TLR4 gene polymorphisms: evidence for protection against type 2 diabetes but not for diabetes-associated ischaemic heart disease

Manolakis, Anastassios C.; Kapsoritakis, Andreas; Tiaka, Elisavet K.; Sidiropoulos, Andreas; Gerovassili, Aggeliki; Satra, Maria; Vamvakopoulou, Dimitra; Tsiopoulos, F.; Παπάνας, Νικόλαος; Skoularigis, Ioannis; Potamianos, Spyros; Vamvakopoulos, Nicholas C.

doi:10.1530/eje-11-0280

Cited by 42 publications

(29 citation statements)

References 34 publications

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“…Th e combination of both recessive alleles has even been observed to provide the greatest protection against T2D (Manolakis et al 2011). However, not all studies confi rm such results (Illig et al 2003;Maldonado-Bernal et al 2011).…”

Section: Discussionmentioning

confidence: 99%

TLR4 polymorphisms seem not to be associated with prediabetes and type 2 diabetes but predispose to diabetic retinopathy; TLR4 polymorphisms in glucose continuum

Zaharieva

Kamenov

Savov

2017

Endocrine Regulations

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Objectives. Compared to type 1 diabetes, the role of the immune and autoimmune pathogenetic mechanisms is much less studied in the type 2 diabetes. Toll-like receptors 4 (TLR4) have a leading role in infl ammation, insulin resistance, and vascular damage. Th is study aimed to analyze the relationship between the polymorphisms in TLR4 gene and diff erent stages in the glucose continuum from prediabetes to the type 2 diabetes and chronic microvascular complications.Materials and Methods. Th e study included 113 patients with the type 2 diabetes, 29 participants with prediabetes, and 28 controls. Polymerase chain reaction (PCR) was used for genotyping Asp299Gly and Th r399Ile polymorphism, followed by restriction analysis.Results. Th e diff erence in the genotype frequency for both polymorphisms in patients with the type 2 diabetes or prediabetes compared to that in controls was not signifi cant. Patients with heterozygous genotype of Asp299Gly polymorphism had a higher prevalence of diabetic retinopathy (42.9%) than participants with homozygous genotype (9.0%) (OR [95%CI]=7.61 [1.41-41.08]; p=0.018). No association was established for diabetic polyneuropathy and nephropathy. Prevalence of chronic diabetes complications was not related to Th r399Ile polymorphism.Conclusion. Our study demonstrates that Asp299Gly and Th r399Ile polymorphisms seem not to be associated with the type 2 diabetes and prediabetes but Asp299Gly may contribute to diabetic retinopathy predisposition.

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Section: Discussionmentioning

confidence: 99%

TLR4 polymorphisms seem not to be associated with prediabetes and type 2 diabetes but predispose to diabetic retinopathy; TLR4 polymorphisms in glucose continuum

Zaharieva

Kamenov

Savov

2017

Endocrine Regulations

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“…Gene polymorphisms in TLRs affect the innate immune response [25]. Previous studies have recognized that polymorphisms in TLRs are associated with the development of diabetes [14,26,27,28,29,30,31,32,33,34,35,36]. Table 5 shows polymorphisms previously associated with diabetes and references.…”

Section: Discussionmentioning

confidence: 99%

Significant Association between Toll-Like Receptor Gene Polymorphisms and Posttransplantation Diabetes Mellitus

Kim

Kim²,

Park³

et al. 2016

Nephron

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Background: Posttransplantation diabetes mellitus (PTDM) is an important metabolic complication after renal transplantation. Activation of the innate immune system via toll-like receptors (TLRs) is implicated in the pathogenesis of insulin resistance and deficiency. Although links between diabetes, dysregulated innate immune responses, and the TLR signaling pathway have been reported, no study so far has investigated their associations with PTDM. In this study, we ascertained whether single nucleotide polymorphisms (SNPs) in TLRs are associated with PTDM in the Korea population. Methods: A total of 305 patients who received renal transplants without previously diagnosed diabetes were included. We analyzed the association between PTDM development and 6 SNPs within 2 genes of TLR2, 1 gene of TLR4, and 3 genes of TRL6. Results: Of 305 patients, PTDM developed in 51 patients (16.6%). Patients in the PTDM group were older than those in the non-PTDM group (45.56 ± 1.28 vs. 38.28 ± 0.71 years). Patients with PTDM had significantly higher allele frequency compared to those without PTDM for the TLR4 rs1927914*T, TLR6 rs3775073*A, TLR6 rs3821985*C, and TLR6 rs1039559*C alleles. Of the 6 SNPs, rs1927914 in the TLR4 gene and rs1039559 in the TLR6 gene were significantly associated with the development of PTDM after adjustment for age, gender, and tacrolimus usage. Conclusions: Our study demonstrates a significant association between SNPs rs1927914 in TLR4 and rs1039559 in TLR6 and PTDM in the renal transplantation recipient group. These data suggest that the activation of the innate immune system and inflammation via TLR activation might have an essential role in the pathogenesis of PTDM in renal transplantation.

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“…Mutations resulting in nonfunctional TLR4 render protection from obesity, insulin resistance, and cardiovascular disease in rodent models [12,13]. In humans, polymorphisms in the TLR4 gene are associated with reduced incidence of heart disease and diabetes [14,15]. We, and others have observed increased expression of TLR4 in skeletal muscle from obese and T2DM humans relative to non-obese, healthy controls [16–18].…”

Section: Introductionmentioning

confidence: 99%

Low Levels of Lipopolysaccharide Modulate Mitochondrial Oxygen Consumption in Skeletal Muscle

Frisard

McMillan

et al. 2015

Metabolism

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Objective We have previously demonstrated that activation of toll-like receptor 4 (TLR4) in skeletal muscle results in an increased reliance on glucose as an energy source and a concomitant decrease in fatty acid oxidation under basal conditions. Herein, we examined the effects of lipopolysaccharide (LPS), the primary ligand for TLR4, on mitochondrial oxygen consumption in skeletal muscle cell culture and isolated mitochondria. Materials/ methods Skeletal muscle cell cultures were exposed to LPS and oxygen consumption was assessed using a Seahorse Bioscience extracellular flux analyzer. Mice were also exposed to LPS and oxygen consumption was assessed in mitochondria isolated from skeletal muscle. Results Acute LPS exposure resulted in significant reductions in cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP)-stimulated maximal respiration (state 3u) and increased oligomycin induced state 4 (state 4O) respiration in C2C12 and human primary myotubes. These findings were observed in conjunction with increased mRNA of uncoupling protein 3 (UCP3), superoxide dismutase 2 (SOD2), and pyruvate dehydrogenase activity. The LPS-mediated changes in substrate oxidation and maximal mitochondrial respiration were prevented in the presence of the antioxidants N-acetylcysteine and catalase, suggesting a potential role of reactive oxygen species in mediating these effects. Mitochondria isolated from red gastrocnemius and quadriceps femoris muscle from mice injected with LPS also demonstrated reduced respiratory control ratio (RCR), and ADP- and FCCP-stimulated respiration. Conclusion LPS exposure in skeletal muscle alters mitochondrial oxygen consumption and substrate preference, which is absent when antioxidants are present.

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TLR4 gene polymorphisms: evidence for protection against type 2 diabetes but not for diabetes-associated ischaemic heart disease

Cited by 42 publications

References 34 publications

TLR4 polymorphisms seem not to be associated with prediabetes and type 2 diabetes but predispose to diabetic retinopathy; TLR4 polymorphisms in glucose continuum

TLR4 polymorphisms seem not to be associated with prediabetes and type 2 diabetes but predispose to diabetic retinopathy; TLR4 polymorphisms in glucose continuum

Significant Association between Toll-Like Receptor Gene Polymorphisms and Posttransplantation Diabetes Mellitus

Low Levels of Lipopolysaccharide Modulate Mitochondrial Oxygen Consumption in Skeletal Muscle

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