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Proinflammatory biomarkers are associated with prediabetes in patients with schizophrenia

Published online by Cambridge University Press:  14 December 2020

Marco Møller Open the ORCID record for Marco Møller [Opens in a new window] ,
Simon Fredholm ,
Mathias E. Jensen ,
Gitta Wörtwein Open the ORCID record for Gitta Wörtwein [Opens in a new window] ,
Julie R. Larsen Open the ORCID record for Julie R. Larsen [Opens in a new window] ,
Tina Vilsbøll Open the ORCID record for Tina Vilsbøll [Opens in a new window] ,
Niels Ødum Open the ORCID record for Niels Ødum [Opens in a new window]  and
Anders Fink-Jensen Open the ORCID record for Anders Fink-Jensen [Opens in a new window]
Marco Møller
Affiliation:
Psychiatric Centre Copenhagen, Rigshospitalet, Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark
Simon Fredholm
Affiliation:
LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
Mathias E. Jensen
Affiliation:
Psychiatric Centre Copenhagen, Rigshospitalet, Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark
Gitta Wörtwein
Affiliation:
Psychiatric Centre Copenhagen, Rigshospitalet, Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark Section of Environmental Health, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
Julie R. Larsen
Affiliation:
Psychiatric Centre Copenhagen, Rigshospitalet, Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark
Tina Vilsbøll
Affiliation:
Steno Diabetes Center Copenhagen, Gentofte, Denmark Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Niels Ødum
Affiliation:
LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
Anders Fink-Jensen*
Affiliation:
Psychiatric Centre Copenhagen, Rigshospitalet, Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
*
*Author for correspondence: Anders Fink-Jensen, Email: [email protected]
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Abstract

Background

Treatment with antipsychotics is associated with an increased risk of type 2 diabetes mellitus (T2D), and increased levels of inflammatory biomarkers are present in patients with T2D. We previously demonstrated that the glucagon-like peptide-1 receptor agonist liraglutide significantly reduced glucometabolic disturbances and body weight in prediabetic, overweight/obese schizophrenia-spectrum disorder patients treated with clozapine or olanzapine. This study aims to assess the involvement of cytokines in the therapeutic effects of liraglutide.

Methods

Serum concentrations of 10 cytokines (interferon-γ [IFN-γ], tumor necrosis factor-α, interleukin 1β [IL-1β], IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, and IL-13) from fasting prediabetic and normal glucose-tolerant (NGT) patients with schizophrenia-spectrum disorders were measured using multiplexed immunoassays. Prediabetic patients were randomized to 16 weeks of treatment with liraglutide or placebo, and cytokines were measured again at the end of the treatment.

Results

IFN-γ (1.98 vs 1.17 pg/ml, P = .001), IL-4 (0.02 vs 0.01 pg/ml, P < .001), and IL-6 (0.73 vs 0.46 pg/ml, P < .001) were significantly higher in prediabetic (n = 77) vs NGT patients (n = 31). No significant changes in cytokine levels following treatment with liraglutide (n = 37) vs placebo (n = 40) were found.

Conclusion

Prediabetic vs NGT patients with schizophrenia treated with clozapine or olanzapine had increased serum levels of several proinflammatory cytokines, further substantiating the link between inflammation and T2D. Treatment with liraglutide did not affect the investigated cytokines. Further testing of these findings in larger numbers of individuals is needed.

Keywords

AntipsychoticsGLP-1inflammationliraglutideprediabetesschizophrenia
Type
Original Research
Information
CNS Spectrums , Volume 27 , Issue 3 , June 2022 , pp. 347 - 354
Copyright
© The Author(s), 2020. Published by Cambridge University Press

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References

Laursen, TM, Nordentoft, M, Mortensen, PB. Excess early mortality in schizophrenia. Annu Rev Clin Psychol. 2014;10:425–448. doi:10.1146/annurev-clinpsy-032813-153657 CrossRefGoogle Scholar
Correll, CU, Carvalho, AF, Fornaro, M, et al. Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large-scale meta-analysis of 3 211 768 patients and 113 383 368 controls. World Psychiatry. 2017;16(2):163–180. doi:10.1002/wps.20420 CrossRefGoogle ScholarPubMed
Hackinger, S, Prins, B, Mamakou, V, et al. Evidence for genetic contribution to the increased risk of type 2 diabetes in schizophrenia. Transl Psychiatry. 2018;8:252. doi:10.1038/s41398-018-0304-6 CrossRefGoogle Scholar
Henderson, DC, Vincenzi, B, Andrea, N V, Ulloa, M, Copeland, PM. Diabetes and psychotic disorders 2 pathophysiological mechanisms of increased cardiometabolic risk in people with schizophrenia and other severe mental illnesses. Lancet Psychiatry. 2015;2(5):452–464. www.thelancet.com/psychiatry.CrossRefGoogle Scholar
Pillinger, T, Beck, K, Gobjila, C, Donocik, JG, Jauhar, S, Howes, OD. Impaired glucose homeostasis in first-episode schizophrenia. JAMA Psychiatry. 2017;74(3):261. doi:10.1001/jamapsychiatry.2016.3803 CrossRefGoogle ScholarPubMed
De Hert, M, Detraux, J, Van Winkel, R, Weiping Yu, W, Correll, CU. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol. 2011;8:114–126. doi:10.1038/nrendo.2011.156 CrossRefGoogle ScholarPubMed
Vancampfort, D, Stubbs, B, Mitchell, AJ, et al. Risk of metabolic syndrome and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder: a systematic review and meta-analysis. World Psychiatry. 2015;14(3):339–347. doi:10.1002/wps.20252 CrossRefGoogle ScholarPubMed
Vancampfort, D, Correll, CU, Galling, B, et al. Diabetes mellitus in people with schizophrenia, bipolar disorder and major depressive disorder: a systematic review and large scale meta-analysis. World Psychiatry. 2016;15(2):166–174. doi:10.1002/wps.20309 CrossRefGoogle ScholarPubMed
Rajkumar, AP, Psych, MRC, Horsdal, HT, et al. Endogenous and antipsychotic-related risks for diabetes mellitus in young people with schizophrenia: a Danish population-based cohort study. Am J Psychiatry. 2017;174(7):686–694. doi:10.1176/appi.ajp.2016.16040442 CrossRefGoogle ScholarPubMed
Leucht, S, Cipriani, A, Spineli, L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382(9896):951–962. doi:10.1016/S0140-6736(13)60733-3 CrossRefGoogle ScholarPubMed
Vilsbøll, T, Krarup, T, Madsbad, S, Holst, JJ. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept. 2003;114(2–3):115–121. doi:10.1016/S0167-0115(03)00111-3 CrossRefGoogle Scholar
Holst, JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87(4):1409–1439. doi:10.1152/physrev.00034.2006 CrossRefGoogle ScholarPubMed
Holst, JJ. Incretin hormones and the satiation signal. Int J Obes. 2013;37(9):1161–1168. doi:10.1038/ijo.2012.208 CrossRefGoogle ScholarPubMed
Marso, SP, Daniels, GH, Brown-Frandsen, K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–322. doi:10.1056/NEJMoa1603827 CrossRefGoogle ScholarPubMed
Marso, SP, Bain, SC, Consoli, A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–1844. doi:10.1056/NEJMoa1607141 CrossRefGoogle ScholarPubMed
JR, Larsen, Vedtofte, L, MSL, Jakobsen, et al. Effect of liraglutide treatment on prediabetes and overweight or obesity in clozapine- or olanzapine-treated patients with schizophrenia spectrum disorder: a randomized clinical trial. JAMA Psychiatry. 2017;74(7):719–728. doi:10.1001/jamapsychiatry.2017.1220 Google Scholar
Siskind, D, Hahn, M, Correll, CU, et al. Glucagon-like peptide-1 receptor agonists for antipsychotic-associated cardio-metabolic risk factors: a systematic review and individual participant data meta-analysis. Diabetes Obes Metab. 2019;21(2):293–302. doi:10.1111/dom.13522 CrossRefGoogle ScholarPubMed
Pickup, JC, Crook, MA. Is type II diabetes mellitus a disease of the innate immune system? Diabetologia. 1998;41(10):1241–1248. doi:10.1007/s001250051058 CrossRefGoogle ScholarPubMed
Donath, MY. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discov. 2014;13(6):465–476. doi:10.1038/nrd4275 CrossRefGoogle Scholar
Eguchi, K, Nagai, R. Islet inflammation in type 2 diabetes and physiology. J Clin Invest. 2017;127(1):14–23. doi:10.1172/JCI88877 CrossRefGoogle ScholarPubMed
Pirola, L, Ferraz, JC. Role of pro- and anti-inflammatory phenomena in the physiopathology of type 2 diabetes and obesity. World J Biol Chem. 2017;8(2):120. doi:10.4331/wjbc.v8.i2.120 CrossRefGoogle ScholarPubMed
Akbari, M, Hassan-Zadeh, V. IL-6 signalling pathways and the development of type 2 diabetes. Inflammopharmacology. 2018;26(3):685–698. doi:10.1007/s10787-018-0458-0 CrossRefGoogle ScholarPubMed
Akash, MSH, Rehman, K, Liaqat, A. Tumor necrosis factor-alpha: role in development of insulin resistance and pathogenesis of type 2 diabetes mellitus. J Cell Biochem. 2018;119(1):105–110. doi:10.1002/jcb.26174 CrossRefGoogle ScholarPubMed
Herder, C, Dalmas, E, Böni-Schnetzler, M, Donath, MY. The IL-1 pathway in type 2 diabetes and cardiovascular complications. Trends Endocrinol Metab. 2015;26(10):551–563. doi:10.1016/J.TEM.2015.08.001 CrossRefGoogle ScholarPubMed
Liu, C, Feng, X, Li, Q, Wang, Y, Li, Q, Hua, M. Adiponectin, TNF-alpha and inflammatory cytokines and risk of type 2 diabetes: a systematic review and meta-analysis. Cytokine. 2015;86:100–109. doi:10.1016/j.cyto.2016.06.028 CrossRefGoogle Scholar
Larsen, CM, Faulenbach, M, Vaag, A, et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007;356(15):1517–1526. doi:10.1056/NEJMoa065213 CrossRefGoogle ScholarPubMed
Lucas, R, Parikh, SJ, Sridhar, S, et al. Cytokine profiling of young overweight and obese female African American adults with prediabetes. Cytokine. 2013;64(1):310–315. doi:10.1016/j.cyto.2013.05.025 CrossRefGoogle ScholarPubMed
Li, B, Feng, W-M, Shen, X-H, Qiu, W, Ye, G-F, Wang, Z. Analysis of inflammatory mediators in prediabetes and newly diagnosed type 2 diabetes patients. J Diabetes Res. 2016;2016:1–10. doi:10.1155/2016/7965317 Google Scholar
Agarwal, A, Hegde, A, Yadav, C, Ahmad, A, Manjrekar, PA, Srikantiah, RM. Assessment of oxidative stress and inflammation in prediabetes—a hospital based cross-sectional study. Diabetes Metab Syndr Clin Res Rev. 2016;10(2):S123–S126. doi:10.1016/j.dsx.2016.03.009 CrossRefGoogle ScholarPubMed
Grossmann, V, Schmitt, VH, Zeller, T, et al. Profile of the immune and inflammatory response in individuals with prediabetes and type 2 diabetes. Diabetes Care. 2015;38(7):1356–1364. doi:10.2337/dc14-3008 CrossRefGoogle ScholarPubMed
Vergès, B, Charbonnel, B. After the LEADER trial and SUSTAIN-6, how do we explain the cardiovascular benefits of some GLP-1 receptor agonists? Diabetes Metab. 2017;43:2–3. doi:10.1016/S1262-3636(17)30067-8 CrossRefGoogle ScholarPubMed
Nauck, MA, Meier, JJ, Cavender, MA, El Aziz, MA, Drucker, DJ. Cardiovascular actions and clinical outcomes with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Circulation. 2017;136(9):849–870. doi:10.1161/CIRCULATIONAHA.117.028136 CrossRefGoogle ScholarPubMed
Jialal, I, Chaudhuri, A. Targeting inflammation to reduce ASCVD in type 2 diabetes. J Diabetes Complications. 2018;33:1–3. doi:10.1016/j.jdiacomp.2018.11.001 CrossRefGoogle ScholarPubMed
Courrèges, J-P, Vilsbøll, T, Zdravkovic, M, et al. Beneficial effects of once-daily liraglutide, a human glucagon-like peptide-1 analogue, on cardiovascular risk biomarkers in patients with type 2 diabetes. Diabet Med. 2008;25(9):1129–1131. doi:10.1111/j.1464-5491.2008.02484.x CrossRefGoogle ScholarPubMed
Daousi, C, Pinkney, JH, Cleator, J, Wilding, JP, Ranganath, LR. Acute peripheral administration of synthetic human GLP-1 (7-36 amide) decreases circulating IL-6 in obese patients with type 2 diabetes mellitus: a potential role for GLP-1 in modulation of the diabetic pro-inflammatory state? Regul Pept. 2013;183(1):54–61. doi:10.1016/j.regpep.2013.03.004 CrossRefGoogle ScholarPubMed
Bułdak, Ł, Machnik, G, Jakub Bułdak, R, et al. Exenatide (a GLP-1 agonist) expresses anti-inflammatory properties in cultured human monocytes/macrophages in a protein kinase A and B/Akt manner. Pharmacol Rep. 2016;68(2):329–337. doi:10.1016/j.pharep.2015.10.008 CrossRefGoogle Scholar
Chaudhuri, A, Ghanim, H, Vora, M, et al. Exenatide exerts a potent antiinflammatory effect. J Clin Endocrinol Metab. 2012;97(1):198–207. doi:10.1210/jc.2011-1508 CrossRefGoogle ScholarPubMed
Hogan, AE, Gaoatswe, G, Lynch, L, et al. Glucagon-like peptide 1 analogue therapy directly modulates innate immune-mediated inflammation in individuals with type 2 diabetes mellitus. Diabetologia. 2014;57(4):781–784. doi:10.1007/s00125-013-3145-0 CrossRefGoogle ScholarPubMed
von Scholten, BJ, Persson, F, Rosenlund, S, et al. Effects of liraglutide on cardiovascular risk biomarkers in patients with type 2 diabetes and albuminuria: a sub-analysis of a randomized, placebo-controlled, double-blind, crossover trial. Diabetes Obes Metab. 2017;19(6):901–905. doi:10.1111/dom.12884 CrossRefGoogle ScholarPubMed
Shirazi, R, Palsdottir, V, Collander, J, et al. Glucagon-like peptide 1 receptor induced suppression of food intake, and body weight is mediated by central IL-1 and IL-6. Proc Natl Acad Sci. 2013;110(40):16199–16204. doi:10.1073/pnas.1306799110 CrossRefGoogle ScholarPubMed
Larsen, JR, Vedtofte, L, Holst, JJ, et al. Does a GLP-1 receptor agonist change glucose tolerance in patients treated with antipsychotic medications? Design of a randomised, double-blinded, placebo-controlled clinical trial. BMJ Open. 2014;4(3):e004227. doi:10.1136/bmjopen-2013-004227 CrossRefGoogle ScholarPubMed
Wilkinson, G, Hesdon, B, Wild, D, et al. Self-report quality of life measure for people with schizophrenia: the SQLS. Br J Psychiatry. 2000;177(1):42–46. doi:10.1192/bjp.177.1.42 CrossRefGoogle ScholarPubMed
Busner, J, Targum, SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007;4(7):28–37. http://www.ncbi.nlm.nih.gov/pubmed/20526405Google ScholarPubMed
Aas, IM. Global Assessment of Functioning (GAF): properties and frontier of current knowledge. Ann Gen Psychiatry. 2010;9:20. doi:10.1186/1744-859X-9-20 CrossRefGoogle ScholarPubMed
Saunders, JB, Aasland, OG, Babor, TF, De La Fuente, JR, Grant, M. Development of the alcohol use disorders identification test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption-II. Addiction. 1993;88(6):791–804. doi:10.1111/j.1360-0443.1993.tb02093.x CrossRefGoogle Scholar
Lee, JW, Devanarayan, V, Barrett, YC, et al. Fit-for-purpose method development and validation for successful biomarker measurement. Pharm Res. 2006;23(2):312–328. doi:10.1007/s11095-005-9045-3 CrossRefGoogle ScholarPubMed
Meso Scale Discovery. MSD MULTI-SPOT Assay system: Proinflammatory Panel 1 (human) Kits. https://www.mesoscale.com/~/media/files/product inserts/proinflammatory panel 1 human insert.pdf.Google Scholar
Kwak, SK, Kim, JH. Statistical data preparation: management of missing values and outliers. Korean J Anesthesiol. 2017;70(4):407–411. doi:10.4097/kjae.2017.70.4.407 CrossRefGoogle ScholarPubMed
Ligthart, S, Ghanbari, M, Brahimaj, A, et al. Novel inflammatory markers for incident pre-diabetes and type 2 diabetes: the Rotterdam Study. Eur J Epidemiol. 2017;32(3):217–226. doi:10.1007/s10654-017-0236-0 Google Scholar
Steinke, JW. Anti-interleukin-4 therapy. Immunol Allergy Clin North Am. 2004;24(4 SPEC. ISS.):599–614. doi:10.1016/j.iac.2004.06.008 CrossRefGoogle ScholarPubMed
Cox, D, Chan, MK, Bahn, S. The potential of immune biomarkers to advance personalized medicine approaches for Schizophrenia. J Nerv Ment Dis. 2015;203(5):393–399. doi:10.1097/NMD.0000000000000289 CrossRefGoogle Scholar
Chan, MK, Guest, PC, Levin, Y, et al. Converging evidence of blood-based biomarkers for schizophrenia: an update. Int Rev Neurobiol. 2011;101:95–144. doi:10.1016/B978-0-12-387718-5.00005-5 CrossRefGoogle ScholarPubMed
Chase, KA, Cone, JJ, Rosen, C, Sharma, RP. The value of interleukin 6 as a peripheral diagnostic marker in schizophrenia. BMC Psychiatry. 2016;16(1):152. doi:10.1186/s12888-016-0866-x CrossRefGoogle Scholar
Boerrigter, D, Weickert, TW, Lenroot, R, et al. Using blood cytokine measures to define high inflammatory biotype of schizophrenia and schizoaffective disorder. J Neuroinflammation. 2017;14(1):188. doi:10.1186/s12974-017-0962-y CrossRefGoogle ScholarPubMed
Steiner, J, Bernstein, HG, Schiltz, K, et al. Immune system and glucose metabolism interaction in schizophrenia: A chicken-egg dilemma. Prog Neuro-Psychopharmacology Biol Psychiatry. 2014;48:287–294. doi:10.1016/j.pnpbp.2012.09.016 CrossRefGoogle ScholarPubMed
Li, H, Peng, S, Li, S, et al. Chronic olanzapine administration causes metabolic syndrome through inflammatory cytokines in rodent models of insulin resistance. Sci Rep. 2019;9(1):1582. doi:10.1038/s41598-018-36930-y CrossRefGoogle ScholarPubMed
Romeo, B, Brunet-Lecomte, M, Martelli, C, Benyamina, A. Kinetics of cytokine levels during antipsychotic treatment in schizophrenia: a meta-analysis. Int J Neuropsychopharmacol. 2018;21(9):828–836. doi:10.1093/ijnp/pyy062 CrossRefGoogle ScholarPubMed
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