Although the global incidence of DM is increasing, the global incidence of DR has been reported to be decreasing.  This finding might be explained by improvements in the control of systemic risk factors in patients with DM. DM-related severe local complications are one of the main causes of blindness worldwide. According to a recent study, DME is causing an increasing number of visual impairments in patients with DM.  DME, which does not result in total blindness, but in severe vision loss, may instead be the main DM-associated severe local complication. Second, advances in optical coherence tomography technology have enabled the identification of DME much more precisely and less invasively than before. Some previous studies have investigated factors associated with DME. However, many of these studies employed a cross-sectional design. [22, 23, 28–32] Although several studies have investigated factors associated with DME development, [14, 33–37] these studies did not report associations between concomitant and systemic diseases with DME. In the present study, we investigated factors associated with DME development among more than 6,000 ICD-10 standard disease codes using a large claim dataset in Japan. Many of the systemic factors significantly associated with the development of DME were considered related to the presence of a severe metabolic impairment, including hyperlipidemia, diabetic ketoacidosis, vessel lumen mass, postoperative of percutaneous coronary angioplasty, lower leg skin ulcer, arrhythmia, diabetic nephropathy, and proteinuria. DM has been identified as an important risk factor for osteoporosis-associated fracture. [38, 39] Among female subjects with type 1 DM, diabetic ketoacidosis in pregnancy can result in an impending abortion. Since DM sometimes results in peripheral vestibular damage and predicts a poor prognosis of typical vestibular pathologies, some patients suffer from benign paroxysmal positional vertigo that is one symptom of Ménière syndrome. Poor visual function due to DME may contribute to increase the risk of falls, resulting cervical and chest contusions. Female patients with DM are more likely to report very irregular menstrual cycles.  Although the present study identified arthritis as a risk factor for developing DME, Tentolouris et al. reported a negative correlation between arthritis and DM.  However, the impact of DM on the incidence of rheumatoid arthritis is not well established.
The present study also revealed some systemic factors that negatively associated with the development of DME. Some previous studies reported a significantly higher prevalence of primary osteoarthritis among subjects with DM than among subjects without DM, as well as significant associations with glycemic control and the duration of diabetes. Obesity may be associated with the onset of osteoarthritis [42–44]. We are unsure why the present study showed a negative impact of orthoarthritis on DME. According to Taylor et al., diabetes may increase the risk of kidney stone formation by altering the composition of the urine, and insulin resistance may play a role in stone formation. 
Several systemic diseases and local diseases that have not been reported to be related to DME development were identified. Interestingly, some factors were identified as negative factors. An explanation for the finding that hay fever and chronic eczema were selected as factors associated with a significant negatively associated factor of DME development may be an impairment in the auto-immune function, as DM deteriorates the auto-immune function and a significantly lower prevalence of allergic rhinitis was observed in subjects with metabolic syndrome, high blood pressure, or impaired fasting glucose levels. 
Many previous studies have focused on of the effects of DM on pathological conditions and disorders. Few studies have investigated factors associated with the development of DME in a large sample. We were unable to precisely investigate the status of glycemic control and severity of DM complications in the present study. Further studies are necessary to clarify these points.
Although some significantly associated systemic factors identified in the current study are consistent with previous reports, some of the identified factors have never been reported to be associated with the development of DME. In addition to diseases that have been reported to serve as risk factors to date, such as renal and circulatory disorders, orthopedic and dermatological diseases were identified to be associated with the development of DME. These diseases may have been identified because the current study included more than 6,000 diseases in the analysis. Furthermore, some factors were found to be negatively associated with DME. Currently, information about the mechanisms of these factors in DME development is limited, and these data must be confirmed in further investigations.
Previous papers have reported some local factors associated with DME development, including DR severity, [33, 34, 47] cataract surgery,  and ocular inflammation,  consistent with the current results. The current study discovered some new local factors associated with DME development, some of which are related to systemic and local DM complications. Retinal vessel occlusion showed the highest OR and was selected as a disease often observed in subjects with retinal circulation disorders and severe diabetic retinopathy. Additionally, eye movement disorder and accommodation paralysis are strongly associated with DME development.
This study also has several limitations. Because the subjects were limited to social insurance subscribers and subscribers to the national health insurance, another major insurance provider in Japan, were not considered, the target sample may be biased. National health insurance is managed by each municipality, increasing the difficulty of integrating and collecting data; thus, while these data were not included in this study. Since subjects in JMDC were employees and their dependents, it is possible that a significant number of senior citizens whose prevalence of DM could be higher than that in JMDC were not included in the database. National health insurance members must also be considered in the future. The use of the diagnosis codes of claims data as diagnostic criteria has several problems. First, the accuracy of the diagnosis is not necessarily high. An investigation of whether some reported risk factors were associated with DME development was impossible because the current database does not contain information about some factors, including the hemoglobin A1c level  and the severity of DR. [33, 34, 47] Genetic factors have also been reported to contribute DME development, such as genes related to VEGF and erythropoietin. [48–52] Unfortunately, claims data do not contain genetic information. In this study, we worked with epidemiological statisticians to accurately detect risk factors associated with DME development from many disease categories, but it was difficult to completely exclude the influence of confounding factors. We excluded some diseases due to a small number of patients, which may have factors that could not detect an association. Inconsistencies between previous reports and the current study may also be partially due to differences in the statistical methods applied. Previous studies have reported that there are differences between DR- and DME-associated factors. In this study, we focused on the factors associated with the development of DME. It will be necessary to examine the factors associated with to the development of DMR and DME using the same database in the future.
In this study, we clarified systemic and local diseases associated with DME development in Japan. Notably, many patients with DM do not undergo periodic eye examinations. Based on these results, factors associated with DME development should be closely monitored. Because DR is sometimes asymptomatic during the period in which laser photocoagulation should be applied, asymptomatic persons should be screened to minimize the risk of vision loss. As the number of DME patients is expected to increase, further studies on the early detection and prevention of DME development are needed.