A human model of inflammatory cardio-metabolic dysfunction; a double blind placebo-controlled crossover trial

BACKGROUND: Chronic inflammation may contribute to insulin resistance (IR), metabolic syndrome and atherosclerosis although evidence of causality is lacking in humans. We hypothesized that very low-dose experimental endotoxemia would induce adipose tissue inflammation and systemic IR during a low-gr...

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Autores principales: Mehta, Nehal N, Heffron, Sean P, Patel, Parth N, Ferguson, Jane, Shah, Rachana D, Hinkle, Christine C, Krishnamoorthy, Parasuram, Shah, Rhia, Tabita-Martinez, Jennifer, Terembula, Karen, Master, Stephen R, Rickels, Michael R, Reilly, Muredach P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3477112/
https://www.ncbi.nlm.nih.gov/pubmed/22709547
http://dx.doi.org/10.1186/1479-5876-10-124
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author Mehta, Nehal N
Heffron, Sean P
Patel, Parth N
Ferguson, Jane
Shah, Rachana D
Hinkle, Christine C
Krishnamoorthy, Parasuram
Shah, Rhia
Tabita-Martinez, Jennifer
Terembula, Karen
Master, Stephen R
Rickels, Michael R
Reilly, Muredach P
author_facet Mehta, Nehal N
Heffron, Sean P
Patel, Parth N
Ferguson, Jane
Shah, Rachana D
Hinkle, Christine C
Krishnamoorthy, Parasuram
Shah, Rhia
Tabita-Martinez, Jennifer
Terembula, Karen
Master, Stephen R
Rickels, Michael R
Reilly, Muredach P
author_sort Mehta, Nehal N
collection PubMed
description BACKGROUND: Chronic inflammation may contribute to insulin resistance (IR), metabolic syndrome and atherosclerosis although evidence of causality is lacking in humans. We hypothesized that very low-dose experimental endotoxemia would induce adipose tissue inflammation and systemic IR during a low-grade but asymptomatic inflammatory response and thus provide an experimental model for future tests of pharmacologic and genomic modulation of cardio-metabolic traits in humans. METHODS: Ten healthy, human volunteers (50% male, 90% Caucasian, mean age 22.7 ± 3.8) were randomized in a double-masked, placebo-controlled, crossover study to separate 36-hour inpatient visits (placebo versus intravenous-LPS 0.6 ng/kg). We measured clinical symptoms via the McGill pain questionnaire and serial vital signs. Plasma and serum were collected for measurement of cytokines, C-reactive protein, insulin and glucose, serial whole blood & subcutaneous adipose tissue mRNA expression were measured by real-time PCR. HOMA-IR, a well-validated measure of IR was calculated to estimate insulin resistance, and frequently sampled intravenous glucose tolerance testing (FSIGTT) was performed to confirm an insulin resistant state. We performed ANOVA and within subject ANOVA to understand the differences in cytokines, adipose tissue inflammation and IR before and after LPS or placebo. RESULTS: There was no significant difference between placebo and LPS in clinical responses of symptom scores, body temperature or heart rate. However, low-dose endotoxemia induced a rapid and transient 25-fold induction of plasma TNF-alpha and 100-fold increase in plasma IL-6 (Figure 1B) (p < 0.001 for both) both peaking at two hours, followed by modest inflammation in adipose tissue with increases in mRNA levels of several inflammatory genes known to modulate adipose and systemic insulin resistance. Adipose tissue mRNA levels of IL-6 (peak 6-fold, ANOVA F = 27.5, p < 0.001) and TNF-alpha (peak 1.8-fold, F = 2.9, p = 0.01) increased with MCP-1 (peak 10-fold, F = 5.6, p < 0.01) and fractalkine (CX3CL1) (peak 15-fold, F = 13.3, p < 0.001). Finally, HOMA-IR was 32% higher following LPS compared to placebo (p < 0.01) and insulin sensitivity declined by 21% following LPS compared to placebo (p < 0.05). CONCLUSIONS: We present a low dose human endotoxemia model of inflammation which induces adipose tissue inflammation and systemic insulin resistance in the absence of overt clinical response. Such a model has the potential for broad and safe application in the study of novel therapeutics and genomic influences in cardio-metabolic disease.
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spelling pubmed-34771122012-10-20 A human model of inflammatory cardio-metabolic dysfunction; a double blind placebo-controlled crossover trial Mehta, Nehal N Heffron, Sean P Patel, Parth N Ferguson, Jane Shah, Rachana D Hinkle, Christine C Krishnamoorthy, Parasuram Shah, Rhia Tabita-Martinez, Jennifer Terembula, Karen Master, Stephen R Rickels, Michael R Reilly, Muredach P J Transl Med Research BACKGROUND: Chronic inflammation may contribute to insulin resistance (IR), metabolic syndrome and atherosclerosis although evidence of causality is lacking in humans. We hypothesized that very low-dose experimental endotoxemia would induce adipose tissue inflammation and systemic IR during a low-grade but asymptomatic inflammatory response and thus provide an experimental model for future tests of pharmacologic and genomic modulation of cardio-metabolic traits in humans. METHODS: Ten healthy, human volunteers (50% male, 90% Caucasian, mean age 22.7 ± 3.8) were randomized in a double-masked, placebo-controlled, crossover study to separate 36-hour inpatient visits (placebo versus intravenous-LPS 0.6 ng/kg). We measured clinical symptoms via the McGill pain questionnaire and serial vital signs. Plasma and serum were collected for measurement of cytokines, C-reactive protein, insulin and glucose, serial whole blood & subcutaneous adipose tissue mRNA expression were measured by real-time PCR. HOMA-IR, a well-validated measure of IR was calculated to estimate insulin resistance, and frequently sampled intravenous glucose tolerance testing (FSIGTT) was performed to confirm an insulin resistant state. We performed ANOVA and within subject ANOVA to understand the differences in cytokines, adipose tissue inflammation and IR before and after LPS or placebo. RESULTS: There was no significant difference between placebo and LPS in clinical responses of symptom scores, body temperature or heart rate. However, low-dose endotoxemia induced a rapid and transient 25-fold induction of plasma TNF-alpha and 100-fold increase in plasma IL-6 (Figure 1B) (p < 0.001 for both) both peaking at two hours, followed by modest inflammation in adipose tissue with increases in mRNA levels of several inflammatory genes known to modulate adipose and systemic insulin resistance. Adipose tissue mRNA levels of IL-6 (peak 6-fold, ANOVA F = 27.5, p < 0.001) and TNF-alpha (peak 1.8-fold, F = 2.9, p = 0.01) increased with MCP-1 (peak 10-fold, F = 5.6, p < 0.01) and fractalkine (CX3CL1) (peak 15-fold, F = 13.3, p < 0.001). Finally, HOMA-IR was 32% higher following LPS compared to placebo (p < 0.01) and insulin sensitivity declined by 21% following LPS compared to placebo (p < 0.05). CONCLUSIONS: We present a low dose human endotoxemia model of inflammation which induces adipose tissue inflammation and systemic insulin resistance in the absence of overt clinical response. Such a model has the potential for broad and safe application in the study of novel therapeutics and genomic influences in cardio-metabolic disease. BioMed Central 2012-06-18 /pmc/articles/PMC3477112/ /pubmed/22709547 http://dx.doi.org/10.1186/1479-5876-10-124 Text en Copyright ©2012 Mehta et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Mehta, Nehal N
Heffron, Sean P
Patel, Parth N
Ferguson, Jane
Shah, Rachana D
Hinkle, Christine C
Krishnamoorthy, Parasuram
Shah, Rhia
Tabita-Martinez, Jennifer
Terembula, Karen
Master, Stephen R
Rickels, Michael R
Reilly, Muredach P
A human model of inflammatory cardio-metabolic dysfunction; a double blind placebo-controlled crossover trial
title A human model of inflammatory cardio-metabolic dysfunction; a double blind placebo-controlled crossover trial
title_full A human model of inflammatory cardio-metabolic dysfunction; a double blind placebo-controlled crossover trial
title_fullStr A human model of inflammatory cardio-metabolic dysfunction; a double blind placebo-controlled crossover trial
title_full_unstemmed A human model of inflammatory cardio-metabolic dysfunction; a double blind placebo-controlled crossover trial
title_short A human model of inflammatory cardio-metabolic dysfunction; a double blind placebo-controlled crossover trial
title_sort human model of inflammatory cardio-metabolic dysfunction; a double blind placebo-controlled crossover trial
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3477112/
https://www.ncbi.nlm.nih.gov/pubmed/22709547
http://dx.doi.org/10.1186/1479-5876-10-124
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