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The Effect of Glucagon on Protein Catabolism During Insulin Deficiency - Exchange of Amino acids across Skeletal Muscle and the Splanchnic Bed

posted on 27.05.2022, 14:16 authored by Haleigh James, Wilson I. Gonsalves, Shankarappa Manjunatha, Surendra Dasari, Ian R. Lanza, Katherine A. Klaus, Adrian Vella, James C. Andrews, K. Sreekumaran Nair


Transient insulin deprivation with concurrent hyperglucagonemia is a catabolic state that can occur in type 1 diabetes. To evaluate glucagon’s catabolic effect in the setting of its glucogenic effect, we measured the regional exchanges of amino-metabolites across muscle and splanchnic beds in 16 healthy humans during either somatostatin followed by glucagon or a saline infusion alone. Despite a >2-fold increase in the regional exchange of amino-metabolites by glucagon, whole body kinetics and concentrations of amino acids (AAs) remained stable. Glucagon increased the splanchnic uptake of not only gluconeogenic but also essential amino acids (EAAs) while increasing their release from the muscle bed. Regional tracer-based kinetics and 3-methyl-histidine release indicate that EAA release from muscle is likely caused by reduced protein synthesis rather than increased protein degradation. Furthermore, many metabolites known to affect insulin action and metabolism were altered by hyperglucagonemia including increase in branched amino acids and keto acids of leucine and isoleucine in arterial plasma. Further, an increase in arterial concentrations of α-aminoadipic acid arising from increased conversion from lysine in the splanchnic bed was noted. These results demonstrate that hyperglucagonemia during hypoinsulinemia increases net muscle protein catabolism and substantially increases the exchange of amino metabolites across splanchnic and muscle beds. 


Grant funding to support this research from the National institutes of Health include R01AG062859 (K.S.N.and UL1 TR000135), and K23CA218742 (W.G.). Additional support was provided by the Mayo Foundation, and the Dr. Emslander Professorship (K.S.N.).