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

IntroductionA 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. ObjectiveTo develop and evaluate a test for measuring glucagon sensitivity towards amino acid and glucose metabolism in humans. Methods and analysisThe 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 [&ge;]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 [&ge;]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. ResultsThese data will be published in peer-reviewed scientific journals and presented at scientific conferences. Ethics and disseminationThe 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 (NCT04907721). 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 studyO_LIThe glucagon sensitivity test is based on several pilot experiments C_LIO_LILiver fat is based on whole-liver imaging and not region of interest (ROI) C_LIO_LIThe glucagon sensitivity test may be limited to assess glucagon sensitivity towards amino acid catabolism and glucose production C_LIO_LIThe glucagon sensitivity test does not use amino acid or glucose tracers which expands the generalizability of such test but also may impair its accuracy C_LI