Glucagon's effect on liver protein metabolism in vivo

Abstract

The postprandial state is characterized by a storage of nutrients in the liver, muscle, and adipose tissue for later utilization. In the case of a protein-rich meal, amino acids (AA) stimulate glucagon secretion by the α-cell. The aim of the present study was to determine the impact of the rise in glucagon on AA metabolism, particularly in the liver. We used a conscious catheterized dog model to recreate a postprandial condition using a pancreatic clamp. Portal infusions of glucose, AA, and insulin were used to achieve postprandial levels, while portal glucagon infusion was either maintained at the basal level or increased by three-fold. The high glucagon infusion reduced the increase in arterial AA concentrations compared with the basal glucagon level (-23%, P < 0.05). In the presence of high glucagon, liver AA metabolism shifted toward a more catabolic state with less protein synthesis (-36%) and increased urea production (+52%). Net hepatic glucose uptake was reduced modestly (-35%), and AA were preferentially used in gluconeogenesis, leading to lower glycogen synthesis (-54%). The phosphorylation of AMPK was increased by the high glucagon infusion (+40%), and this could be responsible for increasing the expression of genes related to pathways producing energy and lowering those involved in energy consumption. In conclusion, the rise in glucagon associated with a protein-rich meal promotes a catabolic utilization of AA in the liver, thereby, opposing the storage of AA in proteins.

Keywords: amino acid metabolism; glucagon; liver.

Fig. 1.

Sinusoidal hormone concentrations (A: insulin; B: glucagon) and nutrient load to the liver (C: glucose; D: amino acids) during a pancreatic clamp in which somatostatin was started at 120 min, together with a portal infusion of insulin and glucagon to increase sinusoidal insulin concentration by four-fold, while keeping glucagon basal (BaGGN) or increasing it three-fold (HiGGN). Portal infusion of glucose and amino acids was also started at 120 min to increase their hepatic loads by 1.5-fold. The experiment was performed on conscious 42-h-fasted dogs (BaGGN, n = 7 and HiGGN, n = 8).

Fig. 2.

Relative phosphorylation of AMPK, mammalian target of rapamycin (mTOR) and p70S6 kinase in liver (A) and muscle (B) measured by Western blot analysis in dogs at the end of a pancreatic clamp simulating postprandial conditions with either a basal (BaGGN) or high level of glucagon (HiGGN) **P < 0.05 between groups.

Fig. 3.

Hepatic gene expression of SNAT2 and SNAT4 (system A transporter of amino acids 2 and 4), phosphoenolpyruvate carboxykinase (PEPCK), glucokinase (GK), carbamoyl-phosphate synthase 1 (CPS-1), caspase-3 (CASP3), and m-calpain (mCALP) (two types of proteolytic systems) in 42-h-fasted dogs at the end of a pancreatic clamp simulating postprandial conditions with either BaGGN or HiGGN. *0.05 < P < 0.10 between groups. **P < 0.05 between groups.