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

Introduction: Glucagon is secreted from pancreatic alpha cells in response to amino acid stimuli and during states of hypoglycemia. 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, perhaps as a consequence of impaired glucagon receptor (GCGR) signaling (glucagon resistance). However, no experimental test exists to assess glucagon resistance in humans. The objective is to develop and evaluate a test for measuring glucagon sensitivity 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 equal to or above 25 kg/m2, but no higher than 40 kg/m2, and 15 individuals with type 1 diabetes with a BMI between 18.6-40 kg/m2. For the subsequent analysis, participants will be grouped according to their percentage of hepatic steatosis in the whole liver measured using the magnetic resonance imaging (MRI) scan. The primary outcome measure will be differences in a novel glucagon sensitivity index between individuals with and without hepatic steatosis 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 Bispebjerg University Hospital. 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 (NCT04907721). Written and oral consent will be obtained from all participants, and the study will adhere to the principles of the Declaration of Helsinki.