Glucagon Resistance at the Level of Amino Acid Turnover and Ureagenesis in Obese Subjects with Hepatic Steatosis

Abstract

Hyperglucagonemia is considered an important pathophysiological trait of type 2 diabetes and occurs also in individuals with obesity. The underlying mechanisms remain unclear. We hypothesized that hyperglucagonemia is a consequence of steatosis-induced glucagon resistance. We examined 15 healthy (BMI: 23.2±1.6 (mean±SD) kg/m2, age 40.9±12.8 years, hepatic steatosis 2:15) and 15 obese individuals (BMI: 33.6±2.1 kg/m2, age 35.8±9.4 years, hepatic steatosis 14:15) in a pancreatic somatostatin clamp with basal insulin (1 mU/kg/h) and low and high glucagon infusion rates (0.6 and 3.0 ng/kg/min). Glucagon sensitivity was assessed as changes in plasma amino acids (AA) and endogenous glucose production (EGP) and urea synthesis (U.S.) measured by tracer techniques. Basal glucagon and AA were significantly higher in obese compared to lean individuals, but no differences in basal EGP or U.S. were observed. In the lean group AA significantly dropped in response to glucagon infusion (p<0,001) whereas no response was observed in the obese group. Accordingly, both glucagon infusion rates resulted in significantly greater EGP and U.S, respectively, in lean vs. obese individuals. In conclusion, our results point to steatosis-induced hepatic glucagon resistance and compensatory glucagon secretion mediated by glucagonotropic amino acids as a likely explanation of obesity-associated hyperglucagonemia. Disclosure M.P. Suppli: None. J.I. Bagger: None. A.B. Lund: Other Relationship; Self; Novo Nordisk A/S. N.J. Wewer Albrechtsen: Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Other Relationship; Self; Mercodia, Alpco. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Vilsbøll: Advisory Panel; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Consultant; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Speaker's Bureau; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Research Support; Self; Eli Lilly and Company, Novo Nordisk A/S. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.