Role of Glucagon in Catabolism and Muscle Wasting of Critical Illness and Modulation by Nutrition

Steven E Thiessen; Sarah Derde; Inge Derese; Thomas Dufour; Chloé Albert Vega; Lies Langouche; Chloë Goossens; Nele Peersman; Pieter Vermeersch; Sarah Vander Perre; Jens J Holst; Pieter J Wouters; Ilse Vanhorebeek; Greet Van den Berghe

doi:10.1164/rccm.201702-0354OC

Role of Glucagon in Catabolism and Muscle Wasting of Critical Illness and Modulation by Nutrition

Steven E Thiessen, Sarah Derde, Inge Derese, Thomas Dufour, Chloé Albert Vega, Lies Langouche, Chloë Goossens, Nele Peersman, Pieter Vermeersch, Sarah Vander Perre, Jens J Holst, Pieter J Wouters, Ilse Vanhorebeek, Greet Van den Berghe

27 Citationer (Scopus)

Abstract

RATIONALE: Critical illness is hallmarked by muscle wasting and disturbances in glucose, lipid, and amino acid homeostasis. Circulating concentrations of glucagon, a catabolic hormone that affects these metabolic pathways, are elevated during critical illness. Insight in the nutritional regulation of glucagon and its metabolic role during critical illness is lacking.

OBJECTIVES: To evaluate whether macronutrient infusion can suppress plasma glucagon during critical illness and study the role of illness-induced glucagon abundance in the disturbed glucose, lipid, and amino acid homeostasis and in muscle wasting during critical illness.

METHODS: In human and mouse studies, we infused macronutrients and manipulated glucagon availability up and down to investigate its acute and chronic metabolic role during critical illness.

MEASUREMENTS AND MAIN RESULTS: In critically ill patients, infusing glucose with insulin did not lower glucagon, whereas parenteral nutrition containing amino acids increased glucagon. In critically ill mice, infusion of amino acids increased glucagon and up-regulated markers of hepatic amino acid catabolism without affecting muscle wasting. Immunoneutralizing glucagon in critically ill mice only transiently affected glucose and lipid metabolism, did not affect muscle wasting, but drastically suppressed markers of hepatic amino acid catabolism and reversed the illness-induced hypoaminoacidemia.

CONCLUSIONS: These data suggest that elevated glucagon availability during critical illness increases hepatic amino acid catabolism, explaining the illness-induced hypoaminoacidemia, without affecting muscle wasting and without a sustained impact on blood glucose. Furthermore, amino acid infusion likely results in a further breakdown of amino acids in the liver, mediated by increased glucagon, without preventing muscle wasting. Clinical trial registered with www.clinicaltrials.gov (NCT 00512122).

Originalsprog	Engelsk
Tidsskrift	American Journal of Respiratory and Critical Care Medicine
Vol/bind	196
Udgave nummer	9
Sider (fra-til)	1131-1143
Antal sider	13
ISSN	1073-449X
DOI	https://doi.org/10.1164/rccm.201702-0354OC
Status	Udgivet - 1 nov. 2017

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10.1164/rccm.201702-0354OC

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Thiessen, S. E., Derde, S., Derese, I., Dufour, T., Vega, C. A., Langouche, L., Goossens, C., Peersman, N., Vermeersch, P., Vander Perre, S., Holst, J. J., Wouters, P. J., Vanhorebeek, I., & Van den Berghe, G. (2017). Role of Glucagon in Catabolism and Muscle Wasting of Critical Illness and Modulation by Nutrition. American Journal of Respiratory and Critical Care Medicine, 196(9), 1131-1143. https://doi.org/10.1164/rccm.201702-0354OC

Thiessen, SE, Derde, S, Derese, I, Dufour, T, Vega, CA, Langouche, L, Goossens, C, Peersman, N, Vermeersch, P, Vander Perre, S, Holst, JJ, Wouters, PJ, Vanhorebeek, I & Van den Berghe, G 2017, 'Role of Glucagon in Catabolism and Muscle Wasting of Critical Illness and Modulation by Nutrition', American Journal of Respiratory and Critical Care Medicine, bind 196, nr. 9, s. 1131-1143. https://doi.org/10.1164/rccm.201702-0354OC

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title = "Role of Glucagon in Catabolism and Muscle Wasting of Critical Illness and Modulation by Nutrition",

abstract = "RATIONALE: Critical illness is hallmarked by muscle wasting and disturbances in glucose, lipid, and amino acid homeostasis. Circulating concentrations of glucagon, a catabolic hormone that affects these metabolic pathways, are elevated during critical illness. Insight in the nutritional regulation of glucagon and its metabolic role during critical illness is lacking.OBJECTIVES: To evaluate whether macronutrient infusion can suppress plasma glucagon during critical illness and study the role of illness-induced glucagon abundance in the disturbed glucose, lipid, and amino acid homeostasis and in muscle wasting during critical illness.METHODS: In human and mouse studies, we infused macronutrients and manipulated glucagon availability up and down to investigate its acute and chronic metabolic role during critical illness.MEASUREMENTS AND MAIN RESULTS: In critically ill patients, infusing glucose with insulin did not lower glucagon, whereas parenteral nutrition containing amino acids increased glucagon. In critically ill mice, infusion of amino acids increased glucagon and up-regulated markers of hepatic amino acid catabolism without affecting muscle wasting. Immunoneutralizing glucagon in critically ill mice only transiently affected glucose and lipid metabolism, did not affect muscle wasting, but drastically suppressed markers of hepatic amino acid catabolism and reversed the illness-induced hypoaminoacidemia.CONCLUSIONS: These data suggest that elevated glucagon availability during critical illness increases hepatic amino acid catabolism, explaining the illness-induced hypoaminoacidemia, without affecting muscle wasting and without a sustained impact on blood glucose. Furthermore, amino acid infusion likely results in a further breakdown of amino acids in the liver, mediated by increased glucagon, without preventing muscle wasting. Clinical trial registered with www.clinicaltrials.gov (NCT 00512122).",

keywords = "Aged, Amino Acids/blood, Animals, Blood Glucose, Critical Illness, Disease Models, Animal, Female, Glucagon/blood, Glucose/administration & dosage, Humans, Insulin/administration & dosage, Male, Mice, Middle Aged, Muscular Atrophy/blood, Parenteral Nutrition/methods, Treatment Outcome",

author = "Thiessen, {Steven E} and Sarah Derde and Inge Derese and Thomas Dufour and Vega, {Chlo{\'e} Albert} and Lies Langouche and Chlo{\"e} Goossens and Nele Peersman and Pieter Vermeersch and {Vander Perre}, Sarah and Holst, {Jens J} and Wouters, {Pieter J} and Ilse Vanhorebeek and {Van den Berghe}, Greet",

year = "2017",

month = nov,

day = "1",

doi = "10.1164/rccm.201702-0354OC",

language = "English",

volume = "196",

pages = "1131--1143",

journal = "American Journal of Respiratory and Critical Care Medicine",

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TY - JOUR

T1 - Role of Glucagon in Catabolism and Muscle Wasting of Critical Illness and Modulation by Nutrition

AU - Thiessen, Steven E

AU - Derde, Sarah

AU - Derese, Inge

AU - Dufour, Thomas

AU - Vega, Chloé Albert

AU - Langouche, Lies

AU - Goossens, Chloë

AU - Peersman, Nele

AU - Vermeersch, Pieter

AU - Vander Perre, Sarah

AU - Holst, Jens J

AU - Wouters, Pieter J

AU - Vanhorebeek, Ilse

AU - Van den Berghe, Greet

PY - 2017/11/1

Y1 - 2017/11/1

N2 - RATIONALE: Critical illness is hallmarked by muscle wasting and disturbances in glucose, lipid, and amino acid homeostasis. Circulating concentrations of glucagon, a catabolic hormone that affects these metabolic pathways, are elevated during critical illness. Insight in the nutritional regulation of glucagon and its metabolic role during critical illness is lacking.OBJECTIVES: To evaluate whether macronutrient infusion can suppress plasma glucagon during critical illness and study the role of illness-induced glucagon abundance in the disturbed glucose, lipid, and amino acid homeostasis and in muscle wasting during critical illness.METHODS: In human and mouse studies, we infused macronutrients and manipulated glucagon availability up and down to investigate its acute and chronic metabolic role during critical illness.MEASUREMENTS AND MAIN RESULTS: In critically ill patients, infusing glucose with insulin did not lower glucagon, whereas parenteral nutrition containing amino acids increased glucagon. In critically ill mice, infusion of amino acids increased glucagon and up-regulated markers of hepatic amino acid catabolism without affecting muscle wasting. Immunoneutralizing glucagon in critically ill mice only transiently affected glucose and lipid metabolism, did not affect muscle wasting, but drastically suppressed markers of hepatic amino acid catabolism and reversed the illness-induced hypoaminoacidemia.CONCLUSIONS: These data suggest that elevated glucagon availability during critical illness increases hepatic amino acid catabolism, explaining the illness-induced hypoaminoacidemia, without affecting muscle wasting and without a sustained impact on blood glucose. Furthermore, amino acid infusion likely results in a further breakdown of amino acids in the liver, mediated by increased glucagon, without preventing muscle wasting. Clinical trial registered with www.clinicaltrials.gov (NCT 00512122).

AB - RATIONALE: Critical illness is hallmarked by muscle wasting and disturbances in glucose, lipid, and amino acid homeostasis. Circulating concentrations of glucagon, a catabolic hormone that affects these metabolic pathways, are elevated during critical illness. Insight in the nutritional regulation of glucagon and its metabolic role during critical illness is lacking.OBJECTIVES: To evaluate whether macronutrient infusion can suppress plasma glucagon during critical illness and study the role of illness-induced glucagon abundance in the disturbed glucose, lipid, and amino acid homeostasis and in muscle wasting during critical illness.METHODS: In human and mouse studies, we infused macronutrients and manipulated glucagon availability up and down to investigate its acute and chronic metabolic role during critical illness.MEASUREMENTS AND MAIN RESULTS: In critically ill patients, infusing glucose with insulin did not lower glucagon, whereas parenteral nutrition containing amino acids increased glucagon. In critically ill mice, infusion of amino acids increased glucagon and up-regulated markers of hepatic amino acid catabolism without affecting muscle wasting. Immunoneutralizing glucagon in critically ill mice only transiently affected glucose and lipid metabolism, did not affect muscle wasting, but drastically suppressed markers of hepatic amino acid catabolism and reversed the illness-induced hypoaminoacidemia.CONCLUSIONS: These data suggest that elevated glucagon availability during critical illness increases hepatic amino acid catabolism, explaining the illness-induced hypoaminoacidemia, without affecting muscle wasting and without a sustained impact on blood glucose. Furthermore, amino acid infusion likely results in a further breakdown of amino acids in the liver, mediated by increased glucagon, without preventing muscle wasting. Clinical trial registered with www.clinicaltrials.gov (NCT 00512122).

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KW - Amino Acids/blood

KW - Animals

KW - Blood Glucose

KW - Critical Illness

KW - Disease Models, Animal

KW - Female

KW - Glucagon/blood

KW - Glucose/administration & dosage

KW - Humans

KW - Insulin/administration & dosage

KW - Male

KW - Mice

KW - Middle Aged

KW - Muscular Atrophy/blood

KW - Parenteral Nutrition/methods

KW - Treatment Outcome

U2 - 10.1164/rccm.201702-0354OC

DO - 10.1164/rccm.201702-0354OC

M3 - Journal article

C2 - 28475354

SN - 1073-449X

VL - 196

SP - 1131

EP - 1143

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

IS - 9

ER -

Role of Glucagon in Catabolism and Muscle Wasting of Critical Illness and Modulation by Nutrition

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