Patterns of Toll-Like Receptor Expressions and Inflammatory Cytokine Levels and Their Implications in the Progress of Insulin Resistance and Diabetic Nephropathy in Type 2 Diabetic Patients.

Rofyda H Aly,Walaa G Hozayen,Osama M Ahmed,Tarek M Ali,Alaa Mohamed Rabea,Amr E Ahmed,Ahmad El Askary

doi:10.3389/fphys.2020.609223

Rofyda H Aly, Walaa G Hozayen + Show 5 more

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https://doi.org/10.3389/fphys.2020.609223

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Abstract

Background: Diabetic nephropathy (DNP) is a type 2 diabetes mellitus (T2DM) chronic complication, which is the largest single cause of end-stage kidney disease. There is an increasing evidence of the role of inflammation and Toll-like receptors (TLRs) as part of innate immune system in its development and progression. In addition, Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) downward signaling causes the production of proinflammatory cytokines, which can induce insulin (INS) resistance in T2DM.Objective: The goal of this study was to estimate the expression of TLRs (TLR2 and TLR4) in relation to inflammation and INS resistance in nephrotic type 2 diabetic patients with or without renal failure and to discuss the role of these TLRs in DNP progression.Patients and Methods: In this study, blood samples were obtained from type 2 diabetic patients with or without renal failure, and patients with non-diabetic renal failure were compared to healthy controls. All participants were tested for analysis of fasting plasma glucose and serum insulin, kidney function tests, C-reactive protein (CRP), and proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), and interleukin 6 (IL-6) as well as expression of TLR2 and TLR4 in peripheral blood (PB). Statistical analysis of data was done by using SPSS.Results: Diabetic patients with renal failure exhibited significant increase in TLR2, TLR4 mRNA expression in PB in comparison with normal subjects, diabetic patients without renal failure and non-diabetic patients with renal failure. Both diabetic patients with or without kidney failure and non-diabetic patients with renal failure had increased TLR2 and TLR4 mRNA expression in association with increased levels of proinflammatory cytokines (TNF-α, IFN-γ, and IL-6) compared to normal subjects. The diabetic patients with kidney failure exhibited the highest elevation of TLRs, Th1 cytokines and CRP in association the highest record of insulin resistance.Conclusion: Toll-like receptor 2 and Toll-like receptor 4 increased expression and Th2 cytokines may have an important role in the progression of DNP and deteriorations in insulin resistance in type 2 diabetic patients. Therefore, TLR2 and TLR4 may be a promising therapeutic target to prevent or retard DNP in type 2 diabetic patients.

Highlights

Diabetes mellitus (DM) is a chronic metabolic endocrinal disease, which is characterized by elevation in blood glucose level and is associated with multiple complications
Analysis of fasting plasma glucose level between the four groups indicated that there was a significant difference between group 1, on one hand, and group 3 (DM + HD) and group 4 (DM) on the other, but there was no significant difference between group 1 and group 2
The calculated Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) value showed that there was a significant difference between group 1 and group 3 (DM + HD)

Summary

Introduction

Diabetes mellitus (DM) is a chronic metabolic endocrinal disease, which is characterized by elevation in blood glucose level and is associated with multiple complications. Proinflammatory cytokines produced by T helper cells (Th1) such as interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) can induce resident renal cells such as tubular epithelial cells, mesangial cells, and podocytes to produce chemokines (Lim and Tesch, 2012) Such chemokines function as “chemoattractant” molecules, playing a key role in inflammatory cell recruitment, migration, and interaction, as well as in cellular adhesion, differentiation, and tissue damage in the setting of DNP (Ruster and Wolf, 2008; Pérez-Morales et al, 2019). Chronic exposure to diabetic substrates damages renal cells, resulting in injury or cell death and the release of intracellular damage-associated molecular patterns (DAMPs) into the extracellular space (Figure 1) This signal is recognized by pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs; Tang and Yiu, 2020). Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) downward signaling causes the production of proinflammatory cytokines, which can induce insulin (INS) resistance in T2DM

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