TY - JOUR

T1 - Signs of Glucagon Resistance After a Two-Week Hypercaloric Diet Intervention

AU - Suppli, Malte Palm

AU - Høgedal, Astrid

AU - Bagger, Jonatan Ising

AU - Chabanova, Elizaveta

AU - van Hall, Gerrit

AU - Forman, Julie Lyng

AU - Christensen, Mikkel Bring

AU - Wewer Albrechtsen, Nicolai Jacob

AU - Holst, Jens Juul

AU - Knop, Filip Krag

N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

PY - 2024

Y1 - 2024

N2 - CONTEXT: Hyperglucagonemia is observed in individuals with obesity and contributes to the hyperglycemia of patients with type 2 diabetes. Hyperglucagonemia may develop due to steatosis-induced hepatic glucagon resistance resulting in impaired hepatic amino acid turnover and ensuing elevations of circulating glucagonotropic amino acids.OBJECTIVE: We evaluated whether glucagon resistance could be induced in healthy individuals by a hypercaloric diet intervention designed to increase hepatic fat content.METHODS: We recruited 20 healthy, male individuals to follow a hypercaloric diet and a sedentary lifestyle for two weeks. Amino acid concentrations in response to infusion of glucagon were assessed during a pancreatic clamp with somatostatin and basal insulin. The reversibility of any metabolic changes was assessed eight weeks after the intervention. Hepatic steatosis was assessed by magnetic resonance spectroscopy.RESULTS: The intervention led to increased hepatic fat content (382 [206; 705]%, P < 0.01). Glucagon infusion led to a decrease in the concentration of total amino acids on all experimental days, but the percentage change in total amino acids was reduced (-2.5 ± 0.5 vs. -0.2 ± 0.7%, P = 0.015) and the average slope of the decline in the total amino acid concentration was less steep (-2.0 ± 1.2 vs. -1.2 ± 0.3 μM/min, P = 0.016) after the intervention compared to baseline. The changes were normalized at follow-up.CONCLUSION: Our results indicate that short-term unhealthy behavior, which increases hepatic fat content, causes a reversible resistance to the effect of glucagon on amino acid concentrations in healthy individuals, which may explain the hyperglucagonemia associated with obesity and diabetes.

AB - CONTEXT: Hyperglucagonemia is observed in individuals with obesity and contributes to the hyperglycemia of patients with type 2 diabetes. Hyperglucagonemia may develop due to steatosis-induced hepatic glucagon resistance resulting in impaired hepatic amino acid turnover and ensuing elevations of circulating glucagonotropic amino acids.OBJECTIVE: We evaluated whether glucagon resistance could be induced in healthy individuals by a hypercaloric diet intervention designed to increase hepatic fat content.METHODS: We recruited 20 healthy, male individuals to follow a hypercaloric diet and a sedentary lifestyle for two weeks. Amino acid concentrations in response to infusion of glucagon were assessed during a pancreatic clamp with somatostatin and basal insulin. The reversibility of any metabolic changes was assessed eight weeks after the intervention. Hepatic steatosis was assessed by magnetic resonance spectroscopy.RESULTS: The intervention led to increased hepatic fat content (382 [206; 705]%, P < 0.01). Glucagon infusion led to a decrease in the concentration of total amino acids on all experimental days, but the percentage change in total amino acids was reduced (-2.5 ± 0.5 vs. -0.2 ± 0.7%, P = 0.015) and the average slope of the decline in the total amino acid concentration was less steep (-2.0 ± 1.2 vs. -1.2 ± 0.3 μM/min, P = 0.016) after the intervention compared to baseline. The changes were normalized at follow-up.CONCLUSION: Our results indicate that short-term unhealthy behavior, which increases hepatic fat content, causes a reversible resistance to the effect of glucagon on amino acid concentrations in healthy individuals, which may explain the hyperglucagonemia associated with obesity and diabetes.

U2 - 10.1210/clinem/dgad666

DO - 10.1210/clinem/dgad666

M3 - Journal article

C2 - 37967235

VL - 109

SP - 955

EP - 967

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 4

ER -