Signs of glucagon resistance after a two-week hypercaloric diet intervention

Hyperglucagonemia is observed in individuals with obesity and contributes to the hyperglycemia of persons with diabetes. Hyperglucagonemia may arise due to reduced hepatic amino acid turnover and ensuing elevations in glucagonotropic amino acids. We recently observed reduced glucagon sensitivity and hyperglucagonemia in individuals with obesity and hypothesized it to be a consequence of steatosis. Here, we evaluated whether reduced glucagon sensitivity could be induced by a short-term hypercaloric diet intervention designed to increase hepatic fat content in healthy individuals. We recruited 20 healthy, lean individuals (BMI: 23 ± 0.3 (mean ± SD) kg/m2) to follow a hypercaloric diet (~5,000 kcal/day) and a sedentary lifestyle for 2 weeks. Amino acid turnover in response to infusion of glucagon was assessed during a pancreatic clamp with somatostatin and basal insulin. Participants were examined before and after the lifestyle-intervention and again after 8 weeks to assess the reversibility of any metabolic changes. Hepatic steatosis was assessed by magnetic resonance spectroscopy. The intervention led to increases in body weight (3.5 [2.8;4.2] (mean [95% confidence interval]) kg, P < 0.0001) and hepatic fat content (382 [206;705]%, P < 0.001). Insulin resistance was evident with unchanged fasting blood glucose levels and a 56% increase in fasting insulin (P < 0.001). Glucagon infusion led to a decrease in the concentration of total amino acids, 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 total amino acid curve was less steep (−2.0 ± 1.2 vs. −1.2 ± 0.3 μM/min, P = 0.016) after the intervention compared to baseline. All metabolic changes were normalized at follow-up. Our results indicate that short-term unhealthy behavior increasing hepatic fat content causes a reversible resistance to the effect of glucagon on amino acid turnover in healthy individuals, which may explain hyperglucagonemia associated with obesity and diabetes. Disclosure M.P.Suppli: None. J.I.Bagger: Speaker's Bureau; Novo Nordisk A/S. J.J.Holst: Advisory Panel; Novo Nordisk A/S, Eli Lilly and Company, Board Member; Bainan Biotech, Antag Therapeutics, Consultant; Alphasights, Eli Lilly and Company, ShouTi Pharma Inc., Zealand Pharma A/S, Other Relationship; Novo Nordisk, Novo Nordisk Pharma, Mayo Clinic, Boehringer-Ingelheim, Scohia Pharma Inc., Research Support; ARLA, European Union, Novo Nordisk Foundation. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck.