Hyperglucagonemia in type 2 diabetes (T2D) may result from impaired hepatic glucagon signaling and consequent reduced glucagon-induced amino acid (AA) turnover leading to higher AA concentrations and stimulation of glucagon secretion. In a double-blinded, cross-over study, blood was sampled from 10 overnight fasted patients with T2D (BMI [mean±SD]: 33.0±5.4 kg/m2; HbA1c: 46.2±6.1 mmol/mol, 6.4±0.6%) and 10 matched healthy controls (BMI: 31.7±4.2 kg/m2; HbA1c: 33.9±3.0 mmol/mol, 5.3±0.3%) after a single-dose of the glucagon receptor antagonist (GRA) LY2409021 or placebo. Total AA and glucagon concentrations are means of 3 samples (15 minutes apart) on 3 GRA and 3 placebo days. Fractioned AA were analyzed from one sample per day. Total AA concentrations were increased by GRA compared to placebo by 1.4 fold in T2D and 1.3 fold in controls (P≤0.001) with threonine, proline and the glucagonotropic AAs alanine and tyrosine exhibiting the greatest increases in T2D (1.6-2 fold) and controls (1.4-1.5 fold). GRA also increased plasma glucagon concentrations by more than 3-fold (P≤0.0001), and the glucagonotropic AAs alanine (R2 0.24, P=0.0012) and tyrosine (R2 0.30, P=0.0002) were correlated to glucagon.
In conclusion, acute inhibition of glucagon receptor signaling by GRA causes hyperaminoacidemia linked to hyperglucagonemia, supporting the importance of the liver-alpha cell axis in regulating circulating glucagon and AA in humans.
S. Haedersdal: None. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp. A.B. Lund: None. K.D. Galsgaard: None. M. Winther-Soerensen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S. T. Vilsbøll: None.
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