|Year : 2020 | Volume
| Issue : 3 | Page : 182-187
Expression of apelin among the individuals of chronic periodontitis, with and without type ii diabetes mellitus: A study using enzyme-linked immunosorbent assay
Tanvi Hirani1, Santosh Kumar1, Viral Patel2, Sagar Hirani3, Irfan Mohammed4, Deepak Shishoo5
1 Department of Periodontology and Implantology, Karnavati School of Dentistry, Karnavati University, Gandhinagar, Gujarat, India
2 Department of Periodontology and Implantology, Gujarat University, Ahmedabad, Gujarat, India
3 Department of Orthodontics, Karnavati School of Dentistry, Karnavati University, Gandhinagar, Gujarat, India
4 Department of Forensic Dentistry, Federal University of Pelotas, Pelotas, Brazil
5 Department of Physiology, Karnavati School of Dentistry, Karnavati University, Gandhinagar, Gujarat, India
|Date of Submission||10-Aug-2020|
|Date of Decision||14-Aug-2020|
|Date of Acceptance||25-Aug-2020|
|Date of Web Publication||22-Sep-2020|
I 202 – Silver Harmony, Shakun Glory Road, Gota, Ahmedabad - 382 481, Gujarat
Source of Support: None, Conflict of Interest: None
Background: This is the first study showing the co-relationship of apelin among chronic periodontitis (CP) and type 2 diabetes mellitus (T2DM). CP has an anti-inflammatory and anti-glycaemic role in our system. In the future, a localised therapeutic dose of apelin can be used to lower the severity of periodontal disease by reducing the inflammation. The objective of the present study is to investigate the levels of serum apelin from patients with CP, CP + T2DM, and healthy individuals. Materials and Methods: This study included 180 individuals that were equally divided into three groups. Group A consisted of healthy individuals, Group B with CP, and Group C with CP + T2DM. Probing pocket depth (PPD) and serum Apelin (AP) were measured. Serum apelin expression was determined using enzyme-linked immunosorbent assay. Statistical analysis was performed using SPSS software. Results: The highest apelin was in CP + T2DM group (24.0 ± 3.78 ng/dl) followed by CP (15.4 ± 2.01 ng/dl) and healthy individuals (7.6 ± 1.18 ng/dl). There was a significant increase in serum apelin (P ≤ 0.05) in Group C individuals. Similarly, PPD was significantly increased in individuals with CP + T2DM. Conclusion: Expression of significant apelin in patients with CP and T2DM suggests a possible role for these adipokines in inflammation and glucose level regulation. In the future, it may be used as a therapeutic agent in curing periodontitis.
Keywords: Adipokines, apelin, chronic periodontitis, diabetes mellitus
|How to cite this article:|
Hirani T, Kumar S, Patel V, Hirani S, Mohammed I, Shishoo D. Expression of apelin among the individuals of chronic periodontitis, with and without type ii diabetes mellitus: A study using enzyme-linked immunosorbent assay. Adv Hum Biol 2020;10:182-7
|How to cite this URL:|
Hirani T, Kumar S, Patel V, Hirani S, Mohammed I, Shishoo D. Expression of apelin among the individuals of chronic periodontitis, with and without type ii diabetes mellitus: A study using enzyme-linked immunosorbent assay. Adv Hum Biol [serial online] 2020 [cited 2021 Mar 1];10:182-7. Available from: https://www.aihbonline.com/text.asp?2020/10/3/182/295844
| Introduction|| |
Diabetes mellitus (DM) is one of the oldest known diseases to humankind. It was reported in the Egyptian manuscript about 3000 years ago. DM was classified as Type I and II in 1936. Type 2 DM (T2DM) was first described as a component of metabolic syndrome in 1988. T2DM is also known as non-insulin-dependent DM and adult-onset DM, and this is the most common form of DM characterised by hyperglycaemia, insulin resistance and relative insulin deficiency. T2DM from the interaction between genetic, environmental and behavioural risk factors. The relationship between T2DM and the prevalence of periodontal disease has been documented, and both the conditions have been considered to be biologically linked. Evidence from the earlier literature suggests that T2DM is a risk factor for periodontal disease., Several types of studies have suggested a bidirectional interrelationship T2DM and periodontitis.
The exact mechanism through which periodontal disease may influence the diabetic condition is still not confirmed, but the various mechanisms has been suggested to describe the impact of T2DM on the periodontium. Earlier researches indicated that the elevated levels of advanced glycation end products in patients with T2DM cause a hyperinflammatory response to periodontal pathogens. This hyperinflammatory response leads to inflammation and compromised immunity. Moreover, periodontitis has contributed to several complications in T2DM patients.
The adipokines or adipocytokines are cytokines secreted by adipose tissue. The first adipokine to be discovered was leptin in 1994. Since then, numerous varieties of adipokines have been discovered. These are complex proteins that are involved in a full array of events related to inflammation and immunity. Adipokines are produced by white adipose tissue. Adipose tissue is considered to be an energy storage organ. At present, it has been thought to have a crucial role in systemic metabolism. The numerous protein secretion by adipose tissue can mediate the metabolic functions of our body. This adipose tissue is a known endocrine organ which secretes >50 molecules, including vastatin, apelin, leptin, adiponectin, resistin and cytokines.
The role of leptin and adiponectin has been extensively studied., In 1998 Tatemoto et al. identified apelin as the ligand of the APJ receptor, a G protein-coupled receptor Apelin gene makes up 77 amino acid preproproteins. At the same time, apelin propeptide contains several doublets of essential amino acids implicating potential proteolytic cleavage sites for endopeptidases. It is known to exert different physiological effects on different systems, mainly on the cardiovascular system. Apelin not only acts on glucose and lipid metabolism but also modulates insulin secretion. Moreover, several animal and human studies have shown that apelin plasma concentration is usually increased during obesity and type 2 diabetes. Apelin, along with its receptor, is expressed in several vital tissues such as heart, skeletal muscle, lungs, brain, etc. One of the animal studies conducted in a standard mouse showed the glucose-lowering effect both in fasted conditions and during a glucose tolerance test. In addition to that of insulin, apelin also stimulates glucose transport. Apelin, besides, increased Akt phosphorylation in muscle manner and interestingly still be able to stimulate glucose uptake in the muscle of obese and insulin-resistant mice. Hence, it results in overall increased insulin sensitivity.
Unravelling the mysterious yet systematic roles of different adipokines in controlling periodontal health and inflammation may reflect the complex nature of multifactorial diseases such as periodontitis and T2DM. The increase in research in this area will gradually but unveil the complex adipokine-mediated mechanism among the inflammatory and metabolic disorders. No previous studies are reporting any association among apelin, periodontitis and DM.
Hence, we decided to take up the present study to investigate the levels of apelin in serum from patients with chronic periodontitis (CP), CP and T2DM and healthy individuals and to correlate the relationship among CP and T2DM. We started the work with a hypothesis that the apelin level increases in individuals with T2DM.
| Materials and Methods|| |
A cross-sectional study was conducted at the general outpatient department of our institute hospital. The sample size was calculated by using the modified Cochran formula . A total of 180 patients (males 113 and females 67) were included in this study from January 2019 to September 2019. The recruited patients were divided into three groups as per their clinical findings of chronic generalised periodontitis (CGP), T2DM and healthy controls. Group 1 consisted of systemically and periodontally healthy (n = 60); Group 2 with systemically healthy with CGP patients (n = 60); and Group 3 with CGP with T2DM (n = 60). Patients criteria for exclusion were as follows: (1) <35 years of age; (2) <15 teeth; (3) aggressive periodontitis; (4) patients who had received periodontal treatment in the previous 12 months; (5) had taken systemic antibiotics, steroids, and/or immunosuppressant therapy within 3 months before periodontal assessment; (6) severe systemic diseases, and (7) pregnancy or lactation.
This research was performed under the Declaration of Helsinki of the World Medical Association (2008) and approved by the ethical committee (KU/17/KSD246). Informed and written consent was obtained from each patient after explaining the full protocol.
A full mouth periodontal examination was performed in all the participants. CP was determined according to the newer classification (2018) of periodontal disease by the European Federation of Periodontology. Probing pocket depth (PPD) were measured in all tooth except the third molars. The complete examination was performed by a single examiner to eliminate inter-examiner bias. Measurements were recorded at four sites per tooth (mesial, distal, buccal, and lingual) using a calibrated the University of North Carolina periodontal probe (UNC 15; Hu-Feiedy, Chicago, IL, USA). The diagnosis of CP was confirmed when ≥3 interproximal sites with CAL ≥3 mm and ≥3 interproximal sites with PPD ≥4 mm was present.
Patients will be considered diabetic if they fulfill the criteria that laid down by the American Diabetic Association. The criteria are as following:
- A1C ≥6.5%. The test should be performed in a laboratory using a method that is National Glycohemoglobin Standardization Program NGSP certified and standardised to the diabetes control and complications tria assay
- Fasting plasma glucose ≥126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h
- 2-h plasma glucose ≥200 mg/dl (11.1 mmol/l) during an oral glucose tolerance test. The test should be performed as described by the World Health Organisation, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water
- In a patient with classic symptoms of hyperglycemia or hyperglycaemic crisis, a random plasma glucose ≥200 mg/dl (11.1 mmol/l).
Serum collection and biomarker analysis
Fasted samples were collected in the morning. Two ml of venous blood was obtained from the antecubital fossa by venipuncture using a 20G needle with 2.5 ml syringe. Blood samples were left in the germ-free environment to clot at room temperature for an hour. Later the clot was centrifuged at 5000 rpm for 15 min to obtain the serum and 0.5 ml of it was immediately transferred to 1.5 ml aliquots and stored at −80° centigrade till the analysis. All the reagents and blood samples were brought to room temperature before proceeding to the analysis. One hundred microlitres of each standard and sample were poured into their respective wells. Wells were covered and incubated for 2.5 h at room temperature. Samples were then discarded from the well and were washed gently for four times by using 1X wash solution. Any remaining wash buffer was removed by aspirating. Plates were inverted against a paper towel to remove excess wash solution. Hundred μl of 1X detection antibodies were poured in each well and incubated for 1 h at room temperature. Then, the solutions were discarded, and 100 μl of streptavidin solution poured in each well. Wells were covered and incubated for 45 min at room temperature. Again, the solution was discarded, and 100 μl of (3,3', 5, 5'-tetramethylbenzidine) one step substrate reagent were added to each well and incubated for 30 min at room temperature in the dark with gentle shaking. In the end, 50 μl of stop solution was added, and absorbance was immediately read at 450 nm.
All the above analysis was performed by the independent government accredited laboratory blinded to clinical data. The clinical investigator was unaware of the laboratory results until the completion of the research work.
ANOVA was also calculated to check the impact of different groups comparing the means of different groups. Post hoc test for multiple comparisons was made using Tukey honestly significant difference (HSD). Pearson correlation test was performed to access the linear relationship between all the groups. All the data were analysed using software (SPSS, version 7 for Windows, IBM, Chicago, IL, USA).
| Results|| |
[Table 1] reveals the demographic distribution of study participants (CGP Patients) according to DM and gender. A total of 200 CGP patients was selected for the study. Out of 120 patients, 60 were with DM II, and 60 were without DM. Sixty healthy patients were selected for controls. Out of 60 CGP patients, 40 were male, and 20 were female, and their mean age was 43.4 ± 5.05 years. Out of 60 CGP patients with T2DM, 36 were male, and 24 were female, and their mean age was 46.4 ± 6.03.
[Table 2] shows the mean value of different parameters in all the groups. Apelin level was found highest in CGP patients with DM (24.0 ± 3.78 ng/dl) as compared to CGP patients without DM (15.4 ± 2.01 ng/dl). Mean PPD of CGP patients with DM was 3.75 ± 0.43 mm and 3.9 ± 0.46 mm of CGP patients alone. Body mass index was also found higher in CGP with DM patients (38.3 ± 4.6).
|Table 2: Mean values of the level of apelin, probing pocket depth and body mass index among healthy subjects, chronic generalised periodontitis patients and chronic generalised periodontitis patients with Type II diabetic mellitus|
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[Table 3] reveals the results of the ANOVA test. Results of Intragroup and intergroup comparison of apelin levels are highly significant. There were similar findings in the case with PPD and BMI.
Post hoc test for multiple comparisons was calculated using Tukey HSD. This is to find the correlation of Apelin with other groups. Results showed that Apelin change was highly significant in relation to all the groups [Table 4]. Pearson correlation showed that apelin had a positive and high degree of correlation with all the groups [Table 5]. The coefficient value lies between 0.5 and 1, which concludes that there is a high degree of correlation between Apelin, BMI and pocket depth [Table 4].
|Table 4: Multiple comparisons of apelin in different groups of patients using Tukey honestly significant difference test|
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|Table 5: Data from Pearson's correlation test to access the linear relationship of apelin with all other parameters|
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| Discussion|| |
To the best of our knowledge, this is the first study to investigate apelin expression in patients with the CGP, CGP + T2DM, with healthy controls. Levels of adipokine expression (apelin) were determined by enzyme-linked immunosorbent assay and were confirmed by relative quantification of mRNA gene expression by real-time polymerase chain reaction. In the present study, the impact of age and sex was limited by assigning an equal number of subjects and selecting patients within a definite age group.
This study shows that the apelin expression level was highest in patients with CGP + T2DM, followed by CGP and healthy patients. Caton et al. in their paper concluded that apelin plasma levels were significantly increased in diabetic patients. This is probably due to its glucose-lowering effect both in fasted conditions and during a glucose tolerance test. Apelin decreases the glucose level by increasing the glucose uptake in vital tissues such as skeletal muscle and adipose tissue. Caton et al. in his paper reported that the apelin stimulated glucose transport in addition to that of Insulin. Apelin not only stimulated the phosphorylation of the adenosine monophosphate -activated protein kinase (AMPK) but also the endothelial NO synthase (eNOS). The importance of both the enzymes above has been demonstrated in an animal study by the use of eNOS mice and DN-AMPK mice (muscle-specific inactive AMPK), respectively. A similar study by Yue et al. reported that apelin stimulated glucose transportin vitro in C2C12 muscle cells through the AMPK pathway but not eNOS. This variation can be because of NOS inhibitors that were inducted in the study by Yue et al. These inhibitors are competent to decrease glucose uptakein vivo in muscle cells but notin vitro as earlier reported by Roy et al. It has been reported that glucose transport is being stimulated in an AMPK-dependent way in human adipose tissue explants. Apelin not only facilitates the entry of glucose in skeletal muscle and adipose tissues but also In vivo, it has been shown to increase myocardial glucose uptake. Apelin has also been reported to increase intestinal glucose absorption. In an animal study by Dray et al. reported that Ingested glucose rapidly induces the secretion in the intestinal lumen of mice. This study also said that, when apelin administration is done intraorally, the quantity of glucose transporters sodium-glucose linked transporter 1 is decreased in enterocytes, and at the same time, Glut2 is increased due to AMPK activation. Some data suggest that glucose arrival in the intestine causes self-absorption by inducing secretion of apelin.
Apelin is one of the essential adipokines which regulates the glucose level. In reduced levels or absence of insulin, apelin is secreted. This, in turn, decreases the glucose level by increasing the glucose uptake in vital tissues such as skeletal muscle and adipose tissue. Hence higher levels of apelin level are reported in the patients with DM.
With the abundance of research work in recent years, it has been proved beyond doubt that periodontitis is an inflammatory disease initiated by oral biofilm. The destruction of the periodontium in the pathogenesis of the disease results from the host response against the biofilm. Periodontal disease is primarily considered as a risk factor for both oral and systemic diseases. Gholizadeh et al. in their study, associated orodigestive cancers to periodontitis associated bacteria., Extensive research shows that porphyromonas gingivalis and Fusobacterium nucleatum directly activate the transduction pathway leading to cell transformation.,
In this study, apelin levels have been significantly increased in the CGP group too. Till date, there are no studies concerning with apelin and periodontitis. Periodontitis is an inflammatory disease; hence, we will attempt to relate apelin with inflammatory conditions. Adipocytokines secreted by adipose tissue play an essential role in reducing inflammation. A marked increase in the apelin levels is found in inflammatory diseases such as hepatitis, Pancreatitis and cardiovascular diseases. Apelin has an essential role in inflammation. In a study by Koguchi et al. reported apelin to be an anti-inflammatory cytokine. It effectively suppressed the expression of inflammation factors such as tumour necrosis factor-alpha (TNF-a) and interleukin (IL)-1b protein. In an animal study, apelin treatment was associated with a significantly decreased amount of macrophage colony-stimulating factor and decreased monocyte chemoattractant protein-1, macrophage inflammatory protein-1a, IL-6, and TNF-a mRNA levels. Endogenous secretion of apelin is needed for the suppuration of inflammation-induced vascular hyperpermeability. Leeper et al. in their study on macrophage inflammation, reported that apelin inhibits the down-modulation of vascular endothelial cadherin by vascular endothelial growth factor, which intern leads to suppression of hyperpermeability. Similarly, apelin can also suppress the inflammation in any non-circulation system diseases. Visser et al. have advised the therapeutic use of apelin in suppressing inflammation. In his study, he reported that apelin improved alveolarisation and angiogenesis, increased lung cGMP levels, and reduced inflammation. Similarly, Leal et al. also suggested a possible association between apelin and inflammation. In contrast to all the studies above, Heinonen et al. reported apelin to promote inflammation in patients with metabolic syndrome after a diet-induced weight loss. The effect and the role of apelin become more complex as furthermore researches are done. If the new finding was to be believed, apelin might play a pro-inflammatory role.
In our study, we have shown a significant apelin increase in the PPD of the CGP + T2DM group. Apelin was also positively and profoundly correlated to all the other groups. This is probably due to the rise in the risk of diabetes-related complications. Inflammatory mediators are considered to play a double role in T2DM, contributing to hyperglycaemia-induced insulin resistance and contributing to diabetic complications. Although bacteria are necessary for the occurrence periodontal disease, a susceptible host is most important. TNF-α, IL-1 β, IL-6 and IL-18, are reportedly increased in DM. This enhanced production of inflammatory cytokines is thought to contribute to bone loss and hence, increase in PPD. This inflammatory process is characterized by the infiltration of leucocytes, which limit the level of bacterial invasion and can be harmful to the periodontal tissue. Destruction of bone and the periodontal ligament (PDL) is caused by a disruption of the homeostatic balance between the host response and bacteria, which causes inflammation very close to the bone.,, This combination of bacterial infection and host response through the activation of osteoclastic factor that is produced by immune cells help them to cause the periodontitis-related bone loss. Several longitudinal studies have shown that the risk of periodontitis is approximately 3–4 times higher in people with diabetes than in non-diabetic subjects. Diabetes also increases the loss of PDL cells that is induced by periodontal infection by increasing the apoptosis of these cells. PDL is a vital source of cells that differentiate into osteoblast; hence, the loss of PDL cells by apoptosis is very significant. Several animal studies have reported that diabetic causes a >2-fold induction of genes that regulate the apoptosis of osteoblasts and fibroblasts following bacterial infection and a five-fold increase in osteoblast apoptosis., The apoptosis of osteoblast prevents the new bone formation after the induction of periodontal disease., Periodontal disease is very closely associated with DM and also similar to other chronic diseases. Continuous hyperglycemia leads to amplified immune-inflammatory responses that are induced by periodontal pathogens. This is probably responsible for the severity of periodontal disease in diabetic.
| Conclusion|| |
Within the limitations of the present study, it can be concluded that the patients with CP + T2DM expressed the highest apelin content followed by the patients with CP and healthy individuals. Apelin plays a vital role in reducing the inflammation and regulating the glucose level in the absence or low level of insulin. In the future, apelin can have therapeutic use in suppressing the inflammation and preventing bone destruction. Further study is needed to understand the role of other apelin subtypes such as apelin-13. Further prospective large-cohort studies are required to confirm these findings and to understand the exact mechanism.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]