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At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
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Critical Care
Published in: Critical Care 1/2016

Open Access 01-12-2016 | Research

Association of diabetes and diabetes treatment with the host response in critically ill sepsis patients

Authors: Lonneke A. van Vught, Brendon P. Scicluna, Arie J. Hoogendijk, Maryse A. Wiewel, Peter M. C. Klein Klouwenberg, Olaf L. Cremer, Janneke Horn, Peter Nürnberg, Marc M. J. Bonten, Marcus J. Schultz, Tom van der Poll

Published in: Critical Care | Issue 1/2016

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Abstract

Background

Diabetes is associated with chronic inflammation and activation of the vascular endothelium and the coagulation system, which in a more acute manner are also observed in sepsis. Insulin and metformin exert immune modulatory effects. In this study, we aimed to determine the association of diabetes and preadmission insulin and metformin use with sepsis outcome and host response.

Methods

We evaluated 1104 patients with sepsis, admitted to the intensive care unit and stratified according to the presence or absence of diabetes mellitus. The host response was examined by a targeted approach (by measuring 15 plasma biomarkers reflective of pathways implicated in sepsis pathogenesis) and an unbiased approach (by analyzing whole genome expression profiles in blood leukocytes).

Results

Diabetes mellitus was not associated with differences in sepsis presentation or mortality up to 90 days after admission. Plasma biomarker measurements revealed signs of systemic inflammation, and strong endothelial and coagulation activation in patients with sepsis, none of which were altered in those with diabetes. Patients with and without diabetes mellitus, who had sepsis demonstrated similar transcriptional alterations, comprising 74 % of the expressed gene content and involving over-expression of genes associated with pro-inflammatory, anti-inflammatory, Toll-like receptor and metabolic signaling pathways and under-expression of genes associated with T cell signaling pathways. Amongst patients with diabetes mellitus and sepsis, preadmission treatment with insulin or metformin was not associated with an altered sepsis outcome or host response.

Conclusions

Neither diabetes mellitus nor preadmission insulin or metformin use are associated with altered disease presentation, outcome or host response in patients with sepsis requiring intensive care.
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Literature
1.
2.
Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348(16):1546–54.CrossRefPubMed
3.
Shah BR, Hux JE. Quantifying the risk of infectious diseases for people with diabetes. Diabetes Care. 2003;26(2):510–3.CrossRefPubMed
4.
Koh GC, Peacock SJ, van der Poll T, Wiersinga WJ. The impact of diabetes on the pathogenesis of sepsis. Eur J Clin Microbiol Infect Dis. 2012;31(4):379–88.CrossRefPubMed
5.
Lontchi-Yimagou E, Sobngwi E, Matsha TE, Kengne AP. Diabetes mellitus and inflammation. Curr Diab Rep. 2013;13(3):435–44.CrossRefPubMed
6.
7.
Chang CW, Kok VC, Tseng TC, Horng JT, Liu CE. Diabetic patients with severe sepsis admitted to intensive care unit do not fare worse than non-diabetic patients: a nationwide population-based cohort study. PLoS One. 2012;7(12), e50729.CrossRefPubMedPubMedCentral
8.
Schuetz P, Jones AE, Howell MD, Trzeciak S, Ngo L, Younger JG, Aird W, Shapiro NI. Diabetes is not associated with increased mortality in emergency department patients with sepsis. Ann Emerg Med. 2011;58(5):438–44.CrossRefPubMedPubMedCentral
9.
Stegenga ME, Vincent JL, Vail GM, Xie J, Haney DJ, Williams MD, Bernard GR, van der Poll T. Diabetes does not alter mortality or hemostatic and inflammatory responses in patients with severe sepsis. Crit Care Med. 2010;38(2):539–45.CrossRefPubMed
10.
Vincent JL, Preiser JC, Sprung CL, Moreno R, Sakr Y. Insulin-treated diabetes is not associated with increased mortality in critically ill patients. Crit Care. 2010;14(1):R12.CrossRefPubMedPubMedCentral
11.
Schuetz P, Yano K, Sorasaki M, Ngo L, St Hilaire M, Lucas JM, Aird W, Shapiro NI. Influence of diabetes on endothelial cell response during sepsis. Diabetologia. 2011;54(5):996–1003.CrossRefPubMed
12.
Dandona P, Aljada A, Mohanty P, Ghanim H, Hamouda W, Assian E, Ahmad S. Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab. 2001;86(7):3257–65.PubMed
13.
Jeschke MG, Klein D, Bolder U, Einspanier R. Insulin attenuates the systemic inflammatory response in endotoxemic rats. Endocrinology. 2004;145(9):4084–93.CrossRefPubMed
14.
Stegenga ME, van der Crabben SN, Blumer RM, Levi M, Meijers JC, Serlie MJ, Tanck MW, Sauerwein HP, van der Poll T. Hyperglycemia enhances coagulation and reduces neutrophil degranulation, whereas hyperinsulinemia inhibits fibrinolysis during human endotoxemia. Blood. 2008;112(1):82–9.CrossRefPubMedPubMedCentral
15.
Stegenga ME, van der Crabben SN, Dessing MC, Pater JM, van den Pangaart PS, de Vos AF, Tanck MW, Roos D, Sauerwein HP, van der Poll T. Effect of acute hyperglycaemia and/or hyperinsulinaemia on proinflammatory gene expression, cytokine production and neutrophil function in humans. Diabet Med. 2008;25(2):157–64.CrossRefPubMedPubMedCentral
16.
Isoda K, Young JL, Zirlik A, MacFarlane LA, Tsuboi N, Gerdes N, Schonbeck U, Libby P. Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells. Arterioscler Thromb Vasc Biol. 2006;26(3):611–7.CrossRefPubMed
17.
Kim J, Kwak HJ, Cha JY, Jeong YS, Rhee SD, Kim KR, Cheon HG. Metformin suppresses lipopolysaccharide (LPS)-induced inflammatory response in murine macrophages via activating transcription factor-3 (ATF-3) induction. J Biol Chem. 2014;289(33):23246–55.CrossRefPubMedPubMedCentral
18.
Vasamsetti SB, Karnewar S, Kanugula AK, Thatipalli AR, Kumar JM, Kotamraju S. Metformin inhibits monocyte-to-macrophage differentiation via AMPK-mediated inhibition of STAT3 activation: potential role in atherosclerosis. Diabetes. 2015;64(6):2028–41.CrossRefPubMed
19.
Klein Klouwenberg PM, Ong DS, Bos LD, de Beer FM, van Hooijdonk RT, Huson MA, Straat M, van Vught LA, Wieske L, Horn J, et al. Interobserver agreement of Centers for Disease Control and Prevention criteria for classifying infections in critically ill patients. Crit Care Med. 2013;41(10):2373–8.CrossRefPubMed
20.
Scicluna BP, Klein Klouwenberg PM, van Vught LA, Wiewel MA, Ong DS, Zwinderman AH, Franitza M, Toliat MR, Nurnberg P, Hoogendijk AJ, et al. A molecular biomarker to diagnose community-acquired pneumonia on intensive care unit admission. Am J Respir Crit Care Med. 2015;192(7):826–35.CrossRefPubMed
21.
van Vught LA, Klein Klouwenberg PM, Spitoni C, Scicluna BP, Wiewel MA, Horn J, Schultz MJ, Nurnberg P, Bonten MJ, Cremer OL, van der Poll T, Consortium M. Incidence, Risk Factors, and Attributable Mortality of Secondary Infections in the Intensive Care Unit After Admission for Sepsis. JAMA. 2016;315(14):1469–1479.
22.
Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003;31(4):1250–6.CrossRefPubMed
23.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373–83.CrossRefPubMed
24.
Zimmerman JE, Kramer AA, McNair DS, Malila FM. Acute Physiology and Chronic Health Evaluation (APACHE) IV: hospital mortality assessment for today’s critically ill patients. Crit Care Med. 2006;34(5):1297–310.CrossRefPubMed
25.
Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22(7):707–10.CrossRefPubMed
26.
Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA. 2014;311(13):1308–16.CrossRefPubMed
27.
Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, Acute Dialysis Quality Initiative. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8(4):R204–12.CrossRefPubMedPubMedCentral
28.
Force ADT, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307(23):2526–33.
29.
Bourgon R, Gentleman R, Huber W. Independent filtering increases detection power for high-throughput experiments. Proc Natl Acad Sci USA. 2010;107(21):9546–51.CrossRefPubMedPubMedCentral
30.
Johnson WE, Li C, Rabinovic A. Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics. 2007;8(1):118–27.CrossRefPubMed
31.
Smyth GK. Limma: linear models for microarray data. Bioinformatics and Computational Biology Solutions using R; Springer. 2005. p. 397–420.
32.
33.
Kornum JB, Thomsen RW, Riis A, Lervang HH, Schonheyder HC, Sorensen HT. Type 2 diabetes and pneumonia outcomes: a population-based cohort study. Diabetes Care. 2007;30(9):2251–7.CrossRefPubMed
34.
Thomsen RW, Hundborg HH, Lervang HH, Johnsen SP, Schonheyder HC, Sorensen HT. Diabetes mellitus as a risk and prognostic factor for community-acquired bacteremia due to enterobacteria: a 10-year, population-based study among adults. Clin Infect Dis. 2005;40(4):628–31.CrossRefPubMed
35.
Graham BB, Keniston A, Gajic O, Trillo Alvarez CA, Medvedev S, Douglas IS. Diabetes mellitus does not adversely affect outcomes from a critical illness. Crit Care Med. 2010;38(1):16–24.CrossRefPubMed
36.
Yende S, van der Poll T, Lee M, Huang DT, Newman AB, Kong L, Kellum JA, Harris TB, Bauer D, Satterfield S, et al. The influence of pre-existing diabetes mellitus on the host immune response and outcome of pneumonia: analysis of two multicentre cohort studies. Thorax. 2010;65(10):870–7.CrossRefPubMedPubMedCentral
37.
Opal SM, van der Poll T. Endothelial barrier dysfunction in septic shock. J Intern Med. 2015;277(3):277–93.CrossRefPubMed
38.
Bertoluci MC, Ce GV, da Silva AM, Wainstein MV, Boff W, Punales M. Endothelial dysfunction as a predictor of cardiovascular disease in type 1 diabetes. World J Diabetes. 2015;6(5):679–92.CrossRefPubMedPubMedCentral
39.
Morigi M, Angioletti S, Imberti B, Donadelli R, Micheletti G, Figliuzzi M, Remuzzi A, Zoja C, Remuzzi G. Leukocyte-endothelial interaction is augmented by high glucose concentrations and hyperglycemia in a NF-kB-dependent fashion. J Clin Invest. 1998;101(9):1905–15.CrossRefPubMedPubMedCentral
40.
Duncan AI, Koch CG, Xu M, Manlapaz M, Batdorf B, Pitas G, Starr N. Recent metformin ingestion does not increase in-hospital morbidity or mortality after cardiac surgery. Anesth Analg. 2007;104(1):42–50.CrossRefPubMed
41.
Christiansen C, Johansen M, Christensen S, O’Brien JM, Tonnesen E, Sorensen H. Preadmission metformin use and mortality among intensive care patients with diabetes: a cohort study. Crit Care. 2013;17(5):R192.CrossRefPubMedPubMedCentral
Metadata
Title
Association of diabetes and diabetes treatment with the host response in critically ill sepsis patients
Authors
Lonneke A. van Vught
Brendon P. Scicluna
Arie J. Hoogendijk
Maryse A. Wiewel
Peter M. C. Klein Klouwenberg
Olaf L. Cremer
Janneke Horn
Peter Nürnberg
Marc M. J. Bonten
Marcus J. Schultz
Tom van der Poll
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2016
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-016-1429-8

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