TY - JOUR

T1 - Development of a glucagon sensitivity test in humans

T2 - Pilot data and the GLUSENTIC study protocol

AU - Kjeldsen, Sasha A.S.

AU - Richter, Michael M.

AU - Jensen, Nicole J.

AU - Nilsson, Malin S.D.

AU - Heinz, Niklas

AU - Nybing, Janus D.

AU - Linden, Frederik H.

AU - Høgh-Schmidt, Erik

AU - Boesen, Mikael P.

AU - Madsbad, Sten

AU - Vilstrup, Hendrik

AU - Schiødt, Frank Vinholt

AU - Møller, Andreas

AU - Nørgaard, Kirsten

AU - Schmidt, Signe

AU - Rashu, Elias B.

AU - Gluud, Lise L.

AU - Haugaard, Steen B.

AU - Holst, Jens J.

AU - Rungby, Jørgen

AU - Wewer Albrechtsen, Nicolai J.

N1 - Publisher Copyright: © 2023 The Authors

PY - 2023

Y1 - 2023

N2 - A physiological feedback system exists between hepatocytes and the alpha cells, termed the liver-alpha cell axis and refers to the relationship between amino acid-stimulated glucagon secretion and glucagon-stimulated amino acid catabolism. Several reports indicate that non-alcoholic fatty liver disease (NAFLD) disrupts the liver-alpha cell axis, because of impaired glucagon receptor signaling (glucagon resistance). However, no experimental test exists to assess glucagon resistance in humans. The objective was to develop an experimental test to determine glucagon sensitivity with respect to amino acid and glucose metabolism in humans. The proposed glucagon sensitivity test (comprising two elements: 1) i.v. injection of 0.2 mg glucagon and 2) infusion of mixed amino acids 331 mg/hour/kg) is based on nine pilot studies which are presented. Calculation of a proposed glucagon sensitivity index with respect to amino acid catabolism is also described. Secondly, we describe a complete study protocol (GLUSENTIC) according to which the glucagon sensitivity test will be applied in a cross-sectional study currently taking place. 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 and 40 kg/m2 will be included. Participants will be grouped according to their degree of hepatic steatosis measured by whole-liver magnetic resonance imaging (MRI). The primary outcome measure will be differences in the glucagon sensitivity index between individuals with and without hepatic steatosis. Developing a glucagon sensitivity test and index may provide insight into the physiological and pathophysiological mechanism of glucagon action and glucagon-based therapies.

AB - A physiological feedback system exists between hepatocytes and the alpha cells, termed the liver-alpha cell axis and refers to the relationship between amino acid-stimulated glucagon secretion and glucagon-stimulated amino acid catabolism. Several reports indicate that non-alcoholic fatty liver disease (NAFLD) disrupts the liver-alpha cell axis, because of impaired glucagon receptor signaling (glucagon resistance). However, no experimental test exists to assess glucagon resistance in humans. The objective was to develop an experimental test to determine glucagon sensitivity with respect to amino acid and glucose metabolism in humans. The proposed glucagon sensitivity test (comprising two elements: 1) i.v. injection of 0.2 mg glucagon and 2) infusion of mixed amino acids 331 mg/hour/kg) is based on nine pilot studies which are presented. Calculation of a proposed glucagon sensitivity index with respect to amino acid catabolism is also described. Secondly, we describe a complete study protocol (GLUSENTIC) according to which the glucagon sensitivity test will be applied in a cross-sectional study currently taking place. 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 and 40 kg/m2 will be included. Participants will be grouped according to their degree of hepatic steatosis measured by whole-liver magnetic resonance imaging (MRI). The primary outcome measure will be differences in the glucagon sensitivity index between individuals with and without hepatic steatosis. Developing a glucagon sensitivity test and index may provide insight into the physiological and pathophysiological mechanism of glucagon action and glucagon-based therapies.

KW - Amino acids

KW - Glucagon

KW - Metabolism

KW - NAFLD

KW - Study protocol

KW - The liver-alpha cell axis

KW - Type 1 diabetes

U2 - 10.1016/j.peptides.2022.170938

DO - 10.1016/j.peptides.2022.170938

M3 - Journal article

C2 - 36596314

AN - SCOPUS:85145843295

VL - 161

JO - Peptides

JF - Peptides

SN - 0196-9781

M1 - 170938

ER -