Involvement of toll-like receptor 4 in alveolar bone loss and glucose homeostasis in experimental periodontitis

Abstract

Background and Objective There is general agreement that certain fatty acids and lipopolysaccharides (LPS) promote inflammation through toll-like receptor 4 (TLR4), and that inflammation promotes insulin resistance. We therefore hypothesized that mice with periodontitis and a TLR4 loss-of-function (LOF) mutation fed a high-fat (HF) diet would develop improved glucose homeostasis compared with wild-type (WT) animals with periodontitis fed a HF diet. Material and Methods Wild-type and TLR4 mutant mice fed a HF diet were divided into four groups (n = 6/group): WT; WT with periodontitis (WT/P); mutant (Mut); and mutant with periodontitis (Mut/P). Periodontitis was induced by placing LPS soaked ligatures around maxillary second molars. Fasting insulin and glucose levels were measured weekly for 10 wk. Glucose tolerance was evaluated at baseline (week 1) and at 9 wk. Insulin signaling (phosphorylation of Akt) and tumor necrosis factor-α (TNF-α) mRNA levels in liver were determined when the mice were killed at week 10. Results Mut/P mice developed less alveolar bone loss compared with WT/P mice (p < 0.05). Fasting glucose levels were improved after 8 wk of feeding a HF diet (weeks 9 and 10) in Mut/P mice compared with Mut, WT and WT/P mice (p < 0.05). Glucose tolerance was impaired in all groups compared with baseline (p < 0.05), except for the Mut/P group. Insulin signaling was improved (p < 0.05), and expression of TNF-α was decreased (p < 0.05) in the liver of Mut/P mice compared with the liver of WT/P mice. Conclusion The TLR4 LOF mutation partially protects against alveolar bone loss and improves glucose homeostasis in mice with periodontitis fed a HF diet.

Porphyromonas gingivalis Lipopolysaccharide Upregulates Insulin Secretion From Pancreatic β Cell Line MIN6

“…IR that developed in these animals was associated with a reduced phosphorylated Akt (p‐Akt)/Akt ratio in the liver upon stimulation with exogenous insulin 10 . The authors have also shown that insulin levels increase during IR/prediabetic development in this animal model 10,11 . Although LPS can stimulate the production of cytokines that promote IR in insulin target organs, 12,13 it has been shown that hyperinsulinemia drives the development of peripheral IR 14 .…”

“…Results from the authors’ previous studies 10,11 using an animal model indicate that IR develops in the setting of periodontitis induced by ligature placement and application of LPS around the gingival sulcus. IR that developed in these animals was associated with a reduced phosphorylated Akt (p‐Akt)/Akt ratio in the liver upon stimulation with exogenous insulin 10 . The authors have also shown that insulin levels increase during IR/prediabetic development in this animal model 10,11 .…”

Periodontitis in Diabetics: Is Collaboration Between Physicians and Dentists Needed?

“…A number of studies have demonstrated that periodontitis lesions release high levels of these cytokines. Therefore, the basic premise underlying the potential influence of periodontitis on the diabetic condition is that proinflammatory cytokines or LPS released locally in gingiva may enter the systemic circulation and influence insulin target organs/tissues in distant sites 48 . Since TNFα is known to impair insulin signaling and cause insulin resistance 49 , it is hypothesized that periodontitis via production of TNFα and possibly other cytokines influences the diabetic condition.…”

“…For example, induction of periodontitis in prediabetic rats causes impaired glucose tolerance 51, 52 . In addition, induction of periodontitis accelerates the development of insulin resistance and the onset of T2DM in animals fed a high fat diet 48 . However, as mentioned above, more research is necessary to understand the inter-relationship between periodontitis and DM, especially the effect of periodontitis on the course of DM progression and end organ damage.…”

Serpine1 Mediates Porphyromonas gingivalis Induced Insulin Secretion in the Pancreatic Beta Cell Line MIN6

“…Results from our previous studies indicate that hyperinsulinemia develops when periodontitis is induced in rats and mice [7,8] and this finding is supported by results from studies that demonstrate that periodontitis promotes insulin resistance in a rat model in part via hyperinsulinemia [6,7]. …”