The effects of TNF-α on GLP-1-stimulated plasma glucose kinetics

Louise Lehrskov-Schmidt; Lars Lehrskov-Schmidt; Signe T Nielsen; Jens Juul Holst; Kirsten Møller; Thomas P J Solomon

doi:10.1210/jc.2014-4244

The effects of TNF-α on GLP-1-stimulated plasma glucose kinetics

Louise Lehrskov-Schmidt, Lars Lehrskov-Schmidt, Signe T Nielsen, Jens Juul Holst, Kirsten Møller, Thomas P J Solomon

Inflammation, Metabolism and Oxidation

13 Citations (Scopus)

Abstract

Context: Glucagon-like peptide-1 (GLP-1) analogs have recently been promoted as antihyperglycemic agents in critically ill patients with systemic inflammation, but the effects of TNF-α on glucose metabolism during GLP-1 administration are unknown. Objective: The objective of the study was to determine whether the infusion of TNF-α at high physiological levels impairs GLP-1's effects on glucose metabolism. Design: This was a randomized, controlled, cross-over trial. Setting: The study was conducted at a hospital clinical research laboratory. Participants: Twelve healthy males (aged 24 ± 3 y; body mass index 22.9 ± 1.3 kg/m²). Interventions: After an overnight fast, either saline (0.9%) or recombinant human TNF-α (1000 ng/m2·h) was infused from t = 0-6 hours. At t = 2 hours, GLP-1 infusion (0.5 pmol/kg·min) began. From t=4-6 hours, the GLP-1 infusion rate was increased to 1.2 pmol/kg·min. Plasma glucose was clamped at 5 mmol/L throughout via a variable rate 20% dextrose infusion. Trials were 7-14 days apart. Main Outcome Measures: Endogenous glucose production (EGP) was measured by the [6,6-²H₂]glucose isotope tracer dilution method. Results: GLP-1 infusion suppressed plasma glucagon (P<.01), elevated plasma insulin, and C-peptide (P <.01) and suppressed EGP (P <.001) during the saline infusion. In contrast, the infusion of TNF-α increased plasma TNF-α and IL-6, elevated body temperature, and blunted the GLP-1-induced suppression of EGP during high-dose GLP-1 infusion (all P <.05, TNF-α vs saline). However, TNF-α infusion lowered plasma GLP-1 during high-dose GLP-1 infusion (P <.001). Conclusions: TNF-α induces systemic inflammation and reduces plasma GLP-1, thereby reducing the suppression of EGP during GLP-1 infusion. This may have clinical relevance if GLP-1 analog drugs are used for the treatment of hyperglycemia in critically ill patients.

Original language	English
Journal	The Journal of clinical endocrinology and metabolism
Volume	100
Issue number	4
Pages (from-to)	E616-E622
Number of pages	7
ISSN	0021-972X
DOIs	https://doi.org/10.1210/jc.2014-4244
Publication status	Published - 1 Apr 2015

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title = "The effects of TNF-α on GLP-1-stimulated plasma glucose kinetics",

abstract = "Context: Glucagon-like peptide-1 (GLP-1) analogs have recently been promoted as antihyperglycemic agents in critically ill patients with systemic inflammation, but the effects of TNF-α on glucose metabolism during GLP-1 administration are unknown. Objective: The objective of the study was to determine whether the infusion of TNF-α at high physiological levels impairs GLP-1's effects on glucose metabolism. Design: This was a randomized, controlled, cross-over trial. Setting: The study was conducted at a hospital clinical research laboratory. Participants: Twelve healthy males (aged 24 ± 3 y; body mass index 22.9 ± 1.3 kg/m2). Interventions: After an overnight fast, either saline (0.9%) or recombinant human TNF-α (1000 ng/m2·h) was infused from t = 0-6 hours. At t = 2 hours, GLP-1 infusion (0.5 pmol/kg·min) began. From t=4-6 hours, the GLP-1 infusion rate was increased to 1.2 pmol/kg·min. Plasma glucose was clamped at 5 mmol/L throughout via a variable rate 20% dextrose infusion. Trials were 7-14 days apart. Main Outcome Measures: Endogenous glucose production (EGP) was measured by the [6,6-2H2]glucose isotope tracer dilution method. Results: GLP-1 infusion suppressed plasma glucagon (P<.01), elevated plasma insulin, and C-peptide (P <.01) and suppressed EGP (P <.001) during the saline infusion. In contrast, the infusion of TNF-α increased plasma TNF-α and IL-6, elevated body temperature, and blunted the GLP-1-induced suppression of EGP during high-dose GLP-1 infusion (all P <.05, TNF-α vs saline). However, TNF-α infusion lowered plasma GLP-1 during high-dose GLP-1 infusion (P <.001). Conclusions: TNF-α induces systemic inflammation and reduces plasma GLP-1, thereby reducing the suppression of EGP during GLP-1 infusion. This may have clinical relevance if GLP-1 analog drugs are used for the treatment of hyperglycemia in critically ill patients.",

author = "Louise Lehrskov-Schmidt and Lars Lehrskov-Schmidt and Nielsen, {Signe T} and Holst, {Jens Juul} and Kirsten M{\o}ller and Solomon, {Thomas P J}",

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T1 - The effects of TNF-α on GLP-1-stimulated plasma glucose kinetics

AU - Lehrskov-Schmidt, Louise

AU - Lehrskov-Schmidt, Lars

AU - Nielsen, Signe T

AU - Holst, Jens Juul

AU - Møller, Kirsten

AU - Solomon, Thomas P J

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N2 - Context: Glucagon-like peptide-1 (GLP-1) analogs have recently been promoted as antihyperglycemic agents in critically ill patients with systemic inflammation, but the effects of TNF-α on glucose metabolism during GLP-1 administration are unknown. Objective: The objective of the study was to determine whether the infusion of TNF-α at high physiological levels impairs GLP-1's effects on glucose metabolism. Design: This was a randomized, controlled, cross-over trial. Setting: The study was conducted at a hospital clinical research laboratory. Participants: Twelve healthy males (aged 24 ± 3 y; body mass index 22.9 ± 1.3 kg/m2). Interventions: After an overnight fast, either saline (0.9%) or recombinant human TNF-α (1000 ng/m2·h) was infused from t = 0-6 hours. At t = 2 hours, GLP-1 infusion (0.5 pmol/kg·min) began. From t=4-6 hours, the GLP-1 infusion rate was increased to 1.2 pmol/kg·min. Plasma glucose was clamped at 5 mmol/L throughout via a variable rate 20% dextrose infusion. Trials were 7-14 days apart. Main Outcome Measures: Endogenous glucose production (EGP) was measured by the [6,6-2H2]glucose isotope tracer dilution method. Results: GLP-1 infusion suppressed plasma glucagon (P<.01), elevated plasma insulin, and C-peptide (P <.01) and suppressed EGP (P <.001) during the saline infusion. In contrast, the infusion of TNF-α increased plasma TNF-α and IL-6, elevated body temperature, and blunted the GLP-1-induced suppression of EGP during high-dose GLP-1 infusion (all P <.05, TNF-α vs saline). However, TNF-α infusion lowered plasma GLP-1 during high-dose GLP-1 infusion (P <.001). Conclusions: TNF-α induces systemic inflammation and reduces plasma GLP-1, thereby reducing the suppression of EGP during GLP-1 infusion. This may have clinical relevance if GLP-1 analog drugs are used for the treatment of hyperglycemia in critically ill patients.

AB - Context: Glucagon-like peptide-1 (GLP-1) analogs have recently been promoted as antihyperglycemic agents in critically ill patients with systemic inflammation, but the effects of TNF-α on glucose metabolism during GLP-1 administration are unknown. Objective: The objective of the study was to determine whether the infusion of TNF-α at high physiological levels impairs GLP-1's effects on glucose metabolism. Design: This was a randomized, controlled, cross-over trial. Setting: The study was conducted at a hospital clinical research laboratory. Participants: Twelve healthy males (aged 24 ± 3 y; body mass index 22.9 ± 1.3 kg/m2). Interventions: After an overnight fast, either saline (0.9%) or recombinant human TNF-α (1000 ng/m2·h) was infused from t = 0-6 hours. At t = 2 hours, GLP-1 infusion (0.5 pmol/kg·min) began. From t=4-6 hours, the GLP-1 infusion rate was increased to 1.2 pmol/kg·min. Plasma glucose was clamped at 5 mmol/L throughout via a variable rate 20% dextrose infusion. Trials were 7-14 days apart. Main Outcome Measures: Endogenous glucose production (EGP) was measured by the [6,6-2H2]glucose isotope tracer dilution method. Results: GLP-1 infusion suppressed plasma glucagon (P<.01), elevated plasma insulin, and C-peptide (P <.01) and suppressed EGP (P <.001) during the saline infusion. In contrast, the infusion of TNF-α increased plasma TNF-α and IL-6, elevated body temperature, and blunted the GLP-1-induced suppression of EGP during high-dose GLP-1 infusion (all P <.05, TNF-α vs saline). However, TNF-α infusion lowered plasma GLP-1 during high-dose GLP-1 infusion (P <.001). Conclusions: TNF-α induces systemic inflammation and reduces plasma GLP-1, thereby reducing the suppression of EGP during GLP-1 infusion. This may have clinical relevance if GLP-1 analog drugs are used for the treatment of hyperglycemia in critically ill patients.

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DO - 10.1210/jc.2014-4244

M3 - Journal article

C2 - 25675385

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JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 4

ER -

The effects of TNF-α on GLP-1-stimulated plasma glucose kinetics

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