Effects Of Periodontal Intervention On Adiponectin,Inflammatory Cytokines And Metabolic Control In Patients With Type2Diabetes And Periodontitis

BackgroundPeriodontitis is the most common chronic inflammatory disease and characterized by periodontal pocket formation, loss of connective tissue attachment and alveolar bone resorption, which can eventually result in tooth loss. Over the past decade, a large number of major research findings suggest that periodontitis not only seriously affects oral health, but also acts as risk factors for diabetes mellitus (DM), chronic coronary heart disease (CHD) and other many systemic diseases. At present, the interaction between periodontitis and systemic diseases has become the research focus of periodontal medicine. Diabetes mellitus is a clinically and genetically heterogeneous group of disorders affecting the metabolism of carbohydrates, lipids and proteins, and hyperglycemia is a main feature, which has emerged as an increasingly common disease over the last decade. DM remains a chronic metabolic disorder that is often associated with unacceptably high disease burden especially in developing countries, and cardiovascular diseases (CVD) are highly contributory to this scenario. It is a significant cause of morbidity and mortality in both developed and developing countries. Therefore, periodontitis and diabetes are both common diseases with high incidences and have negative and harmful impacts on people. A new large Chinese national survey in2009indicates that type2diabetes mellitus (T2DM) has become a serious public health threat in China, suggesting that China is taking over India and becoming the epicenter of diabetes in the world.In recent years a large number of studies have confirmed that there is a bidirectional relationship between the mechanism of T2DM and periodontitis. Evidence has consistently indicated that diabetes is a high risk factor for the incidence and development of periodontitis, and for the increased severity of periodontitis. On the other hand, periodontitis is also a risk factor for the development of diabetes, and for the increased diabetic-related complications such as diabetic nephropathy, CVD, etc. Insulin resistance (IR) and pancreatic β cell dysfunction are the two key factors of diabetes development, and inflammation is a central feature of the pathogenesis of IR and diabetes. Increasing evidence suggests that severe chronic periodontitis represents a sub-clinical septicaemic state, which maybe the risk factor of poor glycemic control and impaired endothelial in the patients with diabetes and periodontitis. It can produce some if Hammatory cytokines, such as C-reactive protein (CRP), tumor necrosis factor-a (TNF-a) and interleukin-6(IL-6) in the local tissue, as well as elevate their circulating levels, and the cytokines mentioned above are associated with reduced insulin sensitivity, poor glycaemic control and dyslipidemia. Therefore, serum levels of IL-6a-i CRP have been shown to be predictor factors of future occurrence of T2DM.Adiponectin is the only adipocytokine secreted specifically by mature adipocytes, which plays an important negative regulatory role in some physiological and pathological processes, including multiple protective roles such as anti-inflammatory, increasing insulin sensitivity, and protection of vascular lesions. Previous studies showed that hypoadiponectinemia is correlated with increased hyperinsulinemia and IR during the development of T2DM. Therefore, some scholars have suggested that adiponectin could act as another independent predictor of future occurrence of T2DM.Deteriorated and dysregulated inflammatory responses are at the heart of the occurrence and development of proposed two-way interaction between diabetes and periodontitis. Therefore, periodontal intervention may not only improve the periodontal status, but also improve systemic health and reduce the occurrence and development of diabetes and diabetic-related complications in patients with diabetes and periodontitis.Recently, many scholars have studied extensively about the effects of periodontal intervention on inflammatory cytokines, glucose and lipid metabolism in diabetic patients with periodontitis, while the findings were controversial. Most scholars believe that effective periodontal therapy can not only reduce periodontal inflammation but also can reduce serum inflammatory cytokines (eg. TNF-a, CRP and IL-6levels), improve glycemic control and reduce glycated haemoglobin (HbAlc), while contrary to the studies of others. Ide et al. indicated that serum inflammatory cytokines such as CRP, TNF-a, IL-6and IL-1Jβ did not change after periodontal surgical treatment in periodontitis patients. And the effect of periodontal intervention on glycemic control had no significant improvement in the studies of Jones et al. and Lalla et al. The effects of periodontal intervention on serum adiponectin were also controversial. The study of Iwamoto et al. showed that adiponectin levels did not change significantly after periodontal treatment in fifteen chronic periodontitis patients with various systemic conditions at high risk for atherosclerosis, while the study of Matsumoto et al. resulted in that the adiponectin levels increased significantly after periodontal treatment in T2DM patients with periodontitis. This could be attributed to considerable differences in methodology, in the sample sizes and compositions of the groups included in the studies. Thus, investigations about periodontal intervention studies are still required to better understand the effects of periodontal intervention on adiponectin, inflammatory cytokines, glucose and lipid metabolism in diabetic patients with periodontitis.Adiponectin gene (adipose most abundant gene transcript1, APM-1) is located on chromosome3q27, wherein the genes for susceptibility to T2DM and metabolic syndrome are also located. Genetic studies have also found that single-nucleotide polymorphisms (SNPs) at multiple sites in APM-1are related to hypoadiponectinemia and T2DM, and the distribution of adiponectin SNPs varied greatly between human races. SNP276G/T has been reported to be associated with serum adiponectin, insulin sensitivity and T2DM, while the association between adiponectin SNP276G/T and serum adiponectin level, IR and T2DM is still remained controversial in different ethnic, even in the same ethnic population. Some of domestic scholars studied the relationship between adiponectin SNP276G/T and T2DM, while the results are also inconsistent. Differences in race, gender and disease status should be taken into account to make a decision of the impact of adiponectin SNP276G/T on serum adiponectin level and IR at present time. Therefore, it is necessary to investigate the relationship among the adiponectin gene SNP276G/T polymorphisms, serum adiponectin level, IR and T2DM in the Chinese population.Up to now, few studies have investigated the distribution of SNP276G/T in APM-1and its effects on adiponectin concentrations, glycaemic control, dyslipidemia and IR in Chinese patients with T2DM and periodontitis. And few studies have investigated the effects of periodontal intervention on adiponectin, metabolic control and IR in Chinese patients with both T2DM and periodontitis with different SNP276G/T genotypes, either.In this study, the patients with periodontitis in different diabetic status (IGT, HbAlc between6.5%-7.5%and7.5%-9.5%) were followed periodontal intervention, the APM-1gene SNP276G/T was genotyped by PCR sequencing, the periodontal clinical indicators (including PD, AL, BI, and P1I), serum adiponectin, inflammatory cytokines (eg. CRP, TNF-a and IL-6), lipid profile, FPG, HbAlc and FINS were measured at baseline and after3months of periodontal intervention, and IR was evaluated by the HOMA-IR (HOMA-IR=FINS×FPG/22.5). In the study, we explored the effects of periodontal intervention on adiponectin concentrations, inflammatory cytokines, metabolic control and IR in the patients with periodontitis in different diabetic status, and we explored the distribution of SNP276G/T in APM-1in the healthy people and patients with both T2DM and periodontitis in Chinese Zhejiang first time. We investigated the effects of APM-1gene SNP276G/T polymorphisms in patients with T2DM and periodontitis on adiponectin, metabolic control and IR, and assessed the changes of periodontal clinical indicators, adiponectin concentrations, metabolic control and IR after periodontal intervention in Chinese patients with T2DM and periodontitis with different SNP276G/T genotypes. Part I Effects of periodontal intervention on adiponectin and inflammatory cytokines in impaired glucose tolerance and type2diabetes patients with periodontitisObjective:To determine the effects of periodontal intervention on periodontal clinical indicators, serum adiponectin, inflammatory cytokines (CRP, TNF-a and IL-6) and HbAlc in the patients with impaired glucose tolerance (IGT) and type2diabetes mellitus (T2DM)(HbAlc between6.5%and7.5%) with chronic periodontitis.Methods:A total of50IGT and106T2DM (HbAlc between6.5%and7.5%) patients with periodontitis were enrolled. The T2DM patients were divided into two groups:DM1group for T2DM without macrovascular disease and DM2group for T2DM with macrovascular disease. Each group was randomly divided into two subgroups according to whether they accepted periodontal intervention (T2DM-T group and T2DM-NT group). The normal control group (NC group) consisted of30healthy adults. The periodontal clinical indicators (including PD, AL, BI, P1I and BOP), serum adiponectin, HbAlc, CRP, TNF-a and IL-6levels were measured at baseline and3months after periodontal intervention.Results:1. The clinical periodontal variables levels of the PD, AL, BI, PLI and BOP were improved significantly in T2DM-T group after3months than that of in T2DM-NT group (all P<0.01).2. The serum adiponectin levels at baseline had decreased tendency with significant difference between each two groups among NC, IGT, DM1and DM2groups, while CRP, TNF-a and IL-6levels had increased tendency with significant difference between the same two groups,(all P<0.01). 3. At3months after periodontal intervention, the serum adiponectin levels were increased than those without periodontal intervention (all P<0.01), while CRP, IL-6and TNF-a significantly decreased in both IGT and DM1groups (all P<0.05).4. In DM2group, only CRP levels at3months after periodontal intervention were significantly decreased (P<0.05).5. Moreover, the HbAlc levels in T2DM patients were improved at3months after periodontal invention (P<0.01).ConclusionPeriodontal intervention reduces periodontal inflammation which is helpful for periodontal health. Periodontal intervention can also increase serum adiponectin levels and reduce serum inflammatory cytokine levels in the patients with impaired glucose tolerance and type2diabetes mellitus (T2DM) with periodontitis. And periodontal intervention can improve glycemic control in the patients with T2DM and periodontitis. The glycemic control improvement may be associated with increased serum adiponectin levels and decreased inflammatory cytokine levels. Part Ⅱ Changes of adiponectin, inflammatory cytokines, insulin resistance and metabolic control after periodontal intervention in patients with moderately poor glycaemic control type2diabetes and periodontitisObjective:To evaluate the effects of periodontal intervention on adiponectin, inflammatory cytokines, insulin resistance (IR), and metabolic control in the patients with periodontitis and T2DM with moderately poor glycaemic control (HbAlc between7.5%and9.5%).Methods:A total of190moderately poor glycaemic control (HbAlc between7.5%and9.5%) T2DM patients with periodontitis were randomly divided into two groups according to whether they performed periodontal intervention:T2DM-NT and T2DM-T group. The periodontal clinical indicators (including PD, AL, BI and P1I), serum adiponectin, CRP, TNF-a, IL-6, lipid profile, HbAlc, fasting insulin (FINS) were measured at baseline and after3months in all the subjects, and IR was evaluated by the HOMA-IR.Results:1. The clinical periodontal variables levels, the PD, AL, BI and PLI were improved significantly in T2DM-T group after3months than that of in T2DM-NT group (all P<0.01).2. After3months, the serum levels of CRP, TNF-a, IL-6, FPG, HbAlc, FINS and HOMA-IR index decreased, adiponectin increased significantly in T2DM-T group than that of in T2DM-NT group (P<0.05or P<0.01). Conclusion:Periodontal intervention reduces periodontal inflammation which is helpful for perinodontal health, and periodontal intervention can improve glycemic control, lipid metabolism, decrease insulin resistance, reduce serum inflammatory cytokine levels and increase serum adiponectin levels in the patients with moderately poor glycaemic control T2DM and periodontitis. And the glycemic control improvement may be associated with increased serum adiponectin levels and decreased inflammatory cytokine levels. Part III Effects of adiponectin gene SNP276G/T on adiponectin, metabolic control and insulin resistance and changes after periodontal intervention in the patients with type2diabetes mellitus and periodontitisObjective:To investigate the distribution of SNP276polymorphisms in adiponectin gene (APM-1) and its influence on periodontal clinical indicators, adiponectin concentrations, metabolic control and insulin resistance (IR) and changes after periodontal intervention, to assess the potential benefit of periodontal intervention in the patients with T2DM and periodontitis with different SNP276G/T genotype.Methods:A total of272patients with T2DM and periodontitis were randomly divided into two groups according to whether they accepted periodontal intervention:T2DM-NT and T2DM-T group. The normal control group consisted of200healthy adults. SNP276G/T was genotyped by PCR sequencing, the periodontal clinical indicators (including PD, AL, BI and PLI), the serum adiponectin, lipid profile, FPG, HbAlc and fasting insulin (FINS) were measured at baseline and after3months in all the subjects, and IR was evaluated by the HOMA-IR.Results:1. T allele frequency of SNP276G/T was significantly lower in the T2DM group than that in the healthy groups (24.9%vs31%, P<0.05).2. Serum adiponectin were significantly lower in patients with T2DM than that in the healthy group (P<0.01).3. At baseline, in patients with GG genotype, adiponectin concentrations were significantly lower than those with GT and TT genotype (P<0.05), significantly higher levels of HbAl c compared to other genotypes (P<0.01), significantly higher levels of FPG and HOMA-IR index compared with that of in the TT genotype (P<0.05).4. After3months, the levels of clinical periodontal variables, PD, AL, BI and PLI were improved significantly in the patients in T2DM-T group compared to those before periodontal intervention (all P<0.01).5. After3months, FPG levels significantly decreased in patients with GG genotype in T2DM-T group compared to those before periodontal intervention (P<0.01), serum HbAlc levels significantly reduced in all genotypes (P<0.01), HOMA-IR index and FINS levels apparently reduced in GG and GT genotypes (P<0.01, P<0.05, respectively), while adiponectin levels significantly increased in all genotypes in T2DM-T group than those before periodontal intervention (all P<0.01).Conclusion:Periodontal intervention can improve clinical periodontal state. And periodontal intervention is also helpful for glucose and lipid metabolism improvement, HOMA-IR index reduction, which may be associated with increased serum adiponectin levels. SNP276G/T of APM-1gene is associated with adiponectin, HbAlc concentration and insulin resistance in patients with T2DM and periodontitis. It may be the G allele of SNP276that is associated with the development of type2diabetes and periodontitis in Chinese Zhejiang Han patients.