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 Citations (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).

Original language	English
Journal	American Journal of Respiratory and Critical Care Medicine
Volume	196
Issue number	9
Pages (from-to)	1131-1143
Number of pages	13
ISSN	1073-449X
DOIs	https://doi.org/10.1164/rccm.201702-0354OC
Publication status	Published - 1 Nov 2017

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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, vol. 196, no. 9, pp. 1131-1143. https://doi.org/10.1164/rccm.201702-0354OC

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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).",

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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",

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

language = "English",

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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 - 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

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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

Abstract

Keywords

UN SDGs

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