Amino acids (aa) stimulate the secretion of glucagon (gcg) and gcg receptor signaling controls aa catabolism, constituting the liver-alpha cell axis. Impairment of the liver-alpha cell axis is observed in diabetes, but how glucose (glc) levels affect this axis is unknown. We investigated the role of glc on the liver-alpha cell axis by 1) isolated perfused pancreas, 2) isolated perfused liver, and 3) a randomized in-vivo study in male mice. The isolated perfused pancreas was used to evaluate the direct effect of low (3.5mM) and high (15mM) glc levels, respectively on aa (10mM arginine) -induced gcg secretion. High glc levels significantly lowered basal gcg secretion, but aa-induced gcg responses were comparable to those at low glc levels (p=0.38) . The direct effect of glc on gcg induced ureagenesis was assessed by isolated single pass perfused liver stimulated with 10mM mixture of 18 aa + 10nM gcg for two periods of 15 min with glc infused at either 1 or 18 mmol/L. The order of glc addition was randomized. Aa and gcg significantly increased urea production compared to baseline, and this was independent of low or high glc levels (p=0.95) . Whole-body effects of glc on the liver-alpha cell axis were assessed in-vivo including four groups receiving an intraperitoneal injection of either Glc-Saline (2 g/kg, Glc/S, n=8) , Glc-Aa (2 g/kg, + 14 g/l, respectively Glc/Aa, n=10) , Saline-Aa (S/Aa, n=10) and saline-saline (volume-matched, S/S, n=10) . Blood samples were obtained at 0,2,4,10 and 20 minutes and levels of glc, gcg, insulin (ins) , and aa were measured. Glc levels did not differ significantly between Glc/S and Glc/Aa groups, but ins and gcg were significantly higher in the G/Aa group. The gcg:ins ratio did not differ between groups. Plasma levels of gcg and aa were not significantly different between the G/Aa and S/Aa groups (p=0.28) . These results suggest that aa overrule the inhibitory effect of glc on gcg secretion and the actions of glucagon on aa catabolism may be independent of glc in mice.


K. Maruszczak: None. C. Rasmussen: None. F. R. Ceutz: None. A. Ørgaard: Employee; Novo Nordisk A/S. E. E. Christensen: None. M. M. Richter: None. J. J. Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. M. Winther-soerensen: None. N. J. Wewer albrechtsen: Research Support; Mercodia AB, Novo Nordisk, Regeneron Pharmaceuticals Inc., Speaker's Bureau; Merck & Co., Inc., Mercodia AB.


NNF Excellence Emerging Investigator Grant ? Endocrinology and Metabolism (Application No. NNF19OC0055001) , EFSD Future Leader Award (NNF21SA0072746) and Independent Research Fund Denmark Sapere Aude Program (1052-00003B) .

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