Anti‐inflammatory role of glucose‐dependent insulinotropic polypeptide in periodontitis

Abstract

Aims/IntroductionThe involvement of glucose‐dependent insulinotropic polypeptide (GIP) on inflammation was explored in atherosclerosis and adipose tissue. Periodontal disease is a chronic inflammatory disease, and is considered one of the diabetic complications. In the present study, to examine the effect of GIP on periodontitis, we induced experimental periodontitis in glucose‐dependent insulinotropic polypeptide receptor‐knockout mice (GIPRKO). We also investigated the anti‐inflammatory effect of GIP in a culture system.Materials and MethodsExperimental periodontitis was induced by ligature wire in GIPRKO and C57BL/C mice. Two weeks after the ligature, immunohistological evaluation and inflammatory messenger ribonucleic acid expression in the gingiva was examined. To elucidate the role of GIP in inflammation, the effects of GIP on lipopolysaccharide‐induced gene expressions in THP‐1 cells were evaluated.ResultsPeriodontitis increased inflammatory cell infiltration, macrophage accumulation and tumor necrosis factor‐α and nitric oxide synthase gene expressions in the gingiva. Periodontitis in GIPRKO showed a marked increase of inflammatory cells in the gingivomucosal tissue. Mac‐1‐positive macrophages and the inflammatory gene expressions were significantly increased in periodontitis in GIPRKO compared with C57BL/C mice periodontitis. Immunohistochemical staining confirmed that GIP receptors were expressed in residual and infiltrated Mac‐1‐positive macrophages. The in vitro study showed that GIP suppressed lipopolysaccharide‐induced tumor necrosis factor‐α and nitric oxide synthase gene expression in a dose‐dependent manner. Furthermore, the inhibitory effect of GIP on lipopolysaccharide‐induced inflammatory gene expressions was at least partially through cyclic adenosine monophosphate/protein kinase A pathway.ConclusionsThese results suggest the beneficial effects of GIP on periodontal disease. In diabetic patients, GIP is expected to have a direct anti‐inflammatory effect on periodontitis in addition to its glucose‐lowering effect.

Oral health, diabetes, and body weight

“…The animal model has the advantage of being able to simulate the pathogenesis of several diseases with greater control of variables (Clause, 1993). The use of streptozotocin to induce the diabetic state in rats via its toxicity to the pancreatic beta cells has also been widely accepted and shows similar results with genetically altered diabetic rat or studies in humans especially with regard to systemic effects of oral infections (Elburki et al, 2016;Samuel, Gomes Filho, Dezan-Junior, & Cintra, 2014;Suzuki et al, 2016). In this model, reduced pancreatic weight is generally observed in rats that have been administered streptozotocin, as compared to normoglycemic rats (Shimizu, Shiratori, Hayashi, Fujiwara, & Horikoshi, 2000), which is consistent with the results of the present study.…”

GIP as a Potential Therapeutic Target for Atherosclerotic Cardiovascular Disease–A Systematic Review

“…The anti-inflammatory effects of GIP have also been observed in other tissues [76,101]. Whole-body deletion of GIPR gene promoted the gingival macrophage infiltration and gene expression levels of Tnf-alpha and inducible nos in a mouse model of periodontitis [76]. The infusion of active GIP (4 pmol/kg/min) reduced the blood levels of IL-6 in LPS-induced endotoxemic mice as well [101].…”

“…On the other hand, the [D-Ala2] GIP injections increased the epididymal gene expression and blood levels of adiponectin [80]. The anti-inflammatory effects of GIP have also been observed in other tissues [76,101]. Whole-body deletion of GIPR gene promoted the gingival macrophage infiltration and gene expression levels of Tnf-alpha and inducible nos in a mouse model of periodontitis [76].…”

“…Indeed, a couple of studies showed the anti-inflammatory effects of GIP in immune cells (Table 1) [76,77]. GIP ranging from 1 to 100 nM dose-dependently suppressed the lipopolysaccharide (LPS)-induced gene expression levels of tumor necrosis factor (TNF) or inducible NOS in human monocyte THP-1 cells, and these effects were abolished by inhibiting adenyl cyclase or PKA, but not exchange protein directly activated by cAMP 2 [76]. This suggests the involvement of GIPR/adenyl cyclase/PKA axis.…”

Glucagon-Like Peptide-1 Receptor Agonist Liraglutide Ameliorates the Development of Periodontitis

“…We previously demonstrated the beneficial effects of glucose-dependent insulinotropic polypeptide (GIP) on periodontitis via its anti-inflammatory effects using ligature-induced experimental periodontitis model mice [ 9 ]. GIP and glucagon-like peptide-1 (GLP-1) are incretin hormones which are secreted from the intestine.…”