Clinical and metabolic factors associated with chronic low-grade inflammation in type 2 diabetic patients

Aim. To identify the clinical and metabolic factors associated with serum concentration of high sensitivity C-reactive protein (hsCRP) and α1-acid glycoprotein (α1-AGP) in patients with type 2 diabetes.

Material and methods. The study involved 210 patients with type 2 diabetes. Levels of hsCRP and α1-AGP were measured using ELISA and compared with those of the control (30 healthy normal individuals). Levels of acute-phase proteins, fat mass and glucose variability (GV) were compared among demographic, anthropometric, biochemical and haematological parameters. The fat mass was determined with Dual-energy X-ray absorptiometry (DEXA). GV parameters including mean amplitude of glycaemic excursions, continuous overlapping net glycaemic action (CONGA), J-index, M-value and mean absolute glucose change (MAG) were derived from continuous glucose monitoring.

Results. Levels of hsCRP and α1-AGP significantly increased (p < 0.0001) in patients with diabetes compared with controls. hsCRP level positively correlated with total, truncal and android fat (r = 0.34, r = 0.28 and r = 0.31; respectively, p < 0.00004). α1-AGP level showed no relationship with fat mass but positively correlated with mean glucose, CONGA, M-value and MAG (r = 0.38, r = 0.36, r = 0.43 and r = 0.4; respectively, p < 0.0001). Patients with the highest hsCRP levels (>75 percentile) had a greater body mass index (p = 0.00009) as well as truncal and android fat mass (p = 0.04 and p = 0.03, respectively) than those with the lowest levels (<25 percentile). High level of α1-AGP (>75 percentile) was associated with urinary albumin/creatinine ratio (p = 0.01) and GV indices (M-value: p = 0.02, MAG: p = 0.04).

Conclusions. Levels of acute-phase proteins (hsCRP and α1-AGP) increased in patients with type 2 diabetes. Levels of hsCRP were associated with fat mass; meanwhile, α1-AGP levels were associated with short-time GV in these patients. The results lend support to the notion that both obesity and enhanced GV are involved in the development of chronic low-grade inflammation associated with type 2 diabetes.

1. Hameed I, Masoodi SR, Mir SA, et al. Type 2 diabetes mellitus: From a metabolic disorder to an inflammatory condition. World J Diabetes. 2015;6(4):598-612. doi: 10.4239/wjd.v6.i4.598

2. Esser N, Legrand-Poels S, Piette J, et al. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract. 2014;105(2):141-150. doi: 10.1016/j.diabres.2014.04.006

3. Kluppelholz B, Thorand B, Koenig W, et al. Association of subclinical inflammation with deterioration of glycaemia before the diagnosis of type 2 diabetes: the KORA S4/F4 study. Diabetologia.2015;58(10):2269-2277. doi: 10.1007/s00125-015-3679-4

4. 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

5. Kengne AP, Batty GD, Hamer M, et al. Association of C-reactive protein with cardiovascular disease mortality according to diabetes status: pooled analyses of 25,979 participants from four U.K. prospective cohort studies. Diabetes Care. 2012;35(2):396-403. doi: 10.2337/dc11-1588

6. Su G, Mi S, Tao H, et al. Association of glycemic variability and the presence and severity of coronary artery disease in patients with type 2 diabetes. Cardiovasc Diabetol. 2011;10:19. doi: 10.1186/1475-2840-10-19

7. Zhang X, Xu X, Jiao X, et al. The effects of glucose fluctuation on the severity of coronary artery disease in type 2 diabetes mellitus. J Diabetes Res. 2013;2013:576916. doi: 10.1155/2013/576916

8. Alizadeh Dehnavi R, Beishuizen ED, van de Ree MA, et al. The impact of metabolic syndrome and CRP on vascular phenotype in type 2 diabetes mellitus. Eur J Intern Med. 2008;19(2):115-121. doi: 10.1016/j.ejim.2007.06.011

9. TODAY GROUP STUDY. Lipid and inflammatory cardiovascular risk worsens over 3 years in youth with type 2 diabetes: the TODAY clinical trial. Diabetes Care. 2013;36(6):1758-1764. doi: 10.2337/dc12-2388

10. Lowe G, Woodward M, Hillis G, et al. Circulating inflammatory markers and the risk of vascular complications and mortality in people with type 2 diabetes and cardiovascular disease or risk factors: the ADVANCE study. Diabetes. 2014;63(3):1115-1123. doi: 10.2337/db12-1625

11. Shimoda M, Kaneto H, Yoshioka H, et al. Influence of atherosclerosis-related risk factors on serum high-sensitivity C-reactive protein levels in patients with type 2 diabetes: Comparison of their influence in obese and non-obese patients. J Diabetes Investig. 2016;7(2):197-205. doi: 10.1111/jdi.12388

12. Vinagre I, Sanchez-Quesada JL, Sanchez-Hernandez J, et al. Inflammatory biomarkers in type 2 diabetic patients: effect of glycemic control and impact of LDL subfraction phenotype. Cardiovasc Diabetol. 2014;13:34. doi: 10.1186/1475-2840-13-34

13. Berton G, Palmieri R, Cordiano R, et al. Acute-phase inflammatory markers during myocardial infarction: association with mortality and modes of death after 7 years of follow-up. J Cardiovasc Med (Hagerstown). 2010;11(2):111-117. doi: 10.2459/JCM.0b013e328332e8e0

14. Hill NR, Oliver NS, Choudhary P, et al. Normal reference range for mean tissue glucose and glycemic variability derived from continuous glucose monitoring for subjects without diabetes in different ethnic groups. Diabetes Technol Ther. 2011;13(9):921-928. doi: 10.1089/dia.2010.0247

15. Service FJ. Glucose variability. Diabetes. 2013;62(5):1398-1404. doi: 10.2337/db12-1396

16. Климонтов В.В., Маякина Н.Е. Вариабельность гликемии при сахарном диабете: инструмент для оценки качества гликемического контроля и риска осложнений // Сахарный диабет. – 2014. – Т. 17. – №2 – C. 76-82. [Klimontov VV, Myakina NE. Glycaemic variability in diabetes: a tool for assessing the quality of glycaemic control and the risk of complications. Diabetes mellitus. 2014;17(2):76-82. doi: 10.14341/DM20142]

17. Debnath M, Agrawal S, Agrawal A, Dubey GP. Metaflammatory responses during obesity: Pathomechanism and treatment. Obes Res Clin Pract. 2016;10(2):103-113. doi: 10.1016/j.orcp.2015.10.012

18. Salazar J, Martinez MS, Chavez-Castillo M, et al. C-Reactive Protein: An In-Depth Look into Structure, Function, and Regulation. Int Sch Res Notices. 2014;2014:653045. doi: 10.1155/2014/653045

19. Hirsch IB. Glycemic Variability and Diabetes Complications: Does It Matter? Of Course It Does! Diabetes Care. 2015;38(8):1610-1614. doi: 10.2337/dc14-2898

20. Mo Y, Zhou J, Li M, et al. Glycemic variability is associated with subclinical atherosclerosis in Chinese type 2 diabetic patients. Cardiovasc Diabetol. 2013;12:15. doi: 10.1186/1475-2840-12-15

21. Muggeo M, Zoppini G, Bonora E, et al. Fasting plasma glucose variability predicts 10-year survival of type 2 diabetic patients: the Verona Diabetes Study. Diabetes Care. 2000;23(1):45-50. doi: 10.2337/diacare.23.1.45

22. El-Osta A, Brasacchio D, Yao D, et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med. 2008;205(10):2409-2417. doi: 10.1084/jem.20081188

23. Li MF, Zhang R, Li TT, et al. High Glucose Increases the Expression of Inflammatory Cytokine Genes in Macrophages Through H3K9 Methyltransferase Mechanism. J Interferon Cytokine Res.2016;36(1):48-61. doi: 10.1089/jir.2014.0172

24. Fournier T, Medjoubi-N N, Porquet D. Alpha-1-acid glycoprotein. BiochimBiophysActa. 2000;1482(1-2):157-171. doi: 10.1016/s0167-4838(00)00153-9

25. Poland DCW, Schalkwijk CG, Stehouwer CDA, et al. Glycoconj J. 2001;18(3):261-268. doi: 10.1023/a:1012412908983

26. Бондарь И.А., Климонтов В.В., Надeев А.П. Мочевая экскреция провоспалительных цитокинов и трансформирующего фактора роста b на ранних стадиях диабетической нефропатии. // Терапевтический архив. – 2008. – Т. 80. – №1. – С. 52-57. [Bondar IA, Klimontov VV, Nadeev AP. Urinary excretion of proinflammatory cytokines and transforming growth factor beta at early stages of diabetic nephropathy. Terapevticheski arkhiv. 2008;80(1):52-57. (In Russ.)].

27. Azab B, Camacho-Rivera M, Taioli E. Average values and racial differences of neutrophil lymphocyte ratio among a nationally representative sample of United States subjects. PLoS One.2014;9(11):e112361. doi: 10.1371/journal.pone.0112361

28. Shiny A, Bibin YS, Shanthirani CS, et al. Association of neutrophil-lymphocyte ratio with glucose intolerance: an indicator of systemic inflammation in patients with type 2 diabetes. Diabetes Technol Ther. 2014;16(8):524-530. doi: 10.1089/dia.2013.0264