Young‐onset diabetes patients in Thailand: Data from Thai Type 1 Diabetes and Diabetes diagnosed Age before 30 years Registry, Care and Network (T1DDAR CN)

ABSTRACT Aims/Introduction There is a lack of current information regarding young‐onset diabetes in Thailand. Thus, the objectives of this study were to describe the types of diabetes, the clinical characteristics, the treatment regimens and achievement of glycemic control in Thai patients with young‐onset diabetes. Materials and Methods Data of 2,844 patients with diabetes onset before 30 years‐of‐age were retrospectively reviewed from a diabetes registry comprising 31 hospitals in Thailand. Gestational diabetes was excluded. Results Based on clinical criteria, type 1 diabetes was identified in 62.6% of patients, type 2 diabetes in 30.7%, neonatal diabetes in 0.8%, other monogenic diabetes in 1.7%, secondary diabetes in 3.0%, genetic syndromes associated with diabetes in 0.9% and other types of diabetes in 0.4%. Type 1 diabetes accounted for 72.3% of patients with age of onset <20 years. The proportion of type 2 diabetes was 61.0% of patients with age of onset from 20 to <30 years. Intensive insulin treatment was prescribed to 55.2% of type 1 diabetes patients. Oral antidiabetic agent alone was used in 50.8% of type 2 diabetes patients, whereas 44.1% received insulin treatment. Most monogenic diabetes, secondary diabetes and genetic syndromes associated with diabetes required insulin treatment. Achievement of glycemic control was identified in 12.4% of type 1 diabetes patients, 30% of type 2 diabetes patients, 36.4% of neonatal diabetes patients, 28.3% of other monogenic diabetes patients, 45.6% of secondary diabetes patients and 28% of genetic syndromes associated with diabetes patients. Conclusion In this registry, type 1 diabetes remains the most common type and the prevalence of type 2 diabetes increases with age. The majority of patients did not achieve the glycemic target, especially type 1 diabetes patients.


INTRODUCTION
Diabetes causes burden individually and nationally, especially if diabetes-related complications develop. Globally, the incidence of type 1 diabetes has been increasing 1 , and a similar trend in type 2 diabetes in children and adolescents has been observed that has accompanied the rise in adolescent obesity 2 . Thailand is also facing an increase in the numbers of patients with diabetes 3 . The incidence rate has increased from 0.15/100,000/year in 1984-1985 4 to 1.65/100,000/year in 1991-1995 5 . An increased prevalence of type 2 diabetes in Thai children and adolescents associated with the rising prevalence of obesity has also been observed 6 . However, there is a lack of current information regarding the types, clinical characteristics and achievement of glycemic control of young-onset diabetes in Thailand.
The Thai Type 1 Diabetes (all ages) and Diabetes diagnosed Age before 30 years Registry, Care and Network (T1DDAR CN), which is a collaboration among the Diabetes Association of Thailand, the Thai Society for Pediatric Endocrinology, the Endocrine Society of Thailand, the National Health Security Office of Thailand, the Siriraj Diabetes Center of the Faculty of Medicine Siriraj Hospital, Mahidol University and the Northern Diabetes Center of the Faculty of Medicine, Chiang Mai University, was established in 2014 7 . The goals of T1DDAR CN were to build a diabetes registry to enhance the network of diabetes care and improve diabetes self-management education and support, which had not previously been standardized in Thailand. The T1DDAR CN strategy has been implemented at and through 31 regional collaborating government tertiary care hospitals (see Appendix 1) 7 .
The objectives of the present study were to characterize the types of diabetes among Thai patients with diabetes diagnosed before age of 30 years, including clinical characteristics, year of diagnosis, treatment regimens and glycemic control. This information will provide healthcare professionals and government policymakers with crucial perspectives specific to the quality of diabetes care among young-onset patients in Thailand.

MATERIALS AND METHODS
The present retrospective study was carried out among 31 T1DDAR CN network hospitals during July 2016 to July 2017. Patients' inclusion criteria were age at diagnosis of diabetes <30 years and current attendance of clinics at each collaborating hospital. Patients with gestational diabetes were excluded. An electronic case record form was developed using the webbased program Research Electronic Data Capture (Vanderbilt University, Nashville, TN, USA). Details specific to electronic data management were published elsewhere 7 .
Patient data, including the type of diabetes, patient characteristics, age of onset, year of diagnosis, number of new cases each year, presentation of diabetic ketoacidosis (DKA) or diabetes symptoms at diagnosis, diabetes autoantibodies, latest glycated hemoglobin (HbA 1c ) value, daily self-monitoring of blood glucose (SMBG) and treatment, were reviewed. Insulin regimen was defined as conventional insulin treatment (insulin 1-3 injections/day) or intensive insulin therapy (multiple daily injections ≥4 injections/day or continuous subcutaneous insulin infusion). Comorbidities, including autoimmune thyroiditis, dyslipidemia and hypertension, were also recorded. Dyslipidemia was diagnosed if the low-density lipoprotein cholesterol (LDL-C) level was >100 mg/dL, or if patients were on hyperlipidemia treatment. Hypertension was diagnosed if patients had elevated blood pressure or were treated with antihypertensive medication 7 . Glycemic control was classified as: (i) good glycemic control: HbA 1c <7.0%; (ii) fair glycemic control: HbA 1c within the range of 7.0-9.0%; and (iii) poor glycemic control: HbA 1c >9%. The present study did not include diabetic complications in the results, as they were published elsewhere 7 .
The study protocol was approved by the Central Research Ethics Committee of Thailand (approval number CREC 009/ 2559BRm), and by the institutional review board of each participating center.

Case definitions
Types of diabetes were classified based on the clinical assessment by pediatric or adult endocrinologists at each participating center. The clinical diagnoses were reviewed and agreed on by the T1DDAR CN investigators. Clinical characteristics, glycemic control and treatment regimens were analyzed based on the type of diabetes according to the World Health Organization 2019 classifications 8 with some modifications. Due to the unavailability of diabetes autoantibodies measurement in the majority of patients, hybrid form of diabetes was not included. Other specific types of diabetes; that is, drug-induced diabetes, disorder of the pancreas, infection-induced diabetes and endocrinopathy-related diabetes, were defined as secondary diabetes. The definitions of different types of diabetes are as follows: Type 1 diabetes Type 1 diabetes is characterized by b-cell destruction (mostly immune-mediated) and absolute insulin deficiency. Patients who presented with acute symptoms, marked hyperglycemia with or without ketoacidosis and required insulin therapy within the first year after diagnosis, with or without the presence of diabetes autoantibodies, were considered as having type 1 diabetes.

Type 2 diabetes
Type 2 diabetes is characterized by various degrees of b-cell dysfunction and insulin resistance. Patients who presented with signs of insulin resistance or had preserved insulin secretion, not requiring insulin therapy to control hyperglycemia within the first year of diagnosis, were diagnosed with type 2 diabetes.

Monogenic diabetes
Diagnosis of monogenic diabetes was made if patients had monogenic defects of b-cell functions, such as neonatal diabetes, maturity onset diabetes of the young (MODY), mitochondrial diabetes, Wolfram syndrome or monogenic defects in insulin action (Rabson-Mendenhall syndrome) 8 . Neonatal diabetes was considered in patients who presented with symptoms of diabetes or who were diagnosed with diabetes within the first 6 months of life. MODY was diagnosed in patients with a family history of diabetes diagnosed before the age of 25 years in at least three consecutive generations with the autosomal dominant pattern. Mitochondrial diabetes was considered in patients with maternally-inherited diabetes with multi-organ involvement, such as encephalopathy, myopathy, sensorineural deafness and pigmentary retinal dystrophy 9 . Wolfram syndrome was diagnosed in patients with childhood-onset diabetes mellitus, optic nerve atrophy, hearing loss, diabetes insipidus and neurodegeneration 10 . Rabson-Mendenhall syndrome was diagnosed in patients with insulin-resistant diabetes with multiple features, including coarse faces, lichenified skin, acanthosis nigricans, fasting hypoglycemia, postprandial hyperglycemia, pineal hyperplasia and growth retardation 11 . In the present study, neonatal diabetes was analyzed separately, whereas patients with MODY and other monogenic diabetes were grouped and analyzed as other monogenic diabetes. Genetic testing was carried out in-house at each center or sent out to an available laboratory.

Secondary diabetes
Secondary diabetes was considered if patients had a diagnosis of drug-induced diabetes, disorder of the pancreas, infectioninduced diabetes or endocrinopathy-related diabetes.
Genetic syndrome associated with diabetes This diagnosis was considered in patients having Prader-Willi syndrome, Down syndrome, Turner syndrome and others.
Other types of diabetes Patients were classified in this type if the diagnosis was uncertain or not consistent with the criteria for any of the aforementioned diabetes diagnoses.

Statistical analysis
Data analysis was carried out using Stata/IC version 14.0 for Windows (StataCorp LP, College Station, TX, USA). Patients with missing data were omitted from the analyses involving that variable, but they were included in other analyses for which data were available. Data are presented as the number and percentage for categorical data, and as mean plus/minus standard deviation for continuous data.

Types of diabetes and numbers of cases diagnosed per year
A total of 2,844 cases of diabetes diagnosed before 30 years-ofage were analyzed. The diagnoses by clinical criteria were patients with type 1 diabetes 62.6%, type 2 diabetes 30.7%, monogenic diabetes 2.5%, secondary diabetes 3.0%, genetic syndromes associated with diabetes 0.9% and other types of diabetes 0.4% (Table 1). Among the 71 patients with monogenic diabetes, 35 had MODY, 23 neonatal diabetes, eight Wolfram syndrome, three mitochondrial diabetes and one Rabson-Mendenhall syndrome. Secondary diabetes was observed in 84 patients ( Table 2). Drug-induced diabetes and disorders of the pancreas were common causes of secondary diabetes. Genetic syndromes associated with diabetes were found in 25 patients, including 13 Prader-Willi syndrome, eight Down syndrome, two Turner syndrome, one Peters-plus syndrome and one mental retardation. When considering the year of diagnosis, we observed a higher number of patients diagnosed with diabetes in recent years compared with earlier years (Figure 1a). Type 1 diabetes was the most common type of diabetes in patients with age of onset 0 to <15 years throughout 1976-2016, and in patients with age of onset 15 to <30 years during 1981-1990 and 1996-2000. An increased percentage of type 2 diabetes in the 0 to <15 age group during 1996-2016 was also observed. Type 2 diabetes was the most common type of diabetes in patients with age of onset 15 to <30 years during 1991-1995, and during 2006-2016 (Figure 1b,c).

Patient characteristics
Females were predominant in all types of diabetes. The overall mean duration of diabetes was 7.1 -6.0 years. The mean age at diagnosis in type 1 diabetes patients was 12.2 -6.8 years, and the youngest case was diagnosed at the age of 10 months. Type 2 diabetes patients had the highest average age of onset (20.8 -6.2 years), with the youngest patient diagnosed at 7.8 years (Table 1). Type 1 diabetes accounted for 72.3% of patients, with age of onset <20 years ( Figure 2). The number of cases diagnosed with type 1 diabetes peaked at 10 to <15 years-of-age, followed by 5 to <10 years-of-age. The proportion of type 2 diabetes increased substantially with age. The proportion of type 2 diabetes was 61.0% of patients with age of onset from 20 to <30 years. Among all types of diabetes, most cases of diabetes were diagnosed between 10 and <15 years-ofage ( Figure 2).     1976  1977  1978  1979  1980  1981  1982  1983  1985  1985  1986  1987  1988  1989  1990  1991  1992  1993  1994  1995  1996  1997  1998  1999  2000  2001  2002  2003  2004  2005  2006  2007  2008  2009    secondary diabetes, genetic syndrome associated with diabetes and other types of diabetes who required insulin therapy were mainly on a conventional insulin regimen (Table 3).

SMBG
The frequency of daily SMBG among our cohort is shown in  (Table 1).

Comorbidities
The prevalence of autoimmune thyroid disease was highest in genetic syndrome associated with diabetes patients (12%), followed by type 1 diabetes patients (4.8%). The prevalence of dyslipidemia and hypertension were highest in type 2 diabetes patients at 55.7% and 33.3%, respectively (Table 1).

DISCUSSION
The results of this nationwide multicenter registry hospitalbased study of young-onset diabetes showed a recent increase in the number of patients diagnosed with diabetes, both type 1 diabetes and type 2 diabetes. The present finding is similar to the SEARCH Diabetes in Youth Study in the USA, which also showed the increased prevalence of both type 1 diabetes and  However, in the present study, the number of patients diagnosed in 2016 was lower than in previous years. We speculate that many patients were taken care of at community and/or general hospitals, and were not referred for care to tertiary care centers during the first year of diagnosis. In this study, type 1 diabetes was found to be more common in the first and the second decades of life, whereas type 2 diabetes was observed to be more common in the third decade of life. The increased number of type 1 diabetes cases diagnosed recently in our registry is similar to the increased incidence reported in the USA 13 and other countries 14 . However, in Finland, a country with a high incidence of type 1 diabetes, the incidence of type 1 diabetes increased during 1953-2006, but since 2006, that trend has been decreasing 15 . Several factors; for example, obesity (accelerator hypothesis), gut microbiome, exposure to several chemicals and early life factors, including maternal diet, mode of delivery, infant feeding, childhood diet and microbial exposure (hygiene hypothesis), might contribute to the increasing incidence of type 1 diabetes in certain populations 16 . The present study found that type 1 diabetes (62.6%) and type 2 diabetes (30.7%) accounted for the majority of cases with young-onset diabetes. This is consistent with a report from a registry of people with diabetes in India with young age at onset (YDR) 17 , which showed a prevalence of type 1 diabetes of 63.9%, and a prevalence of type 2 diabetes of 25.3% 17 . In contrast, a study in Japan showed that 57.4% of patients with early-onset diabetes were found to have type 2 diabetes 18 . The higher proportion of type 1 diabetes in the present study might partly be explained by the possibility that not all patients with type 2 diabetes were referred to the tertiary care centers. Furthermore, the number of patients with type 2 diabetes might be underestimated, because some patients might be asymptomatic and did not seek diagnosis or treatment. Nevertheless, during recent years, an increased percentage of patients diagnosed with type 2 diabetes in both age of onset <15 years and within 15 to <30 years was observed in the present study. Obesity, living an obesogenic lifestyle 19   contribute to the increased numbers of patients with type 2 diabetes. The average age of onset of type 1 diabetes (12.2 years) in the present study is comparable to that of previous studies from the USA, India and Malaysia (10.0-12.9 years) 17,21,22 . The EURODIAB ACE Study Group, SEARCH and YDR reported a peak incidence of type 1 diabetes from 10 to 14 years-ofage 17,22,23 . The present study showed the highest incidence of type 1 diabetes within the same age group (10 to <15 years), followed by 5 to <10 years, and ≤5 years. For type 2 diabetes patients, the mean age of onset ranged from 12 to 21.7 years in previous studies 17,21,22,24,25 , the peak incidence was observed during 15-19 years 22 , and just 8% were diagnosed at age <10 years 25 . In the present study, the mean age of type 2 diabetes onset was 20.8 years, the peak incidence occurred during 26-30 years and just 4.2% were aged <10 years at diagnosis. Our peak incidence was older compared with those reported from previous studies. This is likely due to our expanded inclusion criteria to the age of onset of <30 years.
Regarding presenting symptoms at diagnosis in type 1 diabetes patients, DKA was present in 35.1% and 28.7% in the SEARCH and YDR studies, respectively 26 . A systematic review that included 29,000 patients from 31 countries showed that the frequency of DKA at diagnosis of type 1 diabetes ranged from 12.8 to 80%. The highest frequencies were in the United Arab Emirates, Saudi Arabia and Romania, and the lowest frequencies were in Sweden, the Slovak Republic and Canada 27 . The frequency of DKA in those countries was found to be inversely associated with gross domestic product 27 . In type 2 diabetes, the prevalence of DKA at diagnosis in SEARCH and YDR were 5.5 and 6.6%, respectively 26 . The present study reported a higher prevalence of DKA at diagnosis in both type 1 diabetes and type 2 diabetes patients compared with SEARCH and YDR 26 . This might be explained by a relatively low incidence of young-onset diabetes in Thailand, which could result in relative non-familiarity with diabetes symptoms among parents and patients, and possibly also among physicians. Therefore, increased awareness of diabetes symptoms among the public and among healthcare professionals in Thailand is greatly needed to enhance early diagnosis and to prevent the development of DKA.
Glycemic control and insulin regimen in type 1 diabetes patients varies greatly among countries. The YDR study reported a mean HbA 1c of 11.0%, with 7.2% achieving the glycemic target (HbA 1c <7.5%), whereas the SEARCH study reported a mean HbA 1c of 7.8%, with 42% achieving the glycemic target 28 . In YDR, 52.8% of type 1 diabetes patients were on a once/twice daily regimen; however, 65.1% of patients in the SEARCH study were on a basal-bolus regimen 28 . The Australasian Diabetes Data Network reported that 27% of type 1 diabetes achieved the HbA 1c target, with a majority of patients treated with intensive insulin therapy 29 . In the present study, more than half of type 1 diabetes patients (55.2%) were receiving intensive insulin treatment; however, just 12.4% of our Glycemic control among young type 2 diabetes patients also varies among countries. The YDR study reported a mean HbA 1c of 9.9%, with 18.1% achieving the glycemic target, whereas the SEARCH study reported a mean HbA 1c of 7.2%, with 67.7% achieving the glycemic target 28 . In YDR and SEARCH, 30-43% of type 2 diabetes patients were treated with metformin only, and 33-39% required insulin treatment 28 . Similar to the SEARCH study, the Pediatric Diabetes Consortium, which included young type 2 diabetes patients from 19 centers in the USA, reported an average HbA 1c of 7.8%, whereas the Pediatric Diabetes Prospective registries in Germany, Austria and Luxemburg reported a lower mean HbA 1c of 6.5% 24 . In the present study, 50% of type 2 diabetes patients were treated with an oral antidiabetic agent only. However, glycemic control among type 2 diabetes patients in the present cohort (mean HbA 1c 8.48%) was worse than reported from SEARCH, Pediatric Diabetes Consortium and Pediatric Diabetes Prospective registries 25,28 , and just 30% of patients in the present study achieved the glycemic target. It has been shown that childhood-onset type 2 diabetes has a more progressive nature and higher rate of treatment failure 32 compared with adult-onset type 2 diabetes. The high proportion of patients in this registry that did not achieve glycemic target emphasizes the urgent need to develop a more effective nationwide strategy to improve care, education and support for patients with youngonset diabetes to reduce the burden of diabetes-related complications.
The present study had some limitations. First, this study had a retrospective design. Second, only patients from tertiary public hospitals were enrolled, so the results might not be representative of or generalizable to all of Thailand. It is possible that the higher numbers of patients diagnosed in recent years could be a true increase in the incidence, but we cannot exclude if those diagnosed earlier were lost to follow up nor could we confirm their vitality. It is possible that adult patients with young-onset diabetes were missed from this registry, as the year of diagnosis might have not been consistently recorded, resulting in an underestimation. Third, diagnosis of the different types of diabetes was based solely on clinical manifestation. Distinguishing among the different types of diabetes can be challenging. Diabetes autoantibodies and genetic testing were available in some patients only, potentially resulting in misclassification. Less than 20% of type 2 diabetes patients had diabetes autoantibodies measurement, possibly, some type 2 diabetes patients, requiring insulin treatment, might have latent autoimmune diabetes of adults 33 or a hybrid form of diabetes. Accordingly, to improve the accuracy of diabetes diagnosis and to provide the proper management, a genetic study evaluating the genetic causes of diabetes and diabetes autoantibodies has been implemented in Thailand as part of T1DDAR CN, and that study is ongoing.
In this registry, type 1 diabetes remains the most common type of diabetes among patients aged <20 years. The proportion of type 2 diabetes was found to increase substantially with age, and it has become more prevalent among patients with age of onset from 21 to 30 years. The increase in diabetes diagnoses in recent years might reflect an increase in diabetes incidence. The majority of patients in this registry did not achieve the glycemic target, especially the type 1 diabetes patients.