An absolute or relative lack of insulin and the consequent unrestricted flux of carbohydrate, amino acid and lipid nutrients to the blood results in diabetic ketoacidosis (DKA) in individuals with diabetes mellitus¹. DKA is characterized by hyperglycemia, ketonemia and metabolic acidosis. DKA is a potentially life-threatening acute complication and a common presentation of type 1 diabetes (T1D) at diagnosis. Children and adolescents with type 2 diabetes (T2D) may present with some degree of metabolic de-compensation at diagnosis including ketosis, symptomatic hyperglycemia, and DKA².

DKA and subsequent cerebral edema continues to be a leading cause of morbidity and mortality among children and adolescents with diabetes^3,4. One in four survivors of DKA with cerebral edema also suffer from residual morbidity⁵. Previous reports suggest that DKA at diagnosis is associated with adverse neuro-cognitive outcomes and is an independent predictor of poor longer-term glycemic control among individuals with T1D^6–8.

Recent studies suggests that DKA at diagnosis is more common in populations with lower socioeconomic status and a lower background prevalence of T1D⁹. There are limited data comparing the prevalence and trends in prevalence of DKA among children and adolescents with either T1D or T2D, even in countries with high prevalence of youth onset diabetes. An earlier analysis from the SEARCH registry reported a high but stable trend in the prevalence of DKA among T1D and a 10% yearly decline in DKA among United States (U.S.) youth with T2D at diagnosis¹⁰. However, such data are limited in countries like India, where the absolute number of individuals with youth onset diabetes is quite high. Exploring similarities or variations in DKA burden at diagnosis between countries could provide insights in to developing context specific preventive strategies to reduce mortality and morbidity associated with DKA at diagnosis of diabetes.

Data for this analysis were obtained from the collaborative partnership between SEARCH for Diabetes in Youth (SEARCH) registry in the U.S. and the Registry of People with Diabetes with Youth Age at Onset (YDR) in India.

Our study revealed a significant burden of DKA at diagnosis among individuals with youth-onset T1D from both India and the U.S., especially among those in the younger age groups. The burden of DKA at diagnosis among individuals with T2D was similar in both the registries. The prevalence of DKA at diagnosis with T1D increased over time in SEARCH but remained relatively stable (at high levels) in YDR.

Our current prevalence estimates of DKA at diagnosis with T1D for SEARCH are higher than the estimates from other U.S. studies and the earlier reports from SEARCH itself¹⁰. There are no such data from India to compare the findings from YDR reported here. For T2D, the current study estimates that 5.5% of individuals with youth-onset T2D in SEARCH present in DKA at diagnosis, which is lower than earlier published estimates from SEARCH (11.7% in 2002–03 to 5.7% in 2008–10)¹⁰. In both SEARCH and YDR the prevalence of DKA among individuals with T2D was more pronounced in the 10–14 age group compared to youth in 15–19 age group. This is consistent with earlier reports from SEARCH¹⁰.

DKA prevalence estimates among individuals with T1D for both SEARCH and YDR reported in the current analysis, are much higher than those from UK, Canada and Finland, reported a decade ago^13,14. The EURODIAB project (2001) reported DKA prevalence at diagnosis ranging from 11% to 67% in 11 centers across Europe¹⁵. A recent systematic review summarizing data from 65 studies comprising over 29,000 children in 31 countries concluded that the frequency of DKA at diagnosis ranged from 12.8% to 80%, with highest frequencies in the United Arab Emirates (80%), Saudi Arabia (59%) and Romania (67%), and the lowest in Sweden(14%) and Canada (19 %)⁹. Further, the prevalence of DKA at diagnosis was inversely associated with gross domestic product (GDP) of the countries⁹. There is large heterogeneity in the published literature on DKA at onset/diagnosis, in terms of sample size, period of study, design and method of case identification. Hence, comparisons of our estimate with other studies should be done with caution¹⁶.

The prevalence of DKA at diagnosis seems to be inversely associated with the background prevalence of T1D in the countries⁹. Given the lower incidence of T1D in India, we expected a higher prevalence of DKA among the Indian population compared to U.S.. However, the results were contrary to our expectations, with higher prevalence of DKA in all the age groups in SEARCH compared to YDR. This could be due to several reasons with the distinct possibility of recall or recording bias and underreporting of DKA events in YDR. A principal reason for this could be the difference in methods used to ascertain and confirm the diagnosis of DKA in the two registries. Given the process flow in YDR, the information on DKA was captured from self-report or hospitalization records at the time of registration at a reporting center. Further, there could be a time lag between the date of diagnosis and registration of participants at the reporting centers. In contrast, SEARCH not only had direct access to medical records but was able to confirm the diagnosis of DKA through lab data including serum bicarbonate levels. Since YDR is a clinic-based registry, there could also be referral bias with likely impact on the estimated frequency of DKA.

There is a global variation in mortality associated with DKA at diagnosis among children and adolescents with diabetes. In developed countries, the overall mortality varies from 0.15% to 0.35% while in countries like India and Bangladesh, clinic-based studies report rates ranging from 3.4% to 13.4%¹⁷. Cerebral edema, sepsis and renal failure are the major precipitating factors of DKA-related mortality in the developing world¹⁷. These differential mortality rates may explain the differences seen in the estimated prevalence of DKA across countries. Therefore, the lower prevalence of DKA at diagnosis reported by YDR compared to SEARCH likely reflects a worrisome higher DKA-associated mortality, before T1D is diagnosed, which we were unfortunately unable to study. More efforts are needed to quantify the population level mortality associated with DKA at diabetes diagnosis in India.

The high burden of DKA among younger age groups in both the registries is concerning. Delayed diagnosis, relatively aggressive metabolic deterioration and difficulty in early diagnosis of symptoms in toddlers with T1D make them vulnerable to develop DKA¹⁵. Increasing parental awareness and improving health system preparedness to closely monitor children with genetic risk of T1D have shown promising results in the past¹⁸. However, it remains unclear whether the high propensity for DKA in younger children is a consequence of a particularly aggressive form of diabetes.

Data on temporal changes in DKA prevalence vary between reports from different parts of the globe with some studies reporting a declining trend^14,19, while others finding no change^13,20. Our analysis showed a statistically significant upward trend in the prevalence of DKA among U.S. children and adolescents with T1D after 2009–2010. This is different from earlier reports from SEARCH that showed a high but stable trend between 2002 and 2009¹⁰. The reasons for this increasing trend in DKA at diagnosis of T1D among SEARCH youth in recent years need to be further explored. In YDR, the burden of DKA remained relatively stable during the study period (p=0.1); however, this should be interpreted with caution given the limitations mentioned above. Nevertheless, in both countries, the burden of DKA at diagnosis among individuals with T1D remains unacceptably high.

This report is the one of the first studies to systematically harmonize and compare data on DKA at diagnosis from Asian Indian and U.S. populations. To the best of our knowledge, this is the first study to compare DKA at diagnosis among youth with T2D between U.S. and Indian populations. For both registries, data were collected independent of the present study and over a similar time period. However, the study has several important limitations. As mentioned earlier, there were significant differences in the method of DKA ascertainment between the registries. Moreover, we were unable to study the effect of a potentially high burden of DKA-associated mortality before diagnosis of T1D in India. The sample sizes for T2D in both registries were small and not adequately powered for trend analyses. Further, SEARCH did not have DKA information for years 2006–2008. We were only able to conduct a descriptive analysis of the harmonized data, as there was no physical transfer of data between the registries. However, this comparison is an important first step in our understanding of DKA burden at diagnosis with diabetes in youth, which should lead to further research on potential explanations for observed differences.

Our data show a significant burden of DKA at diagnosis among a racially/ethnically diverse U.S. and an Asian Indian cohort of youth with T1D, especially among the younger age groups. These findings have serious public health implications as the DKA associated hospitalizations and subsequent morbidities dramatically increase the cost of diabetes care. Effective interventions to increase awareness and improve access to health care are required in both countries to prevent DKA at diagnosis among youth onset diabetes.