Association of Lipopolysaccharide-Toll-Like Receptor 4 Signaling and Microalbuminuria in Patients with Type 2 Diabetes Mellitus

Overview

Journal Diabetes Metab Syndr Obes

Publisher Dove Medical Press

Specialty Endocrinology

Date 2022 Oct 20

PMID 36262806

Authors

Lijuan Zhang

Yuanjun Zhang

Juxiang Liu

Yonghong Li

Jinxing Quan

Affiliations

Soon will be listed here.

Abstract

Purpose: Intestinal flora imbalance has been implicated in the activation of innate immunity in the kidneys. However, little is known about the potential links between lipopolysaccharide (LPS)-toll-like. receptor 4 (TLR4) signaling activated by intestinal barrier dysfunction and microalbuminuria in type 2 diabetes mellitus (T2DM).

Patients And Methods: 61 patients with T2DM were stratified based on the absence (n=32) or presence (n=29) of microalbuminuria. There were also 28 control subjects. Urinary albumin excretion rate (UAER), serum levels of LPS, D-lactic acid (DLA), diamine oxidase (DAO), fasting blood glucose (FBG), interleukin-6 (IL-6), glycosylated hemoglobin A1 (HbA1c), and high-sensitivity C-reactive protein (hs-CRP), and TLR4 expression in peripheral blood mononuclear cells (PBMCs) were measured.

Results: hs-CRP, IL-6, LPS, DLA, DAO, and TLR4 were markedly increased in subjects with T2DM compared to the controls (P < 0.05 for all). Moreover, LPS was positively correlated with FBG, HbA1c, hs-CRP, IL-6, UAER, DLA, DAO, and TLR4 (P < 0.05 for all). In addition, TLR4 was positively correlated with UAER, hs-CRP, FBG, DLA, HbA1c, and LPS (P < 0.05 for all). In regression analyses, TLR4, LPS, HbA1c, and hs-CRP were independently associated with UAER (P < 0.05 for all), while FBG, LPS, TLR4, and hs-CRP (P < 0.05 for all) were found to be risk factors for microalbuminuria in T2DM.

Conclusion: Intestinal integrity is compromised in subjects with T2DM, and the activation of LPS-TLR4 signaling might play an important role in the development of microalbuminuria in T2DM.

References

Maqbool M, Cooper M, Jandeleit-Dahm K . Cardiovascular Disease and Diabetic Kidney Disease. Semin Nephrol. 2018; 38(3):217-232. DOI: 10.1016/j.semnephrol.2018.02.003. View

Xu J, Liu Z, Zhan W, Jiang R, Yang C, Zhan H . Recombinant TsP53 modulates intestinal epithelial barrier integrity via upregulation of ZO‑1 in LPS‑induced septic mice. Mol Med Rep. 2017; 17(1):1212-1218. DOI: 10.3892/mmr.2017.7946. View

Jialal I, Major A, Devaraj S . Global Toll-like receptor 4 knockout results in decreased renal inflammation, fibrosis and podocytopathy. J Diabetes Complications. 2014; 28(6):755-61. DOI: 10.1016/j.jdiacomp.2014.07.003. View

Brar P, Kohn B . Use of the microbiome in the management of children with type 2 diabetes mellitus. Curr Opin Pediatr. 2019; 31(4):524-530. DOI: 10.1097/MOP.0000000000000781. View

Navarro-Gonzalez J, Mora-Fernandez C, de Fuentes M, Garcia-Perez J . Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol. 2011; 7(6):327-40. DOI: 10.1038/nrneph.2011.51. View

Patterson E, Ryan P, Cryan J, Dinan T, Ross R, Fitzgerald G . Gut microbiota, obesity and diabetes. Postgrad Med J. 2016; 92(1087):286-300. DOI: 10.1136/postgradmedj-2015-133285. View

Evenepoel P, Poesen R, Meijers B . The gut-kidney axis. Pediatr Nephrol. 2016; 32(11):2005-2014. DOI: 10.1007/s00467-016-3527-x. View

Verzola D, Cappuccino L, DAmato E, Villaggio B, Gianiorio F, Mij M . Enhanced glomerular Toll-like receptor 4 expression and signaling in patients with type 2 diabetic nephropathy and microalbuminuria. Kidney Int. 2014; 86(6):1229-43. DOI: 10.1038/ki.2014.116. View

Miller S, Ernst R, Bader M . LPS, TLR4 and infectious disease diversity. Nat Rev Microbiol. 2004; 3(1):36-46. DOI: 10.1038/nrmicro1068. View

10.

Chuengsamarn S, Rattanamongkolgul S, Sittithumcharee G, Jirawatnotai S . Association of serum high-sensitivity C-reactive protein with metabolic control and diabetic chronic vascular complications in patients with type 2 diabetes. Diabetes Metab Syndr. 2016; 11(2):103-108. DOI: 10.1016/j.dsx.2016.08.012. View

11.

Brownlee M . The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005; 54(6):1615-25. DOI: 10.2337/diabetes.54.6.1615. View

12.

Cani P, Neyrinck A, Fava F, Knauf C, Burcelin R, Tuohy K . Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia. 2007; 50(11):2374-83. DOI: 10.1007/s00125-007-0791-0. View

13.

Dasu M, Devaraj S, Zhao L, Hwang D, Jialal I . High glucose induces toll-like receptor expression in human monocytes: mechanism of activation. Diabetes. 2008; 57(11):3090-8. PMC: 2570406. DOI: 10.2337/db08-0564. View

14.

Chambers E, Byrne C, Morrison D, Murphy K, Preston T, Tedford C . Dietary supplementation with inulin-propionate ester or inulin improves insulin sensitivity in adults with overweight and obesity with distinct effects on the gut microbiota, plasma metabolome and systemic inflammatory responses: a randomised.... Gut. 2019; 68(8):1430-1438. PMC: 6691855. DOI: 10.1136/gutjnl-2019-318424. View

15.

Magnusson M, Magnusson K, Sundqvist T, DENNEBERG T . Impaired intestinal barrier function measured by differently sized polyethylene glycols in patients with chronic renal failure. Gut. 1991; 32(7):754-9. PMC: 1378990. DOI: 10.1136/gut.32.7.754. View

16.

Sohail M, Althani A, Anwar H, Rizzi R, Marei H . Role of the Gastrointestinal Tract Microbiome in the Pathophysiology of Diabetes Mellitus. J Diabetes Res. 2017; 2017:9631435. PMC: 5634576. DOI: 10.1155/2017/9631435. View

17.

Cani P, Bibiloni R, Knauf C, Waget A, Neyrinck A, Delzenne N . Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008; 57(6):1470-81. DOI: 10.2337/db07-1403. View

18.

Sabatino A, Regolisti G, Cosola C, Gesualdo L, Fiaccadori E . Intestinal Microbiota in Type 2 Diabetes and Chronic Kidney Disease. Curr Diab Rep. 2017; 17(3):16. DOI: 10.1007/s11892-017-0841-z. View

19.

Nymark M, Pussinen P, Tuomainen A, Forsblom C, Groop P, Lehto M . Serum lipopolysaccharide activity is associated with the progression of kidney disease in finnish patients with type 1 diabetes. Diabetes Care. 2009; 32(9):1689-93. PMC: 2732155. DOI: 10.2337/dc09-0467. View

20.

Yu W, Li W, Li N, Li J . Influence of acute hyperglycemia in human sepsis on inflammatory cytokine and counterregulatory hormone concentrations. World J Gastroenterol. 2003; 9(8):1824-7. PMC: 4611552. DOI: 10.3748/wjg.v9.i8.1824. View