Discussion
This study showed the incidence and seasonality of incidence of type 1 diabetes in Japan. The incidence was the highest in men aged 40–59 years and women aged 0–19 years. Further, we found a significant time clustering with seasonal patterns of onset of type 1 diabetes in spring (from March to May) for individuals aged under 20 years, but not for those aged ≥20 years in Japan. To the best of our knowledge, this is the first study to report the nationwide incidence of type 1 diabetes.
Our findings are in contrast to previous studies that have shown no seasonality in the incidence of type 1 diabetes across all age ranges in countries with a lower incidence of type 1 diabetes, including Japan.8–10 Meanwhile, we found a seasonality effect in the onset of type 1 diabetes in individuals aged younger than 20 years, but not in those aged ≥20 years. A previous study in China also found an age-related association between season and the incidence of type 1 diabetes. The study reported that the incidence was positively correlated with geographical latitude (r=0.88, p<0.001) in those aged <15 years, but not in those aged 15 years or older.21 These results, including the interaction we showed between age ranges and seasons, may indicate that childhood-onset type 1 diabetes and adult type 1 diabetes have different modes of onset. Further descriptive epidemiological studies are needed to identify the etiology of type 1 diabetes by creating a hypothesis of the factors through descriptive epidemiological studies.
Consistent with previous findings, we found a higher incidence rate of type 1 diabetes in women aged 0–19 years than in men of the same age. Meanwhile, the incidence was higher in men aged ≥20 years than in women of the same age. In addition, the incidence of type 1 diabetes was highest in men aged 40–59 years and in women aged 0–19 years. Although the incidence of type 1 diabetes was previously reported to be higher during adulthood,22 the age at which the highest incidence of type 1 diabetes differs between men and women has not been reported. Slowly progressive type 1 diabetes is also well recognized in Japan, as in many other Asian countries. Although this type of diabetes is not seen in children, a previous study showed that it accounts for half of all type 1 cases in adults.23 Thus, the incidence of type 1 diabetes was high in adults of that study, as patients diagnosed with slowly progressive type 1 diabetes were included.
Our study examined the best clinical diagnostic criteria for type 1 diabetes based on the opinions of clinicians, aiming to decrease the proportion of patients identified by our definition as having type 1 diabetes who truly do not have such a diagnosis. Validation studies were performed to evaluate the validity of the diagnostic criteria, and the extent of misclassification was quantified. In all groups, the kappa coefficient indicated moderate or substantial agreement (table 3, figure 3). Both PPV and sensitivity were well balanced, so that the number of patients with type 1 diabetes was similar using both diagnostic criteria at any sex and age group. For older groups, there were more misclassifications, but their impact on the incidence of type 1 diabetes was considered to be small.
A previous study in Taiwan reported that the incidence of type 1 diabetes in 2000 was 4.21, 2.93, 1.59, 2.04/100 000 person-years at the age of 0–19, 20–39, 40–59, 60–79 years, respectively.24 As shown in online supplemental table 5, we found a higher incidence of type 1 diabetes among patients aged >20 years. An underestimation of the incidence could be expected in the previous study because of Taiwan’s stringent requirements to apply for a catastrophic illness certificate. As shown in figure 2, the incidence rate was small even when tabulated every 3 months. Furthermore, as shown in figure 3, our diagnostic criteria were validated.
The incidence rate of type 1 diabetes varies worldwide.25 Until the early 2000s, the worldwide incidence rate of type 1 diabetes was reported to be increasing, with reported annual increases of 2%–5% in Europe, the Middle East, and Australia.16 26–29 However, our results suggest no significant trends in increases in the onset of type 1 diabetes in Japan, although this might have been affected by the short observation period of 3 years.
According to the Information Center for Specific Pediatric Chronic Diseases in Japan, 500–600 individuals aged 0–15 years develop diabetes annually.30 In the current study, 404 (172 boys, 132 girls), 437 (170 boys, 267 girls), and 452 (199 boys, 253 girls) individuals aged 0–14 years developed type 1 diabetes during the first, second, and third year of the study period, respectively, consistent with the results of previous studies.8–10 Because we defined the patient’s age according to the age at the last use of insurance from September 2017 to March 2018, patients aged 12–15 years were included in the age group of 15 years and older. As shown in online supplemental table 6, 1895 patients aged 0–19 years developed type 1 diabetes within the 3-year study period, consistent with the findings that 500–600 patients aged 0–15 years develop diabetes annually.31
The strengths of the study include the high generalizability of the results, as we used all data available on the NDB. Moreover, using the NDB allowed us to include a sample cohort with minimal selection bias15 and to include all patients with type 1 diabetes. The incidence rate has important implications in both clinical and public health policy. However, it would be prohibitive to conduct a randomized controlled trial or prospective cohort study for an in-depth investigation of the role of a specific risk factor in the etiology of a disease because such a study would be too large and expensive.
Meanwhile, this study had several limitations. First, we defined patients with type 1 diabetes in the NDB as those recognized of having any of the type 1 diabetes diagnosis codes, who were prescribed medication for type 1 diabetes (insulin), and who had medical examinations codes about self-monitoring of blood glucose as patients with type 1 diabetes. In the validation study, our definition was considered to be valid and consistent with Japanese diabetes clinical practice. We did not include patients who were not treated with self-monitoring of blood glucose. However, since only very few patients do not self-monitor their blood glucose after the onset of type 1 diabetes, our patient selection procedure was appropriate. Second, the NDB does not include any laboratory data, such as plasma glucose levels. Thus, we could not confirm the levels of blood glucose, hemoglobin A1c, or any types of antibodies, such as antiglutamic acid decarboxylase antibody, when type 1 diabetes occurred. As an alternative indicator, we defined the condition of type 1 diabetes in the NDB using codes, and the number of children with type 1 diabetes was similar to that in a previous report.30 Third, we could not review the medical data (eg, body weight, smoking history, and family history) of each patient in detail. Although time-independent confounders (eg, genetic factors) or unmeasured confounders can be adjusted in a self-controlled case series study design, it remains an observational study. Further, the confounders cannot be completely adjusted. Fourth, the health check-ups performed at schools usually occur in April and May, which could have affected the results. If our result that the incidence of type 1 diabetes is higher in spring was only affected by the health check-up period, the incidence in March should have been lower than that in April and May. However, as seen in online supplemental table 6, this was not the case. Finally, we selected individuals who used their insurance before and after the observation period. Although we considered our definition reasonable, we cannot exclude the possibility of overestimating the incidence of type 1 diabetes.
In conclusion, the incidence of type 1 diabetes is highest among Japanese men aged 40–59 years and Japanese women aged 0–19 years. In addition, we found that the incidence of younger-onset diabetes increases in spring (from March to May). This descriptive epidemiological study can help clarify the etiology of type 1 diabetes.