The Role of Glucagon during Critical Illness and Its Modulation By Macronutrients

Presentation Number: SUN 596
Date of Presentation: April 2nd, 2017

Steven E Thiessen*1, Ilse Vanhorebeek1, Sarah Derde1, Inge Derese1, Thomas Dufour1, Chloé Nadège Albert1, Lies Langouche1, Chloë Goossens1, Nele Peersman1, Pieter Vermeersch1, Sarah Vander Perre1, Jens J Holst2, Pieter Wouters1 and Greet Van den Berghe1
1KU Leuven, Leuven, Belgium, 2University of Copenhagen, Denmark

Abstract

Critical illness, requiring vital organ support to avoid imminent death, is hallmarked by metabolic disturbances, such as hyperglycemia, increased lipolysis and hypoaminoacidemia, as well as by profound muscle wasting (1;2). Guidelines recommend amino acid administration to prevent such muscle wasting (3). Glucagon, a catabolic hormone that affects these metabolic pathways and can induce muscle wasting, is increased during critical illness (4;5). Altered nutritional modulation of glucagon is known to contribute to the catabolic phenotype of diabetes (6). We assessed whether glucagon can be modulated by nutrition and investigated its metabolic role during critical illness.

In critically ill human patients (n=174), we evaluated the effect of administering glucose, together with insulin, and of total parenteral nutrition (TPN) on plasma glucagon, in comparison with glucagon concentrations in matched healthy controls (n=20). In critically ill mice with sepsis, induced by cecal ligation and puncture, we assessed the effect of amino acid administration on plasma glucagon in a first study and immunoneutralized glucagon in a second study to evaluate its effects on glucose, lipid and amino acid metabolism and muscle wasting in the early (10 or 30 hrs) and/or prolonged (3 days) phase of critical illness.

In patients, plasma glucagon concentrations were elevated from day 1 in the intensive care unit onwards up until day 7 (P≤0.0001) and correlated with severity of illness (ρ=0.51, P<0.0001). Providing glucose and insulin did not significantly lower glucagon (P=0.07), whereas TPN increased glucagon (P=0.02). In critically ill mice, amino acid administration increased plasma glucagon (P<0.0001). Glucagon neutralization only transiently affected glucose and lipid metabolism, with a decrease in the illness-induced hyperglycemia (P<0.0001) and signs of stimulated rather than decreased lipolysis (P=0.002) at 10 hrs. Glucagon neutralization reversed the illness-induced hypoaminoacidemia (P≤0.0001), accompanied by lowered markers of hepatic amino catabolism (P≤0.02 at 30 hrs), but did not affect muscle wasting at any time point (P≥0.56). In contrast, the rise in glucagon with amino acid administration was accompanied by increased markers of hepatic amino acid catabolism (P≤0.005), but also did not affect markers of muscle catabolism (P≥0.23).

In conclusion, combined glucose and insulin administration did not suppress, whereas amino acids further increased the elevated glucagon concentrations during critical illness. Glucagon only transiently affected glucose and lipid metabolism during critical illness, but induced hypoaminoacidemia by promoting hepatic amino acid catabolism, without affecting muscle wasting. These findings raise concerns about the usefulness of amino acid administration as strategy to prevent muscle wasting during critical illness.

 

Nothing to Disclose: SET, IV, SD, ID, TD, CN, LL, CG, NP, PV, SV, JJH, PW, GV