific-ethical committee of the Capital region of Denmark (H-20023717) and registered with Danish Data protection Agency (P-2021-39) 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data are avaliable upon request [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04907721&atom=%2Fmedrxiv%2Fearly%2F2022%2F11%2F11%2F2022.11.05.22281981.atom