TLR4 Expression by Liver Resident Cells Mediates the Development of Glucose Intolerance and Insulin Resistance in Experimental Periodontitis

Ilievski, Vladimir; Cho, Yale; Katwala, Priya; Rodriguez, H. E.; Tulowiecka, Margaret; Kurian, David; Leoni, Lara; Christman, John W.; Unterman, Terry G.; Watanabe, Keiko

doi:10.1371/journal.pone.0136502

Cited by 21 publications

(24 citation statements)

References 41 publications

(42 reference statements)

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“…These results suggest that changes in the microbiota and/or intestinal permeability in response to periodontopathic bacteria may have metabolic consequences. Using a similar animal model and a similar time course as used in our current study, we previously noted no significant increase in plasma cytokine levels in animals that were administered LPS in the gingival sulci for 18 weeks, but there were significant differences in serum LPS levels [5]. In addition, these animals developed significant glucose intolerance and alveolar bone loss.…”

Section: Discussionsupporting

confidence: 59%

“…As Pg may be present at low levels in healthy subgingival plaque/biofilms, applying Pg to the oral cavity for short durations may not results in chronic periodontitis. Results from our previous studies indicate that application of LPS into the gingival sulci/periodontal pockets (without spilling out from the pockets) results in glucose intolerance and significant amount of alveolar bone loss [5]. Thus, monitoring glucose intolerance is one way to determine underlying systemic effects that relate to the development of periodontitis.…”

Section: Discussionmentioning

confidence: 99%

“…In previous studies, we have established animal models of induced periodontitis and studied the causality linking periodontitis to the development of glucose intolerance (GI), hyperinsulinemia (HI), and insulin resistance (IR), all hallmarks of prediabetes. Results from our previous studies demonstrate that animals with LPS/bacterial product-induced periodontitis develop prediabetes [4,5] and that bacterial products/LPS are an important initiator of HI, GI, and IR [5]. However, the global impact of periodontitis on metabolism in organs distant from the oral cavity has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

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Experimental Periodontitis Results in Prediabetes and Metabolic Alterations in Brain, Liver and Heart: Global Untargeted Metabolomic Analyses

et al. 2016

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Results from epidemiological studies suggest that there is an association between periodontitis and prediabetes, however, causality is not known. The results from our previous studies suggest that induction of periodontitis leads to hyperinsulinemia glucose intolerance and insulin resistance, all hallmarks of prediabetes. However, global effects of periodontitis on critical organs in terms of metabolic alterations are unknown. We determined the metabolic effects of periodontitis on brain, liver, heart and plasma resulting from Porphyromonas gingivalis induced periodontitis in mice. Periodontitis was induced by oral application of the periodontal pathogen, Porphyromonas gingivalis for 22 weeks. Global untargeted biochemical profiles in samples from these organs/plasma were determined by liquid and gas chromatography/mass spectrometry and compared between controls and animals with periodontitis. Oral application of Porphyromonas gingivalis induced chronic periodontitis and hallmarks of prediabetes. The results of sample analyses indicated a number of changes in metabolic readouts, including changes in metabolites related to glucose and arginine metabolism, inflammation and redox homeostasis. Changes in biochemicals suggested subtle systemic effects related to periodontal disease, with increases in markers of inflammation and oxidative stress most prominent in the liver. Signs of changes in redox homeostasis were also seen in the brain and heart. Elevated bile acids in liver were suggestive of increased biosynthesis, which may reflect changes in liver function. Interestingly, signs of decreasing glucose availability were seen in the brain. In all three organs and plasma, there was a significant increase in the microbiome-derived bioactive metabolite 4-ethylphenylsulfate sulfate in animals with periodontitis. The results of metabolic profiling suggest that periodontitis/bacterial products alter metabolomic signatures of brain, heart, liver, and plasma in the prediabetic state. These data provide scientific community valuable metabolic signatures that become the basis for understanding the impact of periodontitis on a systemic disease and potentially targets for therapeutic intervention.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Experimental Periodontitis Results in Prediabetes and Metabolic Alterations in Brain, Liver and Heart: Global Untargeted Metabolomic Analyses

et al. 2016

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“…In our previous studies, we used application of LPS to the gingival sulci, placement of silk sutures with application of LPS and oral application of Pg . In each of these model systems, we detected alveolar bone loss and all animals (experimental group) developed prediabetes.…”

Section: Discussionmentioning

confidence: 99%

Oral application of a periodontal pathogen impacts SerpinE1 expression and pancreatic islet architecture in prediabetes

Ilievski

Bhat

Suleiman-Ata

et al. 2017

J of Periodontal Research

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Background and Objectives Epidemiological studies suggest a close association between periodontitis and prediabetes/insulin resistance but whether periodontitis causes prediabetes in humans is not known. Using various animal models, we have recently established that periodontitis can be an initiator of prediabetes which is characterized by glucose intolerance, hyperinsulinemia, and insulin resistance. In addition, our in vitro studies indicated that Porphyromonas gingivalis (Pg) induced insulin secretion in MIN6 β cells and this induction was in part SerpinE1 (plasminogen activator inhibitor 1, PAI1) dependent. However, the mechanism(s) by which periodontitis induces prediabetes is not known. Since α and β cells in pancreatic islets are the major modulators of glucose levels, we investigated whether experimental periodontitis by oral application of a periodontal pathogen caused molecular and/or cellular alterations in pancreatic islets and whether SerpinE1 was involved in this process. Materials and Methods We induced periodontitis in C57BL/6 mice by oral application of a periodontal pathogen, Pg, and determined changes that occurred in islets following 22 weeks of Pg application. Pancreatic islet architecture was determined by 2-D and 3-D immunofluorescence microscopy and SerpinE1 and its substrate uPA as well as insulin, glucagon and Pg/gingipain in islets was detected by immunofluorescence. The presence of apoptotic islet cells was determined by both histochemical and immunofluorescence TUNEL assays. To further investigate the direct effect of Pg on apoptosis and the involvement of SerpinE1 in this process, we used SerpinE1 knockdown and scrambled control clones of the MIN6 pancreatic β cell line. Results Pg/gingipain was detected in both the periodontium and pancreas in the experimental group. Islets from animals that were administered Pg orally (experimental group) developed significant changes in islet architecture, upregulation of SerpinE1, and increased β cell apoptosis compared with the control group. We also observed that exposure of MIN6 cells to Pg in vitro resulted in apoptosis. However, apoptosis was significantly reduced when SerpinE1 expression by MIN6 cells was knocked down. Conclusion Oral application of the periodontal pathogen Pg to C57BL/6 mice induces periodontitis, translocation of Pg/gingipain to the pancreas, and results in complex alterations in pancreatic islet morphology. SerpinE1 appears to be involved in this process.

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“…In diabetic periodontitis, significantly increased inflammatory cytokines could be found in serum and gingival cervical fluid [6]. Previous studies have confirmed immune and inflammatory responses in the gingival epithelium play an initial role on the onset and development of diabetic periodontitis [7, 8].…”

Section: Introductionmentioning

confidence: 99%

Comparison of Experimental Diabetic Periodontitis Induced byPorphyromonas gingivalisin Mice

Wang

Zhang

Aprecio

et al. 2016

Journal of Diabetes Research

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Periodontitis is one of the severe complications in diabetic patients and gingival epithelium plays an initial role on the onset and progression of this disease. However the potential mechanism is yet sufficiently understood. Meanwhile, the research on the correlational experimental animal models was also insufficient. Here, we established periodontitis with type 2 diabetes in db/db and Tallyho/JngJ (TH) mice and periodontitis with type 1 diabetes in streptozotocin induced diabetes C57BL/6J (STZ-C57) mice by oral infection of periodontal pathogen Porphyromonas gingivalis W50. We demonstrated that periodontal infected mice with high blood glucose levels showed dramatically more alveolar bone loss than their counterparts, in which infected db/db mice exhibited the most bone defects. No contrary impact could be observed between this periodontal infection and onset and severity of diabetes. The expressions of PTPN2 were inhibited whereas the expression of JAK1, STAT1, and STAT3 increased dramatically in gingival epithelia and the serum TNF-α also significantly increased in the mice with diabetic periodontitis. Our results indicated that the variations of inflammation-related protein expressions in gingival epithelia might lead to the phenotype differences in the mice with diabetic periodontitis.

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TLR4 Expression by Liver Resident Cells Mediates the Development of Glucose Intolerance and Insulin Resistance in Experimental Periodontitis

Cited by 21 publications

References 41 publications

Experimental Periodontitis Results in Prediabetes and Metabolic Alterations in Brain, Liver and Heart: Global Untargeted Metabolomic Analyses

Experimental Periodontitis Results in Prediabetes and Metabolic Alterations in Brain, Liver and Heart: Global Untargeted Metabolomic Analyses

Oral application of a periodontal pathogen impacts SerpinE1 expression and pancreatic islet architecture in prediabetes

Comparison of Experimental Diabetic Periodontitis Induced byPorphyromonas gingivalisin Mice

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