Abstract
This study evaluated the influence of type 2 diabetes mellitus on bone loss, bone repair and cytokine production in hyperglycemic rats, treated or not with metformin. The animals were distributed as follow: Non-Hyperglycemic (NH), Non Hyperglycemic with Ligature (NH-L), Treated Non Hyperglycemic (TNH), Treated Non Hyperglycemic with Ligature Treated (TNH-L), Hyperglycemic (H), Treated Hyperglycemic (TH), Hyperglycemic with Ligature (H-L), Treated Hyperglycemic with Ligature (TH-L). At 40th day after induction of hyperglycemia, the groups NH-L, TNH-L, H-L, TH-L received a ligature to induce periodontitis. On the 69th, the TNH, TNH-L, TH, TH-L groups received metformin until the end of the study. Bone repair was evaluated at histometric and the expression levels of Sox9, RunX2 and Osterix. Analysis of the ex-vivo expression of TNF-α, IFN-γ, IL-12, IL-4, TGF-β, IL-10, IL-6 and IL-17 were also evaluated. Metformin partially reverse induced bone loss in NH and H animals. Lower OPG/RANKL, increased OCN and TRAP expression were observed in hyperglycemic animals, and treatment with metformin partially reversed hyperglycemia on the OPG/RANKL, OPN and TRAP expression in the periodontitis. The expression of SOX9 and RunX2 were also decreased by hyperglycemia and metformin treatment. Increased ex vivo levels of TNF-α, IL-6, IL-4, IL-10 and IL-17 was observed. Hyperglycemia promoted increased IL-10 levels compared to non-hyperglycemic ones. Treatment of NH with metformin was able to mediate increased levels of TNF-α, IL-10 and IL-17, whereas for H an increase of TNF-α and IL-17 was detected in the 24- or 48-hour after stimulation with LPS. Ligature was able to induce increased levels of TNF-α and IL-17 in both NH and H. This study revealed the negative impact of hyperglycemia and/or treatment with metformin in the bone repair via inhibition of transcription factors associated with osteoblastic differentiation.
Highlights
Diabetes mellitus is a metabolic disorder with multiple etiology that generates a chronic systemic state of hyperglycemia, with Type 2 being more common, affecting approximately 90% of diabetic individuals
No changes were detected in the OPG/RANKL, OCN and OPN proportions for the different experimental groups in the absence of ligature-induced periodontitis, the present study showed a lower OPG/RANKL proportion, and increase in expression of OCN and Tartrate-Resistant Acid Phosphatase (TRAP) in the hyperglycemic animals, results that were in agreement with those described by Silva et al [23] and Gennaro et al [25]
In an endeavor to understand the negative impact of hyperglycemia and treatment with metformin on alveolar bone repair, the present study evaluated the levels of SOX9, RunX2 and Osterix, transcription factors associated with osteoblast differentiation
Summary
Diabetes mellitus is a metabolic disorder with multiple etiology that generates a chronic systemic state of hyperglycemia, with Type 2 being more common, affecting approximately 90% of diabetic individuals. There is a scarcity of studies in the that have used experimental models of diabetes type 2 and ligature-induced periodontitis. The authors demonstrated that 4 weeks after inserting the ligature, the presence of periodontitis promoted disturbances in glucose homeostasis of diabetic rats, thereby harming the pre-diabetic state. In 2008, the effect of experimental ligature-induced periodontitis associated with a diet rich in fats [8] was evaluated in diabetic and obese rats of the Zucker lineage relative to insulin resistance. The results showed that ligature-induced periodontitis harmed the glucose homeostasis in diabetic rats fed on a diet rich in fats. More recently [9], a pre-clinical study observed an increase in inflammatory response and osteoclastogenesis in Goto-Kakizaki rats with ligature-induced periodontitis via TNF production. Hasegawa et al [10] demonstrated a lower osseointegration capacity in type 2 diabetic rats, and in a similar manner Wang et al [11] demonstrated rats of the Goto-Kakizaki lineage had a larger quantity of fibrous tissue around implants installed in the femoral regions that the nondiabetic control group animals had
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