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.