Association of Tumor Necrosis Factor Alpha, Interleukin 6, and C-Reactive Protein with the Risk of Developing Type 2 Diabetes: A Retrospective Cohort Study of Rural Thais

Abstract

The linkage of obesity, inflammation, and type 2 diabetes mellitus (T2DM) has been extensively investigated for over a decade. However, the association between inflammatory biomarkers, including C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α), and T2DM is still inconsistent and limited. Thus, this study is aimed at elucidating the association between inflammatory marker levels and the risk of developing T2DM in many aspects. Among 296 subjects enrolled in 2013, 248 non-T2DM subjects who were completely reinvestigated in 2014 and 2015 were included in a 2-year retrospective analysis. Multivariate logistic regression was performed to evaluate the association of baseline inflammatory marker levels and variation with incidence of T2DM. After the 2-year follow-up, 18.6% of total subjects had developed T2DM. The risk of developing T2DM was significantly increased in subjects with a high level of baseline CRP (OR=4.02, 95% CI: 1.77-9.12, P=0.001), and a stronger impact was found with the combination of high CRP and IL-6 levels (OR=5.11, 95% CI: 1.27-20.49, P=0.021). One-year inflammatory marker variation analysis also revealed the significant association of elevated TNF-α and risk of developing T2DM (OR=4.88, 95% CI: 1.01-23.49, P=0.048). In conclusion, besides consideration of CRP levels alone, our findings suggested that IL-6 outstandingly plays a contributing role in T2DM progression and elevated TNF-α levels over time could be a potential predictor of T2DM.

High Mobility Group Box-1 and Diabetes Mellitus Complications: State of the Art and Future Perspectives

“…Several studies focused their attention on the role of inflammation in the pathogenesis of DM. In particular, many authors demonstrated that elevated levels of C-reactive protein (CRP), IL-6, TNF-α predict the development of T2DM [4][5][6][7][8][9]. Hotamisligil and colleagues found that levels of TNF-α are elevated in the adipose tissue of obese insulin-resistant rodents and obese humans, and that the neutralization of TNF-α in insulin-resistant rodents resulted in an increase peripheral uptake of glucose in response to insulin [10,11].…”

<p>The Clinical Utility of Salivary Biomarkers in the Identification of Type 2 Diabetes Risk and Metabolic Syndrome</p>

“…TNF-α is a pro-inflammatory, cell signaling protein that plays critical roles in inflammatory and autoimmune responses, cellular events such as apoptosis and cell differentiation, and oxidative stress. [88][89][90] Elevated concentrations of TNF-α are associated with insulin resistance, making it a contributory biomarker of type 2 diabetes. [88][89][90][91] TNF-α works to reduce the expression of glucose transporter type 4 (GLUT-4) and serine phosphorylation of insulin receptor substrate 1 (IRS-1), both of which are critical for the synthesis of insulin.…”

“…[88][89][90] Elevated concentrations of TNF-α are associated with insulin resistance, making it a contributory biomarker of type 2 diabetes. [88][89][90][91] TNF-α works to reduce the expression of glucose transporter type 4 (GLUT-4) and serine phosphorylation of insulin receptor substrate 1 (IRS-1), both of which are critical for the synthesis of insulin. [92][93][94] TNF-α activates the endothelial production of adhesion molecules such as intracellular adhesion molecule-1.…”

“…[92][93][94] If an increase in TNF-α concentration occurs, additional GLUT-4 and serine phosphorylation of IRS-1 are suppressed, thereby activating additional intracellular adhesion molecule-1, leading to an increased risk of developing type 2 diabetes. [88][89][90] Furthermore, studies report type 2 diabetics demonstrating a 17-39% increase in TNF-α concentrations versus healthy controls. 90,95 Multiple studies have tested different races, ages, and genders and have continued to show elevated TNF-α concentrations in patients with type 2 diabetes, suggesting TNF-α as a risk factor of type 2 diabetes (Figure 1).…”

Serum Cytokine Dependent Hematopoietic Cell Linker (CLNK) as a Predictor for the Duration of Illness in Type 2 Diabetes Mellitus

“…For example, Previous investigations have broadly revealed the relationship of high C-reactive protein (CRP) levels with IR and progression of T2DM (Phosat et al 2017). While interleukine (IL)-6 plays an exceptional role in the development of T2DM and elevated TNF-α levels over time could be a potential predictor of T2DM over time (Lainampetch et al 2019). In addition to cytokines released in response to several stimuli and immune system dysregulation (Banerjee and Saxena 2012), adaptor proteins are another type, which is a very important constituent of signaling transduction systems both beyond and within the immune system (Verma et al 2020).…”