Low-grade inflammation and inflammatory mediators in individuals with prediabetes

Dejan M. Marinković; Tamara Dragović; Ivan Stanojević; Predrag V. Djurić; Bratislav Dejanović; Jelena Rakočević; Saša Kiković; Dragana Malović; Ivana Stevanović; Petar Ristić; Marijana Petrović; Zoran Lj.  Hajduković

doi:10.2298/VSP240328056M

Dejan M. Marinković Military Medical Academy, *Clinic for Endocrinology, Belgrade, Serbia; †University of Defence, Faculty of Medicine of the Military Medical Academy, Belgrade, Serbia
Tamara Dragović Military Medical Academy, *Clinic for Endocrinology, Belgrade, Serbia; †University of Defence, Faculty of Medicine of the Military Medical Academy, Belgrade, Serbia
Ivan Stanojević University of Defence, Faculty of Medicine of the Military Medical Academy, Belgrade, Serbia
Predrag V. Djurić University of Defence, Faculty of Medicine of the Military Medical Academy, Belgrade, Serbia
Bratislav Dejanović Institute for Medical Biochemistry, Belgrade, Serbia
Jelena Rakočević University of Belgrade, Faculty of Medicine, Institute for Histology and Embryology “Aleksandar Đ. Kostić”, Belgrade, Serbia
Saša Kiković Military Medical Academy, Clinic for Endocrinology, Belgrade, Serbia
Dragana Malović Military Medical Academy, Clinic for Endocrinology, Belgrade, Serbia
Ivana Stevanović Military Medical Academy, Institute for Medical Research, Belgrade, Serbia †University of Defence, Faculty of Medicine of the Military Medical Academy, Belgrade, Serbia;
Petar Ristić Military Medical Academy, Clinic for Endocrinology, Belgrade, Serbia
Marijana Petrović University of Defence, Faculty of Medicine of the Military Medical Academy, Belgrade, Serbia
Zoran Lj. Hajduković Military Medical Academy, Clinic for Endocrinology, Belgrade, Serbia

DOI: https://doi.org/10.2298/VSP240328056M

Keywords: biomarkers;, blood glucose;, diabetes mellitus, type 2;, prediabetic state.

Abstract

Background/Aim. Prediabetes is a condition that refers to the state of hyperglycemia not sufficiently high to reach the diagnostic values for type 2 diabetes mellitus (T2DM). This condition often precedes the appearance of T2DM. The association between the development of early glycoregulation disorders and the state of low-grade chronic inflammation is still not sufficiently well understood. The aim of the study was to assess the values of different inflammatory mediators and biomarkers in individuals with prediabetes. Methods. This cross-sectional, observational study included 60 respondents divided into two groups: the prediabetes group (PDG) with 31 patients and the healthy control group (HCG) with 29 respondents. Serum values of seven selected cytokines/biomarkers were compared between the two groups. Examined biomarkers were: interleukin (IL)-1β, IL-6, IL-8, IL-18, tumor necrosis factor (TNF)-α, E-selectin, and vascular endothelial growth factor (VEGF)-A. In addition, the values of body mass index (BMI), waist circumference (WC), blood pressure (BP), serum triglyceride (TG), fasting plasma glucose (FPG), and glycated hemoglobin (HbA1c) were also compared between the two groups. Results. PDG patients had statistically significantly higher TNF-α values compared to the HCG patients (73 pg/mL vs. 55 pg/mL, p = 0.024). A trend towards higher levels of IL-8 and IL-1β and lower levels of E-selectin, VEGF-A, and IL-18 was registered in PDG patients but without statistical significance. Furthermore, PDG patients had higher values of BMI, WC, systolic BP, serum TG, FPG, and HbA1c when compared to HCG. Conclusion. The results of our study suggest the importance of inflammation and some inflammatory mediators in the pathogenesis of early glycoregulation disorder. We believe that the main goal of future studies should focus on anti-inflammatory therapy in prediabetes.

References

Tabak AG, Herder C, Rathmann W, Brunner EJ, Kivimaki M. Prediabetes: a high-risk state for diabetes development. Lancet 2012; 379(9833): 2279–90.

ADA, Standards of Medical Care in Diabetes-2020. Clin Diabetes 2020; 38(1): 10–38.

Nadeem A, Mumtaz S, Naveed AK, Aslam M, Siddiqui A, Lodhi GM, et al. Gene-gene, geneenvironment, gene-nutrient interactions and single nucleotide polymorphisms of inflammatory cytokines. World J Diabetes. 2015; 6(4): 642–47.

Wang Z, Shen XH, Feng WM, Ye G, Qiu W, Li B. Analysis of Inflammatory Mediators in Prediabetes and Newly Diagnosed Type 2 Diabetes Patients. J Diabetes Res 2016; 2016: 7965317. doi:10.1155/2016/7965317

Tabak AG, Jokela M, Akbaraly TN, Brunner EJ, Kivimaki M, Witte DR. Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study. Lancet 2009; 373(9682): 2215–21.

Saxena M, Srivastava N, Banerjee M. Association of IL6, TNF-α and IL-10 gene polymorphisms with type 2 diabetes mellitus. Mol Biol Rep 2013; 40: 6271-79.

Brahimaj A, Ligthart S, Ghanbari M, Arfan Ikram M, Hofman A, Franco OH, et al. Novel inflammatory markers for incident pre-diabetes and type 2 diabetes: the Rotterdam Study. Eur J Epidemiol 2017; 32: 217–226.

Grossmann V, Schmitt VH, Zeller T, Panova-Noeva M, Schulz A, Laubert-Reh D, et al. Profile of the immune and inflammatory response in individuals with prediabetes and type 2 diabetes. Diabetes Care 2015; 38: 1356-1364.

Wang М, Li Y, Li S, Lv J. Endothelial Dysfunction and Diabetic Cardiomyopathy. Front Endocrinol 2022; 13: 851941. doi: 10.3389/fendo.2022.851941

Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006; 116(7): 1793–801. This paper links low-grade inflammation with insulin resistance in type 2 diabetes.

Schmidt MI, Duncan BB, Sharrett AR, Lindberg G, Savage PJ, Offenbacher S, et al. Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study. Lancet 1999; 353(9165): 1649–52.

Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001; 286(3): 327–34.

Duncan BB, Schmidt MI, Pankow JS, Ballantyne CM, Couper D, Vigo A,et al. Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes 2003; 52(7): 1799–805.

Garcia C, Feve B, Ferre P, Halimi S, Baizri H, Bordier L, et al. Diabetes and inflammation: fundamental aspects and clinical implications. Diabetes Metab 2010; 36(5): 327–38.

Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 2011; 11: 98–107.

Maschirow L, Khalaf K, Al-Aubaidy HA, Jelinek HF. Inflammation, coagulation, endothelial dysfunction and oxidative stress in prediabetes - biomarkers as a possible tool for early disease detection for rural screening. Clin Biochem 2015; 48: 581-585.

Weaver JR, Odanga JJ, Breathwaite EK, Treadwell ML, Murchinson AC, Walters G, et all. An increase in inflammation and islet dysfunction is a feature of prediabetes. Diabetes Metab Res Rev 2021; 37(6): e3405. https://doi.org/10.1002/dmrr.3405

Gupta S, Maratha A, Natarajan A, Miggin S, Hoashi S. Analysis of Inflammatory Cytokines in Pre-Diabetic Subjects. Curr Res Diabetes Obes J 2017; 4(5): 555647. DOI: 10.19080/CRDOJ.2017.04.555647

Cruz NG, Sousa LP, Sousa MO, Pietrani NT, Fernandes AP, Gomes KB. The linkage between inflammation and Type 2 diabetes mellitus. Diabetes Res Clin Pract 2013; 99: 85–92.

Herder C, Brunner EJ, Rathmann W, Strassburger K, Tabák AG, Schloot NC, et al. Elevated levels of the anti-inflammatory interleukin-1 receptor antagonist precede the onset of type 2 diabetes: the Whitehall II study. Diabetes Care 2009; 32: 421–423.

King GL. The role of inflammatory cytokines in diabetes and its complications. J Periodontol 2008; 79: 1527–1534.

Stagakis I, Bertsias G, Karvounaris S, Kavousanaki M, Virla D, Raptopoulou A, et al. Anti-tumor necrosis factor therapy improves insulin resistance, beta cell function and insulin signaling in active rheumatoid arthritis patients with high insulin resistance. Arthritis Res Ther 2012; 14: R141. doi: 10.1186/ar3874

Marques-Vidal P, Bastardo F, Von Kanel R, Paccaud F, Preisig M,Waeber G, Vollenweider P. Association between circulating cytokine levels, diabetes and insulin resistance in a population-based sample (CoLaus study). Clin Endocrinol 2013; 78: 232–241.

Tangvarasittichai S, Pongthaisong S, Tangvarasittichai O. Tumor necrosis factor-Α, interleukin-6, C-reactive protein levels and insulin resistance associated with type 2 diabetes in abdominal obesity women. Indian J Clin Biochem 2016; 31(1): 68–74. doi: 10.1007/s12291-015-0514-0.

Guzman-Flores JM, Munoz-Valle JF, Sanchez-Corona J, Cobian JG, Medina-Carrillo L, Garcia-Zapien AG, et al. Tumor necrosis factor-alpha gene promoter −308G/A and −238G/A polymorphisms in Mexican patients with type 2 diabetes mellitus. Disease Markers 2011; 30: 19–24.

Spranger J, Kroke A, Mohlig M, Hoffmann K, Bergmann MM, Ristow M, et al. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes 2003; 52(3): 812-817.

Akash MS, 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: 105-110.

Vilahur G, Ben-Aicha S, Badimon L. New insights into the role of adipose tissue in thrombosis. Cardiovasc Res 2017; 113: 1046-1054.

Al-Shukaili A, Al-Ghafri S, Al-Marhoobi S, Al-Abri S, Al-Lawati J, Al-Maskari M. Analysis of inflammatory mediators in type 2 diabetes patients. Int J Endocrinol 2013; 2013: 976810. https://doi.org/10.1155/2013/976810

Shu YN, Dong LH, Li H, Pei QQ, Miao SB, Zhang F, et al. CKII-SIRT1-SM22 alpha loop evokes a self-limited inflammatory response in vascular smooth muscle cells. Cardiovasc Res 2017; 113: 1198-1207.

Jansen T, Kroller-Schon S, Schonfelder T, Foretz M, Viollet B, Daiber A, et al. Alpha1AMPK deletion in myelomonocytic cells induces a pro-inflammatory phenotype and enhances angiotensin IIinduced vascular dysfunction. Cardiovasc Res 2018; 114: 1883-1893.

Chou CH, Hung CS, Liao CW, Wei LH, Chen CW, Shun CT, et al. IL-6 trans-signalling contributes to aldosterone-induced cardiac fibrosis. Cardiovasc Res 2018; 114: 690-702.

Tsigos C, Papanicolaou DA, Kyrou I, Defensor R, Mitsiadis CS, Chrousos GP. Dose-dependent effects of recombinant human interleukin-6 on glucose regulation. J Clin Endocrinol Metab 1997; 82: 4167-4170.

Stith RD, Luo J. Endocrine and carbohydrate responses to interleukin-6 in vivo. Circ Shock 1994; 44: 210-215.

Tiftikcioglu BI, Duksal T, Bilgin S, Kose S, Zorlu Y. Association between the levels of IL-6, sE-selectin and Distal sensory nerve conduction studies in patients with prediabetes. Eur Neurol 2016; 75: 124-131.

Colak A, Akinci B, Diniz G, Turkon H, Ergonen F, Yalcin H, et al. Postload hyperglycemia is associated with increased subclinical inflammation in patients with prediabetes. Scand J Clin Lab Invest 2013; 73(5): 422-427.

He Q, Dong M, Pan Q, Wang X, Guo L. Correlation between changes in inflammatory cytokines and the combination with hypertension in patients with type 2 diabetes mellitus. Minerva Endocrinol. 2019; 44(3): 252-258. doi:10.23736/S0391-1977.18.02822-5.

Sari MI, Tala ZZ, Wahyuni DD. Association between Glycated Hemoglobin with the Levels of Serum Proinflammatory Cytokines and Antioxidants in Patients with Type 2 Diabetes Mellitus in Universitas Sumatera Utara Hospital. Open Access Maced J Med Sci. 2019; 7(5): 715-720.

Williams A, Greene N, Kimbro K. Increased circulating cytokine levels in African American women with obesity and elevated HbA1c. Cytokine. 2020; 128:154989.