Direct effects of locally administered lipopolysaccharide on glucose, lipid, and protein metabolism in the placebo-controlled, bilaterally infused human leg

Mads Buhl; Ermina Bosnjak; Mikkel H. Vendelbo; Jakob Gjedsted; Roni R. Nielsen; Thomas K. Hafstrøm; Esben T. Vestergaard; Niels Jessen; Else Tønnesen; Andreas B. Møller; Steen B. Pedersen; Henriette Pilegaard; Rasmus Sjørup Biensø; Jens O.L. Jørgensen; Niels Møller

doi:10.1210/jc.2012-3836

Direct effects of locally administered lipopolysaccharide on glucose, lipid, and protein metabolism in the placebo-controlled, bilaterally infused human leg

Mads Buhl, Ermina Bosnjak^*, Mikkel H. Vendelbo, Jakob Gjedsted, Roni R. Nielsen, Thomas K. Hafstrøm, Esben T. Vestergaard, Niels Jessen, Else Tønnesen, Andreas B. Møller, Steen B. Pedersen, Henriette Pilegaard, Rasmus Sjørup Biensø, Jens O.L. Jørgensen, Niels Møller

^*Corresponding author for this work

Molecular Integrative Physiology

13 Citations (Scopus)

Abstract

Context: Accumulating evidence suggests that chronic exposure to lipopolysaccharide (LPS, endotoxin) maycreate a constant low-grade inflammation, leading to insulin resistance and diabetes. All previous human studies assessing the metabolic actions of LPS have used systemic administration, making discrimination between direct and indirect effects impossible. Objective: We sought to define the direct, placebo-controlled effects of LPS on insulin resistance and protein and lipid metabolism in the infused human leg without systemic interference from cytokines and stress hormones. Design: This was a randomized, placebo-controlled, single-blinded study. Participants and Intervention: We studied 8 healthy volunteers with bilateral femoral vein and artery catheters during a 3-hour basal and 3-hour hyperinsulinemic-euglycemic clamp period with bilateral muscle biopsies in each period during infusion with saline and LPS. Results: Overall, LPS perfusion significantly decreased leg glucose uptake, and during the clamp LPS decreased glucose arteriovenous differences (0.65 ± 0.07 mmol/L vs 0.73 ± 0.08 mmol/L). Net palmitate release was increased by LPS, and secondary post hoc testing indicated increased palmitate isotopic dilution, although primary ANOVA tests did not reveal significant dilution. Leg blood flows, phenylalanine, lactate kinetics, cytokines, and intramyocellular insulin signaling were not affected by LPS. LPS thus directly inhibits insulin-stimulated glucose uptake and increases palmitate release in the perfused human leg without detectable effects on amino acid metabolism. Conclusions: These data strongly suggest that the primary metabolic effect of LPS is increased lipolysis and muscle insulin resistance, which, together with secondary insulin resistance, caused by systemic cytokine and stress hormone release may lead to overt glucose intolerance and diabetes.

Original language	English
Journal	Journal of Clinical Endocrinology and Metabolism
Volume	98
Issue number	5
Pages (from-to)	2090-2099
Number of pages	10
ISSN	0021-972X
DOIs	https://doi.org/10.1210/jc.2012-3836
Publication status	Published - 2013

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Buhl, M., Bosnjak, E., Vendelbo, M. H., Gjedsted, J., Nielsen, R. R., Hafstrøm, T. K., Vestergaard, E. T., Jessen, N., Tønnesen, E., Møller, A. B., Pedersen, S. B., Pilegaard, H., Biensø, R. S., Jørgensen, J. O. L., & Møller, N. (2013). Direct effects of locally administered lipopolysaccharide on glucose, lipid, and protein metabolism in the placebo-controlled, bilaterally infused human leg. Journal of Clinical Endocrinology and Metabolism, 98(5), 2090-2099. https://doi.org/10.1210/jc.2012-3836

Direct effects of locally administered lipopolysaccharide on glucose, lipid, and protein metabolism in the placebo-controlled, bilaterally infused human leg. / Buhl, Mads; Bosnjak, Ermina; Vendelbo, Mikkel H. et al.
In: Journal of Clinical Endocrinology and Metabolism, Vol. 98, No. 5, 2013, p. 2090-2099.

Research output: Contribution to journal › Journal article › Research › peer-review

Buhl, M, Bosnjak, E, Vendelbo, MH, Gjedsted, J, Nielsen, RR, Hafstrøm, TK, Vestergaard, ET, Jessen, N, Tønnesen, E, Møller, AB, Pedersen, SB, Pilegaard, H, Biensø, RS, Jørgensen, JOL & Møller, N 2013, 'Direct effects of locally administered lipopolysaccharide on glucose, lipid, and protein metabolism in the placebo-controlled, bilaterally infused human leg', Journal of Clinical Endocrinology and Metabolism, vol. 98, no. 5, pp. 2090-2099. https://doi.org/10.1210/jc.2012-3836

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title = "Direct effects of locally administered lipopolysaccharide on glucose, lipid, and protein metabolism in the placebo-controlled, bilaterally infused human leg",

abstract = "Context: Accumulating evidence suggests that chronic exposure to lipopolysaccharide (LPS, endotoxin) maycreate a constant low-grade inflammation, leading to insulin resistance and diabetes. All previous human studies assessing the metabolic actions of LPS have used systemic administration, making discrimination between direct and indirect effects impossible. Objective: We sought to define the direct, placebo-controlled effects of LPS on insulin resistance and protein and lipid metabolism in the infused human leg without systemic interference from cytokines and stress hormones. Design: This was a randomized, placebo-controlled, single-blinded study. Participants and Intervention: We studied 8 healthy volunteers with bilateral femoral vein and artery catheters during a 3-hour basal and 3-hour hyperinsulinemic-euglycemic clamp period with bilateral muscle biopsies in each period during infusion with saline and LPS. Results: Overall, LPS perfusion significantly decreased leg glucose uptake, and during the clamp LPS decreased glucose arteriovenous differences (0.65 ± 0.07 mmol/L vs 0.73 ± 0.08 mmol/L). Net palmitate release was increased by LPS, and secondary post hoc testing indicated increased palmitate isotopic dilution, although primary ANOVA tests did not reveal significant dilution. Leg blood flows, phenylalanine, lactate kinetics, cytokines, and intramyocellular insulin signaling were not affected by LPS. LPS thus directly inhibits insulin-stimulated glucose uptake and increases palmitate release in the perfused human leg without detectable effects on amino acid metabolism. Conclusions: These data strongly suggest that the primary metabolic effect of LPS is increased lipolysis and muscle insulin resistance, which, together with secondary insulin resistance, caused by systemic cytokine and stress hormone release may lead to overt glucose intolerance and diabetes.",

author = "Mads Buhl and Ermina Bosnjak and Vendelbo, {Mikkel H.} and Jakob Gjedsted and Nielsen, {Roni R.} and Hafstr{\o}m, {Thomas K.} and Vestergaard, {Esben T.} and Niels Jessen and Else T{\o}nnesen and M{\o}ller, {Andreas B.} and Pedersen, {Steen B.} and Henriette Pilegaard and Biens{\o}, {Rasmus Sj{\o}rup} and J{\o}rgensen, {Jens O.L.} and Niels M{\o}ller",

year = "2013",

doi = "10.1210/jc.2012-3836",

language = "English",

volume = "98",

pages = "2090--2099",

journal = "Journal of Clinical Endocrinology and Metabolism",

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T1 - Direct effects of locally administered lipopolysaccharide on glucose, lipid, and protein metabolism in the placebo-controlled, bilaterally infused human leg

AU - Buhl, Mads

AU - Bosnjak, Ermina

AU - Vendelbo, Mikkel H.

AU - Gjedsted, Jakob

AU - Nielsen, Roni R.

AU - Hafstrøm, Thomas K.

AU - Vestergaard, Esben T.

AU - Jessen, Niels

AU - Tønnesen, Else

AU - Møller, Andreas B.

AU - Pedersen, Steen B.

AU - Pilegaard, Henriette

AU - Biensø, Rasmus Sjørup

AU - Jørgensen, Jens O.L.

AU - Møller, Niels

PY - 2013

Y1 - 2013

N2 - Context: Accumulating evidence suggests that chronic exposure to lipopolysaccharide (LPS, endotoxin) maycreate a constant low-grade inflammation, leading to insulin resistance and diabetes. All previous human studies assessing the metabolic actions of LPS have used systemic administration, making discrimination between direct and indirect effects impossible. Objective: We sought to define the direct, placebo-controlled effects of LPS on insulin resistance and protein and lipid metabolism in the infused human leg without systemic interference from cytokines and stress hormones. Design: This was a randomized, placebo-controlled, single-blinded study. Participants and Intervention: We studied 8 healthy volunteers with bilateral femoral vein and artery catheters during a 3-hour basal and 3-hour hyperinsulinemic-euglycemic clamp period with bilateral muscle biopsies in each period during infusion with saline and LPS. Results: Overall, LPS perfusion significantly decreased leg glucose uptake, and during the clamp LPS decreased glucose arteriovenous differences (0.65 ± 0.07 mmol/L vs 0.73 ± 0.08 mmol/L). Net palmitate release was increased by LPS, and secondary post hoc testing indicated increased palmitate isotopic dilution, although primary ANOVA tests did not reveal significant dilution. Leg blood flows, phenylalanine, lactate kinetics, cytokines, and intramyocellular insulin signaling were not affected by LPS. LPS thus directly inhibits insulin-stimulated glucose uptake and increases palmitate release in the perfused human leg without detectable effects on amino acid metabolism. Conclusions: These data strongly suggest that the primary metabolic effect of LPS is increased lipolysis and muscle insulin resistance, which, together with secondary insulin resistance, caused by systemic cytokine and stress hormone release may lead to overt glucose intolerance and diabetes.

AB - Context: Accumulating evidence suggests that chronic exposure to lipopolysaccharide (LPS, endotoxin) maycreate a constant low-grade inflammation, leading to insulin resistance and diabetes. All previous human studies assessing the metabolic actions of LPS have used systemic administration, making discrimination between direct and indirect effects impossible. Objective: We sought to define the direct, placebo-controlled effects of LPS on insulin resistance and protein and lipid metabolism in the infused human leg without systemic interference from cytokines and stress hormones. Design: This was a randomized, placebo-controlled, single-blinded study. Participants and Intervention: We studied 8 healthy volunteers with bilateral femoral vein and artery catheters during a 3-hour basal and 3-hour hyperinsulinemic-euglycemic clamp period with bilateral muscle biopsies in each period during infusion with saline and LPS. Results: Overall, LPS perfusion significantly decreased leg glucose uptake, and during the clamp LPS decreased glucose arteriovenous differences (0.65 ± 0.07 mmol/L vs 0.73 ± 0.08 mmol/L). Net palmitate release was increased by LPS, and secondary post hoc testing indicated increased palmitate isotopic dilution, although primary ANOVA tests did not reveal significant dilution. Leg blood flows, phenylalanine, lactate kinetics, cytokines, and intramyocellular insulin signaling were not affected by LPS. LPS thus directly inhibits insulin-stimulated glucose uptake and increases palmitate release in the perfused human leg without detectable effects on amino acid metabolism. Conclusions: These data strongly suggest that the primary metabolic effect of LPS is increased lipolysis and muscle insulin resistance, which, together with secondary insulin resistance, caused by systemic cytokine and stress hormone release may lead to overt glucose intolerance and diabetes.

U2 - 10.1210/jc.2012-3836

DO - 10.1210/jc.2012-3836

M3 - Journal article

C2 - 23543661

AN - SCOPUS:84877711759

SN - 0021-972X

VL - 98

SP - 2090

EP - 2099

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 5

ER -

Direct effects of locally administered lipopolysaccharide on glucose, lipid, and protein metabolism in the placebo-controlled, bilaterally infused human leg

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