Glyburide is anti-inflammatory and associated with reduced mortality in melioidosis

Gavin C.K.W. Koh; Rapeephan R. Maude; M. Fernanda Schreiber; Direk Limmathurotsakul; W. Joost Wiersinga; Vanaporn Wuthiekanun; Sue J. Lee; Weera Mahavanakul; Wipada Chaowagul; Wirongrong Chierakul; Nicholas J. White; Tom Van Der Poll; Nicholas P.J. Day; Gordon Dougan; Sharon J. Peacock

doi:10.1093/cid/ciq192

Glyburide is anti-inflammatory and associated with reduced mortality in melioidosis

Gavin C.K.W. Koh, Rapeephan R. Maude, M. Fernanda Schreiber, Direk Limmathurotsakul, W. Joost Wiersinga, Vanaporn Wuthiekanun, Sue J. Lee, Weera Mahavanakul, Wipada Chaowagul, Wirongrong Chierakul, Nicholas J. White, Tom Van Der Poll, Nicholas P.J. Day, Gordon Dougan, Sharon J. Peacock

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Abstract

Background. Patients with diabetes mellitus are more prone to bacterial sepsis, but there are conflicting data on whether outcomes are worse in diabetics after presentation with sepsis. Glyburide is an oral hypoglycemic agent used to treat diabetes mellitus. This KATP-channel blocker and broad-spectrum ATP-binding cassette (ABC) transporter inhibitor has broad-ranging effects on the immune system, including inhibition of inflammasome assembly and would be predicted to influence the host response to infection.Methods. We studied a cohort of 1160 patients with gram-negative sepsis caused by a single pathogen (Burkholderia pseudomallei), 410 (35%) of whom were known to have diabetes. We subsequently studied prospectively diabetics with B. pseudomallei infection (n = 20) to compare the gene expression profile of peripheral whole blood leukocytes in patients who were taking glyburide against those not taking any sulfonylurea.Results. Survival was greater in diabetics than in nondiabetics (38% vs 45%, respectively, P =. 04), but the survival benefit was confined to the patient group taking glyburide (adjusted odds ratio. 47, 95% confidence interval. 28-.74, P =. 005). We identified differential expression of 63 immune-related genes (P =. 001) in patients taking glyburide, the sum effect of which we predict to be antiinflammatory in the glyburide group.Conclusions. We present observational evidence for a glyburide-associated benefit during human melioidosis and correlate this with an anti-inflammatory effect of glyburide on the immune system.

Original language	English
Pages (from-to)	717-725
Number of pages	9
Journal	Clinical Infectious Diseases
Volume	52
Issue number	6
DOIs	https://doi.org/10.1093/cid/ciq192
Publication status	Published - 15 Mar 2011
Externally published	Yes

Bibliographical note

Funding Information:
Financial support. This work was supported by the Wellcome Trust of Great Britain (G.C.K.W.K., R.R.,M.F.S., D.L., V.W., S.J.L., W. Chaowagul, W. Chierakul, N.J.W., N.P.J.D., G.D., and S.J.P.); Foundation for 385 the National Institutes of Health (Grand Challenges in Global Health Initiative to M.F.S.); The Netherlands Organisation for Scientific Research (W.J.W.

Funding Information:
and T.V.D.P.); Sappasthiprasong Hospital (W.M.); The AMC Research Council, BEGETU, the European Union, de Landsteiner Stichting voor Bloedtransfusie 390 Research, and de Nederlands Astma Fonds (T.v.d.P.); The Bill & Melinda Gates Foundation (N.P.J.D. and N.J.W.); and the National Institutes of Health, Health Protection Agency (UK), European Union, and the UK Clinical Research Collaboration (S.J.P.).

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Koh, G. C. K. W., Maude, R. R., Schreiber, M. F., Limmathurotsakul, D., Wiersinga, W. J., Wuthiekanun, V., Lee, S. J., Mahavanakul, W., Chaowagul, W., Chierakul, W., White, N. J., Van Der Poll, T., Day, N. P. J., Dougan, G., & Peacock, S. J. (2011). Glyburide is anti-inflammatory and associated with reduced mortality in melioidosis. Clinical Infectious Diseases, 52(6), 717-725. https://doi.org/10.1093/cid/ciq192

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title = "Glyburide is anti-inflammatory and associated with reduced mortality in melioidosis",

abstract = "Background. Patients with diabetes mellitus are more prone to bacterial sepsis, but there are conflicting data on whether outcomes are worse in diabetics after presentation with sepsis. Glyburide is an oral hypoglycemic agent used to treat diabetes mellitus. This KATP-channel blocker and broad-spectrum ATP-binding cassette (ABC) transporter inhibitor has broad-ranging effects on the immune system, including inhibition of inflammasome assembly and would be predicted to influence the host response to infection.Methods. We studied a cohort of 1160 patients with gram-negative sepsis caused by a single pathogen (Burkholderia pseudomallei), 410 (35%) of whom were known to have diabetes. We subsequently studied prospectively diabetics with B. pseudomallei infection (n = 20) to compare the gene expression profile of peripheral whole blood leukocytes in patients who were taking glyburide against those not taking any sulfonylurea.Results. Survival was greater in diabetics than in nondiabetics (38% vs 45%, respectively, P =. 04), but the survival benefit was confined to the patient group taking glyburide (adjusted odds ratio. 47, 95% confidence interval. 28-.74, P =. 005). We identified differential expression of 63 immune-related genes (P =. 001) in patients taking glyburide, the sum effect of which we predict to be antiinflammatory in the glyburide group.Conclusions. We present observational evidence for a glyburide-associated benefit during human melioidosis and correlate this with an anti-inflammatory effect of glyburide on the immune system.",

author = "Koh, {Gavin C.K.W.} and Maude, {Rapeephan R.} and Schreiber, {M. Fernanda} and Direk Limmathurotsakul and Wiersinga, {W. Joost} and Vanaporn Wuthiekanun and Lee, {Sue J.} and Weera Mahavanakul and Wipada Chaowagul and Wirongrong Chierakul and White, {Nicholas J.} and {Van Der Poll}, Tom and Day, {Nicholas P.J.} and Gordon Dougan and Peacock, {Sharon J.}",

note = "Funding Information: Financial support. This work was supported by the Wellcome Trust of Great Britain (G.C.K.W.K., R.R.,M.F.S., D.L., V.W., S.J.L., W. Chaowagul, W. Chierakul, N.J.W., N.P.J.D., G.D., and S.J.P.); Foundation for 385 the National Institutes of Health (Grand Challenges in Global Health Initiative to M.F.S.); The Netherlands Organisation for Scientific Research (W.J.W. Funding Information: and T.V.D.P.); Sappasthiprasong Hospital (W.M.); The AMC Research Council, BEGETU, the European Union, de Landsteiner Stichting voor Bloedtransfusie 390 Research, and de Nederlands Astma Fonds (T.v.d.P.); The Bill & Melinda Gates Foundation (N.P.J.D. and N.J.W.); and the National Institutes of Health, Health Protection Agency (UK), European Union, and the UK Clinical Research Collaboration (S.J.P.).",

year = "2011",

month = mar,

day = "15",

doi = "10.1093/cid/ciq192",

language = "English",

volume = "52",

pages = "717--725",

journal = "Clinical Infectious Diseases",

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Koh, GCKW, Maude, RR, Schreiber, MF, Limmathurotsakul, D, Wiersinga, WJ, Wuthiekanun, V, Lee, SJ, Mahavanakul, W, Chaowagul, W, Chierakul, W, White, NJ, Van Der Poll, T, Day, NPJ, Dougan, G & Peacock, SJ 2011, 'Glyburide is anti-inflammatory and associated with reduced mortality in melioidosis', Clinical Infectious Diseases, vol. 52, no. 6, pp. 717-725. https://doi.org/10.1093/cid/ciq192

TY - JOUR

T1 - Glyburide is anti-inflammatory and associated with reduced mortality in melioidosis

AU - Koh, Gavin C.K.W.

AU - Maude, Rapeephan R.

AU - Schreiber, M. Fernanda

AU - Limmathurotsakul, Direk

AU - Wiersinga, W. Joost

AU - Wuthiekanun, Vanaporn

AU - Lee, Sue J.

AU - Mahavanakul, Weera

AU - Chaowagul, Wipada

AU - Chierakul, Wirongrong

AU - White, Nicholas J.

AU - Van Der Poll, Tom

AU - Day, Nicholas P.J.

AU - Dougan, Gordon

AU - Peacock, Sharon J.

N1 - Funding Information: Financial support. This work was supported by the Wellcome Trust of Great Britain (G.C.K.W.K., R.R.,M.F.S., D.L., V.W., S.J.L., W. Chaowagul, W. Chierakul, N.J.W., N.P.J.D., G.D., and S.J.P.); Foundation for 385 the National Institutes of Health (Grand Challenges in Global Health Initiative to M.F.S.); The Netherlands Organisation for Scientific Research (W.J.W. Funding Information: and T.V.D.P.); Sappasthiprasong Hospital (W.M.); The AMC Research Council, BEGETU, the European Union, de Landsteiner Stichting voor Bloedtransfusie 390 Research, and de Nederlands Astma Fonds (T.v.d.P.); The Bill & Melinda Gates Foundation (N.P.J.D. and N.J.W.); and the National Institutes of Health, Health Protection Agency (UK), European Union, and the UK Clinical Research Collaboration (S.J.P.).

PY - 2011/3/15

Y1 - 2011/3/15

N2 - Background. Patients with diabetes mellitus are more prone to bacterial sepsis, but there are conflicting data on whether outcomes are worse in diabetics after presentation with sepsis. Glyburide is an oral hypoglycemic agent used to treat diabetes mellitus. This KATP-channel blocker and broad-spectrum ATP-binding cassette (ABC) transporter inhibitor has broad-ranging effects on the immune system, including inhibition of inflammasome assembly and would be predicted to influence the host response to infection.Methods. We studied a cohort of 1160 patients with gram-negative sepsis caused by a single pathogen (Burkholderia pseudomallei), 410 (35%) of whom were known to have diabetes. We subsequently studied prospectively diabetics with B. pseudomallei infection (n = 20) to compare the gene expression profile of peripheral whole blood leukocytes in patients who were taking glyburide against those not taking any sulfonylurea.Results. Survival was greater in diabetics than in nondiabetics (38% vs 45%, respectively, P =. 04), but the survival benefit was confined to the patient group taking glyburide (adjusted odds ratio. 47, 95% confidence interval. 28-.74, P =. 005). We identified differential expression of 63 immune-related genes (P =. 001) in patients taking glyburide, the sum effect of which we predict to be antiinflammatory in the glyburide group.Conclusions. We present observational evidence for a glyburide-associated benefit during human melioidosis and correlate this with an anti-inflammatory effect of glyburide on the immune system.

AB - Background. Patients with diabetes mellitus are more prone to bacterial sepsis, but there are conflicting data on whether outcomes are worse in diabetics after presentation with sepsis. Glyburide is an oral hypoglycemic agent used to treat diabetes mellitus. This KATP-channel blocker and broad-spectrum ATP-binding cassette (ABC) transporter inhibitor has broad-ranging effects on the immune system, including inhibition of inflammasome assembly and would be predicted to influence the host response to infection.Methods. We studied a cohort of 1160 patients with gram-negative sepsis caused by a single pathogen (Burkholderia pseudomallei), 410 (35%) of whom were known to have diabetes. We subsequently studied prospectively diabetics with B. pseudomallei infection (n = 20) to compare the gene expression profile of peripheral whole blood leukocytes in patients who were taking glyburide against those not taking any sulfonylurea.Results. Survival was greater in diabetics than in nondiabetics (38% vs 45%, respectively, P =. 04), but the survival benefit was confined to the patient group taking glyburide (adjusted odds ratio. 47, 95% confidence interval. 28-.74, P =. 005). We identified differential expression of 63 immune-related genes (P =. 001) in patients taking glyburide, the sum effect of which we predict to be antiinflammatory in the glyburide group.Conclusions. We present observational evidence for a glyburide-associated benefit during human melioidosis and correlate this with an anti-inflammatory effect of glyburide on the immune system.

UR - http://www.scopus.com/inward/record.url?scp=79953764920&partnerID=8YFLogxK

U2 - 10.1093/cid/ciq192

DO - 10.1093/cid/ciq192

M3 - Article

C2 - 21293047

AN - SCOPUS:79953764920

SN - 1058-4838

VL - 52

SP - 717

EP - 725

JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

IS - 6

ER -

Glyburide is anti-inflammatory and associated with reduced mortality in melioidosis

Abstract

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