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Abstract
Objective Multiple studies have reported a potential contribution of human cytomegalovirus (HCMV) to the pathogenesis of type 1 diabetes and post-transplantation diabetes. However, the association between HCMV and type 2 diabetes mellitus (T2DM) remains unclear. In this paper, we employ the meta-analysis approach to investigate the potential correlation between HCMV infection and T2DM.
Method The data of our study were collected from PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure and WAN FANG databases from inception to November 2022. Using the Review Manager V.5.4 software, the meta-analysis was performed.
Results A total of 18 139 patients from 22 studies were included in our analysis. In the Asian subgroup, the patients with T2DM group had a significantly higher frequency of HCMV infection and older age compared with the healthy group. In the European, the frequency of HCMV infection in the T2DM was lower than the healthy group, although this difference was not statistically significant. After adjusting for demographic factors, the adjusted OR of T2DM for risk of by HCMV status was not found to be significant (adjusted OR=1.19, 95% CI=0.88 to 1.62, p>0.05). Additionally, T2DM with vasculopathy had a significantly higher rate of HCMV infection compared with those without vasculopathy (OR=1.87, 95% CI=1.24 to 2.83, p<0.05). Among T2DM with HCMV infection, there were significant increases in fasting blood glucose levels and the proportion of CD8+ T lymphocytes. Conversely, fasting blood insulin levels, the proportion of CD4+ T lymphocyte and the CD4+/CD8+ ratio were significantly decreased compared with the healthy group.
Conclusion At present, the available evidence does not provide a clear understanding of whether there is a significant association between T2DM and HCMV infection. Additionally, T2DM with HCMV infection exhibited significantly worse blood glucose regulation and immune markers, as well as a higher frequency of vasculopathy.
PROSPERO registration number CRD42022342066.
- virology
- diabetes & endocrinology
- general diabetes
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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STRENGTHS AND LIMITATIONS OF THIS STUDY
Our paper first conducted the analysis of the association between human cytomegalovirus (HCMV) infection and type 2 diabetes mellitus (T2DM) by examining peripheral blood and serum samples.
We conducted a study that examined the relationship between HCMV infection and T2DM specifically in the context of vasculopathy.
We explored the relationship between HCMV infection and blood glucose regulation and immune function, with a particular focus on key indicators such as fasting blood glucose, fasting blood insulin and T lymphocyte subsets.
The majority of our study participants were of Asian and European, which limits the generalisability of our statistical findings to specific regions and populations.
The studies included in our analysis primarily consisted of case–control and cross-sectional designs, which are unable to establish a temporal relationship between HCMV infection and the development of T2DM.
Introduction
In recent years, there has been a significant increase in the prevalence of type 2 diabetes mellitus (T2DM) worldwide, primarily due to changes in diet and lifestyle. The regions experiencing the highest growth rates of T2DM are Asia, the Middle East and North Africa.1 According to the International Diabetes Federation, the total number of individuals with T2DM worldwide reached 537 million in 2021, and it is projected to reach 783 million by 2045.2 T2DM has emerged as one of the fastest-growing diseases globally. Implementing timely preventive measures and targeted treatments is crucial for improving the overall health of the global population.3
Human cytomegalovirus (HCMV) is a common DNA herpes virus that is widely prevalent in the human population. It exhibits a latent phase with high species specificity.4 In most cases, when individuals with normal immune function are initially infected with HCMV, they typically experience an asymptomatic infection, meaning they do not show any noticeable symptoms.5
On recognition of HCMV, the immune system of the host initiates efforts to eliminate the virus. However, complete removal of all viral particles by host cells is often not achieved, leading to the establishment of latent infection in undifferentiated monocytes and endothelial cells for extended periods.6 7 Over time, HCMV is captured, processed and presented by T cells, resulting in the expansion of specific T cell clones. Eventually, there is an increase in the number of T cells that lack immune activity against HCMV, while the proportion of T cells with HCMV immune activity gradually declines, leading to a diminished inhibitory effect on the virus.8 As the body’s immune response fluctuates, HCMV undergoes irregular or periodic micro DNA replication, resulting in chronic low-grade inflammation.9 When the immune system becomes compromised, HCMV can undergo reactivation and generate a large number of infectious viral particles. During this reactivation phase, HCMV triggers a series of inflammatory reactions that can cause cellular damage and contribute to the onset and progression of various inflammatory diseases. Recent research has established a close association between HCMV infection and inflammatory conditions such as atherosclerosis, Crohn’s disease, pneumonia, myocarditis and others.10
Inflammation is a significant risk factor for diabetes and plays a crucial role in the onset and progression of various complications associated with diabetes.11 Extensive research studies have demonstrated a strong correlation between inflammatory HCMV infection and the development of type 1 diabetes.12–15 However, the relationship between HCMV infection and T2DM remains unclear and requires further investigation.
T2DM is the most prevalent form of diabetes, accounting for 90%–95% of all diabetes cases worldwide.16 Its associated cardiovascular complications are the leading cause of mortality. T2DM has emerged as a significant public health concern, posing a major threat to public safety.17 Increasing evidence indicates that inflammation plays a crucial role in regulating glucose metabolism in T2DM and contributes to the development of chronic complications associated with the disease.18 19 Therefore, it is essential to investigate the relationship between the inflammatory response triggered by HCMV infection and T2DM. In our study, we conducted a meta-analysis to compare the frequency of HCMV infection between patients with T2DM and healthy individuals. Additionally, we analysed the impact of HCMV infection on blood markers and associated vascular complications to explore the potential association between HCMV and T2DM.
Method
Literature search
The data used in our study were sourced from several reputable databases, including PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure and Wan Fang. We conducted a comprehensive search for relevant studies using a combination of subject-specific keywords and free-text terms. A detailed description of our search strategy can be found in online supplemental table S1.
Supplemental material
Inclusion and exclusion criteria
Types of studies
In this paper, we included case–control, cross-sectional and cohort studies that conducted biological assays specifically on peripheral blood samples. However, studies that solely performed assays on tissue samples were excluded from our analysis.
Types of participants
Our study specifically targeted individuals who were diagnosed with T2DM either by a physician or based on the diagnostic criteria recommended by the WHO,20 21 the Guideline for the Prevention and Treatment of T2DM in China22 23 and the American Diabetes Association.24 25 We excluded studies that included patients with T1DM, cases where the type of diabetes mellitus was not clearly indicated, individuals who had undergone organ transplantation or had serious underlying diseases, pregnant females, and other special patient populations.
Types of comparison
To assess the relationship between HCMV and T2DM, we conducted comparisons in the following areas:
Prevalence of HCMV infection among individuals with and without T2DM.
Comparison of the OR of T2DM by seropositive and seronegative for HCMV.
Comparison of the OR of HCMV infection by individuals with and without vasculopathy in T2DM.
Comparison of the glucose regulation and T lymphocyte subset indicators between individuals with and without HCMV infection in T2DM.
These comparisons were designed to investigate the potential correlation between HCMV and T2DM and to explore any associations between HCMV infection and the prevalence and characteristics of T2DM, and associated complications.
Types of outcome measures
HCMV infection was determined by the investigators using serological methods or peripheral blood cell detection techniques. These methods involved testing for the presence of HCMV-DNA, HCMV-IgG antibodies and HCMV-IgM antibodies. It is important to note that cases of CMV disease were excluded from our analysis.
Subjects included in this study cover the major vascular diseases that are associated with T2DM. These complications included diabetic retinopathy, diabetic nephropathy and atherosclerotic diseases such as carotid atherosclerosis, angina, myocardial infarction, cerebral thrombosis and lower extremity arterial headaches.
In patients with T2DM, blood glucose levels and immune function serve as crucial monitoring indicators. To evaluate the relationship between T2DM and HCMV infection, we conducted an analysis focusing on two aspects: glucose regulation and the T lymphocyte subset indicators.
We examined the following parameters related to glucose regulation: fasting blood glucose level (FBG), fasting blood insulin (INS), 2-hour postprandial blood glucose (PBG), glycosylated haemoglobin, and type A1C (HbA1c).
The indicators of T lymphocyte subsets: the proportion of CD4+, CD8+ T cells and the CD4+/CD8+ ratio.
Data screening and assessment
In this study, two researchers, Wang and Chen, conducted independent literature searches and extracted pertinent data. The collected basic information encompassed various details, including the author, publication year, country, sample location, study design, population characteristics, age and gender distribution of participants, the method employed for HCMV detection, sample selection criteria, the total population of subjects, number of subjects with HCMV positivity, number of subjects without HCMV infection, number of subjects with T2DM and number of healthy subjects.
For assessing the quality of the included case–control and cohort studies, we employed the Newcastle-Ottawa Scale.26 To evaluate the quality of the included cross-sectional studies, we used the Agency for Healthcare Research and Quality Scale.27
Statistical analysis
A meta-analysis was conducted on the collected data using Review Manager V.5.4 software. Correlation analysis statistics such as OR, 95% CI and mean difference (MD)/standardised mean difference (SMD) were employed for analysing the association between dichotomous variables and numerical variables, respectively.
Heterogeneity among the included studies was assessed using the p value and I2 statistic. If the p value was <0.1 or the I2 statistic exceeded 50%, it indicated the presence of statistical heterogeneity. In such cases, efforts are made to identify and address the source of heterogeneity through subgroup analyses or sensitivity analysis. To address the heterogeneity among the included studies, we performed subgroup analyses when examining the differences in HCMV prevalence between individuals with and without T2DM. The studies were divided into two subgroups based on geographical regions: Asia and Europe. To evaluate the influence of individual studies on the observed heterogeneity, we conducted sensitivity analyses. The analysis involved excluding one study at a time and examining the effect of the results on overall heterogeneity. By iteratively removing each study and reassessing the heterogeneity, we were able to determine the extent to which each study contributed to the heterogeneity observed in the meta-analysis. If it is not possible to eliminate the heterogeneity, a random effects model is used for the analysis. Conversely, if the p value was greater than or equal to 0.1 and the I2 statistic was less than or equal to 50%, a fixed-effects model was employed. The Z-test was utilised to determine the statistical significance, considering a p value of <0.05 as indicating a significant difference.
Additionally, we employed Egger’s test and Funnel plots, using Stata V.17.0 statistical software, to evaluate the potential presence of publication bias. This test was specifically applied when there were more than 10 estimates available in a single analysis.28 If the obtained p value is <0.05, it indicates the presence of publication bias.
Patient and public involvement
Patients and the public were not involved in the design of this study.
Results
Study selection and characteristics
As outlined in online supplemental figure S1, we identified a total of 1473 records using our retrieval strategy. Subsequently, 90 articles underwent a comprehensive full-text review (online supplemental table S2), resulting in the inclusion of 22 articles involving 18 139 participants in our study.17 29–49 Online supplemental table S3 presents the fundamental characteristics of these 22 selected studies (the detailed quality assessments are presented in online supplemental table S4). Among the included studies, 17 studies provided data on the prevalence of HCMV within the population under investigation. Furthermore, three studies reported adjusted OR. These OR were calculated after accounting for major confounding variables, enabling a more accurate assessment of the association between HCMV infection and T2DM. Additionally, five studies conducted a comparative analysis of indicators related to glucose regulation and T lymphocyte subsets between two groups: individuals with T2DM who had HCMV infection and those without HCMV infection. This comparative approach aids in understanding the potential impact of HCMV infection on these specific indicators among individuals with T2DM.
Supplemental material
Prevalence
A total of 17 studies were included in the analysis, examining the difference in HCMV prevalence between individuals with and without T2DM. We observed heterogeneity among the included studies (I2=70%, p<0.1) (online supplemental figure S2). To address this, we performed a subgroup analysis by dividing the population into two groups based on geographical distribution: Asia and Europe. The subgroup analysis revealed no statistical heterogeneity among the studies conducted in the European population (I2=0%, p>0.1) (figure 1). However, there was significant heterogeneity among the studies in the Asian subgroup (I2=33%, p>0.1). To this end, a sensitivity analysis was conducted specifically for this aspect of the study. Notably, on excluding the study by Faraj et al, the heterogeneity significantly decreased (I2=31%, p>0.1) (figure 1). This observation suggests that the inclusion of this particular study, which solely focused on women as research subjects, introduced heterogeneity compared with other studies. Consequently, we excluded this study from further analysis.
Supplemental material
Prevalence of HCMV infection among individuals with and without T2DM in Asia and Europe. HC, healthy control group; HCMV, human cytomegalovirus; T2DM, type 2 diabetes mellitus.
In the Asian subgroup, we observed a significant difference in the average age between the patients with T2DM group and the healthy control group, with the former having a higher average age. Furthermore, the frequency of HCMV infection in the patients with T2DM group was significantly higher than that in the healthy control group, with an OR of 4.75 (95% CI: 3.76 to 6.00, p<0.05) (figure 1). On the other hand, in the European subgroup, there were no significant differences in age and gender between the patients with T2DM group and the healthy control group (p>0.05). The frequency of HCMV infection in the patients with T2DM group was lower than that in the control group, although the difference was not statistically significant, with an OR of 0.72 (95% CI: 0.44 to 1.19, p>0.05) (figure 1).
Furthermore, we conducted a meta-analysis involving three studies that adjusted for various demographic factors such as age, gender, race/ethnicity, education and body mass index. After accounting for these demographic factors, the adjusted OR for the risk of T2DM in individuals seropositive for HCMV compared with seronegative individuals was found to be not statistically significant (OR=1.19, 95% CI=0.88 to 1.62, p>0.05) as depicted in figure 2.
ORs of type 2 diabetes mellitus by seropositive and seronegative for human cytomegalovirus.
We identified five studies that investigated the relationship between HCMV infection rates and T2DM in individuals with and without vasculopathy. No heterogeneity was observed among these studies. Among the four studies that provided age and gender information, the average age of patients with T2DM with vasculopathy was 57.26±10.72, while the average age of patients with T2DM without vasculopathy was 55.67±10.79. There were no statistically significant differences in gender and age between the two groups (p>0.05). Based on these findings, a meta-analysis was conducted, which revealed that patients with T2DM with vasculopathy had a significantly higher HCMV infection rate compared with those without vasculopathy (OR=1.87, 95% CI=1.24 to 2.83, p<0.05) (figure 3).
ORs of human cytomegalovirus infection by individuals with and without vasculopathy in T2DM. T2DM, type 2 diabetes mellitus.
Indicators
In individuals with T2DM, there is a correlation between HCMV infection and various indicators related to glucose regulation and T lymphocyte subsets. In comparison to individuals with T2DM who do not have HCMV infection, those with HCMV infection exhibited significantly higher average levels of FBG with an MD of 1.53 (95% CI=1.21 to 1.86, p<0.05) (figure 4A). They also had a significantly higher CD8+ T lymphocyte proportion with an MD of 2.41 (95% CI=1.55 to 3.27, p<0.05) (figure 5A). Additionally, they exhibited significantly lower average levels of INS (SMD=−1.06, 95% CI=−1.33 to –0.78, p<0.05) (figure 4B), CD4+ T lymphocyte proportion (MD=−1.92, 95% CI=−2.83 to –1.01, p<0.05) (figure 5B), and the CD4+/CD8+ ratio (MD=−0.14, 95% CI=−0.18 to –0.11, p<0.05) (figure 5C). However, there were no significant differences observed in PBG levels and HbA1c levels between patients with T2DM with and without HCMV infection. The MD for PBG was 0.42 (95% CI: −0.85 to 1.69, p>0.05) (figure 4C), and for HbA1c, it was 0.55 (95% CI=−0.09 to 1.18, p>0.05) (figure 4D).
Comparison of the glucose regulation indicators between individuals with and without HCMV infection in type 2 diabetes mellitus. (A) Fasting blood glucose level; (B) fasting blood insulin; (C) 2-hour postprandial blood glucose; (D) glycosylated haemoglobin, type A1c (HbA1c). HCMV, human cytomegalovirus.
Comparison of the T lymphocyte subset indicators between individuals with and without HCMV infection in T2DM. (A) The proportion of CD8+ T lymphocytes; (B) the proportion of CD4+ T lymphocytes; (C) CD4+/CD8+. HCMV, human cytomegalovirus; T2DM, type 2 diabetes mellitus.
Publication bias
When conducting an analysis that involves more than 10 studies, it is crucial to consider the potential impact of publication bias. In our research, we included 12 relevant studies to examine the difference in the frequency of HCMV infection between individuals with T2DM and healthy individuals in the Asian population. To evaluate each study’s susceptibility to publication bias, we employed Eegg’s test and Funnel plots. Funnel plots (online supplemental figure S3) did not demonstrate obvious asymmetry, and the outcomes of Eegg’s test indicated that none of the included studies exhibited publication bias, as demonstrated by a p value of 0.7464.
Supplemental material
Discussion
HCMV is a DNA herpes virus that exhibits a high incidence worldwide, varying from 40% to 90% in different regions.50 In most individuals, HCMV persists as a latent infection that remains asymptomatic. However, the long-term effects of this latent infection on the host often go unnoticed.51 Recent evidence has increasingly indicated that HCMV infection may act as a risk factor for various conditions such as gastrointestinal cancer,52 atherosclerosis53 and several inflammatory diseases, including diabetes.10 18 Furthermore, HCMV infection has been associated with an increased risk of morbidity and mortality related to coronary heart disease and stroke.54 The presence of latent HCMV contributes to chronic low-grade inflammation and impacts glucose metabolism.55 In a prolonged state of elevated blood sugar levels, the immune function of the body becomes compromised, leading to more frequent reactivation of latent HCMV. This, in turn, exacerbates the inflammatory response and contributes to the onset and progression of T2DM. Therefore, the relationship between HCMV infection and various diseases has garnered significant attention in recent times.
We conducted a comprehensive review of relevant studies investigating the association between HCMV infection and T2DM, primarily focusing on case–control, cross-sectional and cohort studies published in recent years. Among these studies, Wu et al examined 623 patients in China and reported a significantly higher frequency of HCMV infection in patients with T2DM compared with healthy controls.35 However, this study did not adjust for basic clinical indicators such as age and gender. Weiliang Lin and Jian Xia found a significantly higher frequency of HCMV infection in patients with T2DM compared with healthy individuals after adjusting for basic indicators including age and gender.29 39 In a European study by Chen et al,47 which included 549 elderly individuals over the age of 85, it was observed that the proportion of HCMV seropositive elderly individuals with T2DM was significantly higher after accounting for potential confounding factors in the non-T2DM control group (17.2% vs 7.9%). However, Schmidt et al and Lutsey et al analysed the adjusted OR of T2DM for HCMV infection and found no significant association between HCMV infection and T2DM after adjusting for demographic variables.17 46 In summary, previous studies have not reached a consistent conclusion regarding the relationship between HCMV infection and T2DM. The contradictory findings may be attributed to the limited sample sizes in each study, which may hinder the detection of statistically significant results. In our study, we conducted a comprehensive analysis by integrating all relevant studies, including a total of 18 139 patients. Our meta-analysis revealed significant differences in HCMV infection frequency between patients with T2DM and healthy individuals in the Asian population. However, the age of patients with T2DM was also significantly higher than that of the healthy group. Age has been identified as a risk factor for both T2DM and HCMV infection,56 but the relevant studies conducted in the Asian population did not adjust for age in their analyses. Within the European population, the relevant studies took into account sociological factors such as age and gender. In these cases, no statistically significant difference was found in the frequency of HCMV infection between individuals with T2DM and healthy individuals. Additionally, we included three studies in our analysis that adjusted for basic indicators and conducted a meta-analysis. After adjusting for sociological factors such as age and gender, the meta-analysis of the adjusted OR for T2DM by HCMV status did not yield a statistically significant result. In summary, there is currently no clear positive association established between HCMV infection and T2DM across various populations. Further research is necessary to evaluate the frequency of HCMV infection in diverse populations while appropriately controlling for confounding variables.
Vasculopathy is a prevalent comorbidity in individuals with T2DM and is recognised as a leading cause of disability and mortality in these patients.57 Lin and Morteza et al conducted HCMV-PCR detection on arterial wall samples from patients with T2DM and found that approximately 32%–41% of patients with T2DM tested positive for HCMV-DNA, which was significantly higher than the rate observed in patients without T2DM.58 59 Another study conducted by Mercy Guech-Ongey investigated HCMV infection in patients with T2DM with coronary heart disease.60 The analysis showed that patients with T2DM with HCMV seropositive had a higher rate of secondary cardiovascular disease within a 3-year period compared with the serum-negative group (15% vs 6.9%). Moreover, Ni et al discovered that among patients with T2DM, there was a higher frequency of HCMV infection in those with vascular lesions.37 In our analysis, no significant differences in age and gender were observed between the experimental group and the control group. Building on these findings, we identified a significantly higher frequency of HCMV infection in patients with T2DM with vasculopathy compared with those without vasculopathy. Taking into account the findings of previous studies and our results, we preliminarily believe that HCMV infection is associated with T2DM with vascular lesions. This association may be influenced by the following factors.The impact of HCMV infection on vasculopathy in patients with T2DM is attributed to the latent properties of HCMV in monocytes and endothelial cells.6 61 Latent HCMV in endothelial cells triggers DNA replication, leading to increased secretion of adhesion factors by endothelial cells and, consequently, long-term enhancement of vascular permeability.62 63 Latent HCMV in monocytes promotes the expression of inflammation-related factors such as interleukin-6, tumor necrosis factor-alpha and monocyte chemoattractant protein-1, which increases the adherence of white blood cells to vascular endothelial cells and enhances the inflammatory response.64–66 Moreover, latent HCMV reactivation releases virus particles that cause lytic infection in endothelial cells, resulting in endothelial cell death and increased vascular permeability, thereby promoting the development of vasculopathy associated with T2DM.67
Regarding the relationship between HCMV infection and indicators of glucose metabolism, previous studies conducted by Xue et al and Liang et al have discovered that HCMV primarily affects fasting glucose metabolism in patients with T2DM, specifically FBG and INS levels.38 48 Wang et al found that higher levels of HCMV DNA were associated with increased FBG (r=0.982) and decreased INS (r=−0.983).49 Additionally, Xia et al suggested that apart from fasting glucose metabolism indicators, HCMV is also closely associated with PBG and HbA1c levels in patients with T2DM.29 The results of our meta-analysis revealed statistically significant differences in FBG and INS levels between patients with T2DM with HCMV infection and the control group. No statistically significant difference was observed in PBG and HbA1c levels between the two groups. These findings may be attributed to the effect of HCMV infection, which might be accelerating islet cell apoptosis via at least two possible mechanisms. First, HCMV can undergo repeated reactivation within the islet cells, leading to the impairment of their function and accelerating their apoptosis.47 68 Second, HCMV infection can stimulate the accumulation of a large number of monocytes around the islets, thereby creating an inflammatory microenvironment.69 This inflammatory environment can subsequently interfere with the insulin-secreting function of the islet cells, resulting in a reduction in insulin levels.
Studies have demonstrated that HCMV infection can influence the immune function of the body.70 The proportions of CD4+ and CD8+ T lymphocytes, as well as the CD4+/CD8+ ratio, are crucial indicators for assessing immune function.71 Multiple studies have revealed that HCMV infection can moderately affect both innate and adaptive immunity, leading to significant alterations in the number of CD8+ and CD4+ T lymphocytes, which are key components of the body’s adaptive immune cells.72–74 Previous research consistently demonstrates that patients with T2DM with HCMV infection exhibit poorer immune indicators.29 30 38 Our findings indicated that patients with T2DM with HCMV infection exhibited a significant decrease in the proportion of CD4+ T lymphocytes and CD4+/CD8+ ratio, along with a notable increase in the proportion of CD8+ T lymphocytes compared with the control group. These results suggest that HCMV infection is associated with a decline in immune function in patients with T2DM. The decline in immune function observed in individuals with HCMV infection may be attributed to the following reasons. On primary HCMV infection, viral particles that cannot be cleared by the immune system undergo irregular replication and reactivation within the body, leading to chronic inflammatory stimulation and elevated systemic levels of proinflammatory cytokines.75 Prolonged and sustained low-level activation of HCMV not only weakens the body’s response to pathogens but also accelerates the deterioration of the immune system, resulting in immune dysfunction. Concurrently, immune dysfunction enhances the reactivation frequency of latent HCMV, exacerbates the inflammatory response, and thereby contributes to the onset and progression of T2DM.76
Several limitations to our study should be acknowledged. First, our study population was limited to Asian and European populations, which may restrict the generalisability of our findings to other geographical regions and populations. Additionally, the HCMV detection methods employed in the included studies varied in terms of sensitivity and specificity, which could introduce bias to the pooled estimates. Furthermore, the studies retrieved in our analysis primarily consisted of case–control and cross-sectional studies, which are unable to establish a temporal relationship between HCMV infection and the development of T2DM. To address these limitations, future research should include cohort studies to further investigate and validate the association between HCMV infection and T2DM.
Conclusion
The current findings can not provide a definitive answer regarding the significant association between HCMV infection and T2DM. After excluding the confounding effects of baseline indicators, we did not observe a statistically significant difference in the adjusted OR for T2DM by HCMV status. Additionally, our analysis revealed a higher frequency of vascular lesions in patients with T2DM with HCMV infection, along with poorer indicators of glucose metabolism and immune function in the HCMV-positive group. These observations may be attributed to the inflammatory response triggered by HCMV infection. Future studies should focus on longitudinal investigations and basic research to explore the temporal and causal relationship between T2DM and HCMV infection.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Ethics statements
Patient consent for publication
Ethics approval
Not applicable.
Acknowledgments
This work was supported by the China Association of Gerontology and Geriatrics Project (No. 2020-lub-921).
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors This subject is supported by the China Association of Gerontology and Geriatrics Project (No. 2020-lub-921). The fund was hosted by XY and supported the study of the molecular mechanism of chronic latent CMV-induced immunosenescence involved in the regulation of diabetic retinopathy. Understanding the associations between human cytomegalovirus infection and type 2 diabetes is an important part of experimental conclusions. As the first author, XW focuses on research implementation, data analysis and processing, manuscript writing. The corresponding author, XY, is XW’s supervisor and the guarantor of the manuscript, mainly responsible for research guidance, research funds and revising the manuscript. The main work of JC and ZC includes literature retrieval, data extraction and proofreading. All the authors read and approved the final manuscript.
Funding This work was supported by China Association of Gerontology and Geriatrics Project (No.2020-lub-921). The molecular mechanism of chronic latent CMV-induced immunosenescence involved in the regulation of diabetic retinopathy.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.