Survey of Current Medical Treatments for Childhood-Onset Type 2 Diabetes Mellitus in Japan

The prevalence of childhood-onset type 2 diabetes mellitus has increased dramatically over the past two or three decades in Japan, but epidemiological and clinical data remain limited. This survey was conducted to elucidate the current use of antidiabetic medications and the efficacy, safety and problems associated with the use of these agents. Clinical data on 259 children (younger than 18 yr of age; 121 boys and 138 girls) with type 2 diabetes treated at 42 medical centers throughout Japan between June and September 2003 were analyzed. Sixty-nine percent of all the type 2 diabetic patients (78% of the boys, 63% of the girls) were obese (percent overweight ≥ 20%) at the time of diagnosis. Overall, 172 subjects (66%) were treated using anti-hyperglycemic agents, including α-glucosidase inhibitors (α-GI), insulin, metformin and sulfonylureas (SUs). Many patients who were initially treated with a single medication eventually required insulin alone or in combination with an additional agent, suggesting that their diabetic control had deteriorated during the course of treatment. The HbA1c level of the 14 subjects who received only metformin decreased significantly without an improvement in obesity. Three cases with adverse events were reported, but causal relations with anti-hyperglycemic agents were not clear. In conclusion, mainly α-GI, insulin and metformin have been prescribed for childhood-onset type 2 diabetes patients in Japan. The results of this survey suggest that metformin is safe and effective for the treatment of type 2 diabetes with obesity in children and adolescents.     

Type 2 diabetes in a 5‐year‐old and single center experience of type 2 diabetes in youth under 10

The worrisome rise in pediatric type 2 diabetes (T2DM) is most prevalent among minority ethnic/racial populations. Typically, T2DM occurs during puberty in high risk obese adolescents with evidence of insulin resistance. Screening for T2DM in obese youth can be a daunting task for pediatricians and differentiating between pediatric T1DM and T2DM in obese youth can be challenging for pediatric endocrinologists. There is very limited data regarding the prevalence of T2DM among youth < 10 years of age. Here we present the case of a 5‐year‐old Hispanic male diagnosed with T2DM after referral by his pediatrician for abnormal weight gain, acanthosis nigricans and an elevated HbgA1c. He subsequently became symptomatic for diabetes with confirmed hyperglycemia and HbgA1c of 9.7% (83 mmol/mol) at the time of formal diagnosis. Type 1 diabetes autoantibodies (GAD65, Islet, and ZincT8) and monogenic diabetes genetic tests were negative. Due to elevated liver enzymes and baseline HbgA1c, he received basal insulin as his initial therapy. In this paper, we will discuss this case and present an IRB approved retrospective review of the characteristics of the 20 T2DM patients <10 years of age identified to date in our pediatric diabetes center. This review highlights that while uncommon, the diagnosis of T2DM merits consideration even in prepubertal children. This is especially true when working with a high risk population, such as our Hispanic South Texas youth.     

儿童1型糖尿病90例

目的探讨儿童1型糖尿病(IDDM)的发病情况、临床特点、远期并发症及酮症酸中毒(DKA)的治疗。方法回顾性分析1993～2003年我院90例IDDM患儿的发病情况,临床特点,远期并发症,并探讨DKA的治疗。结果10～16岁儿童发病率最高,感染是诱发DKA的常见原因,未长期坚持胰岛素治疗易导致IDDM远期并发症的发生。结论小剂量胰岛素持续静滴、纠正水电解质紊乱、调节酸碱平衡是抢救DKA的关键;坚持长期胰岛素治疗是防治远期并发症IDDM的关键。     

新诊断儿童1型糖尿病109例的临床特征

目的探讨近年新诊断儿童1型糖尿病的临床特征。方法对1999年1月1日～2005年4月30日浙江大学医学院附属儿童医院住院且为首次发病的109例1型糖尿病的临床资料进行回顾性分析,按照有无酮症酸中毒和有无低钾血症分别进行分组比较,正态分布的数据用x±s表示,采用为卡方及t检验,非正态分布的资料用中位数表示,采用Mann-WhiteyU检验进行组间比较。结果新诊断1型糖尿病儿童非酮症酸中毒(DKA)组病程明显较DKA组长,平均住院时间和糖化血红蛋白明显低于DKA组。入院时有感染诱因者21例(19.3%);伴低钾血症48例(44%),非低钾血症61例(56%);DKA组低钾血症的比率为26/47(55.3%),明显高于非DKA组的22/62(35.5%)。低钾组出现心悸、胸闷及倦怠症状出现频率为39.6%、35.4%,而非低钾组上述症状的频率分别是11.5%、16.4%,两组差异有显著性。所有患儿无1例死亡,出院后治疗依从性不一致。结论感染可能导致患儿糖尿病的进展和临床表现的出现。低钾血症组的症状较重。可能是临床症状的不典型导致了糖尿病不能及时被发现。     

1型糖尿病并低三碘甲状腺氨酸综合征201例

目的探讨1型糖尿病(T1DM)及糖尿病酮症酸中毒(DKA)患儿并低三碘甲状腺氨酸(T3)综合征的临床特点。方法采用放射免疫分析法检测91例T1DM并DKA患儿(DKA组)及110例单纯T1DM患儿(非DKA组)血清T3、甲状腺素(T4)、促甲状腺激素(TSH)水平,观察2组T3、T4下降例数及水平,并将DKA组分为轻、中、重3个亚组,观察不同组别中甲状腺激素变化特点。结果 DKA组易发生T3、T4下降,DKA组T3[(0.54±0.51)μg.L-1]、T4[(5.65±2.80)μg.L-1]与非DKA组T3[(1.02±0.38)μg.L-1]、T4[(9.28±2.85)μg.L-1]比较,差异均有统计学意义(Pa<0.000 1)。中、重度DKA组与非DKA组T3比较,差异有统计学意义(Pa<0.000 1),轻、中、重度DKA组与非DKA组T4比较,差异均有统计学意义(Pa<0.000 4,0.000 1)。DKA组与非DKA组TSH比较,差异无统计学意义(P>0.05)。结论 T1DM患儿甲状腺激素检测的结果主要表现为T3降低,部分伴T4降低,其疾病的严重程度与甲状腺激素降低程度一致,T1DM并DKA患儿的T3、T4水平均有明显下降,提示T1DM患儿需重视甲状腺激素的检测,利于早期防治。     

基础加餐时胰岛素治疗儿童1型糖尿病的疗效

目的 观察应用基础加餐时胰岛素治疗儿童1型糖尿病(T1DM)的临床效果.方法 15例T1DM患儿采用传统治疗方案治疗平均16个月:双时相低精蛋白锌胰岛素30/70,2/3量早餐前30 min皮下注射,1/3量晚餐前30 min皮下注射;之后采用基础加餐时治疗方案治疗至少12个月:3餐前0～15 min门冬胰岛素皮下注射,睡前甘精胰岛素皮下注射.观察基础加餐时方案治疗后糖化血红蛋白(HbA1c)水平、胰岛素用量和低血糖发生情况.结果 15例T1DM患儿应用基础加餐时胰岛素类似物治疗后3、6、9、12个月的HbA1c与传统治疗相比降低(t=7.15、4.88、3.46、5.28,Pa<0.01),3、6、9、12个月的HbA1c相互间比较差异无统计学意义(t=2.08、1.64、1.73、1.85、1.96、1.66,Pa>0.05).胰岛素用量差异无统计学意义(t=1.56,P>0.05).传统方法治疗期间,7例发生严重低血糖,改用基础加餐时胰岛素治疗方案后,无一例发生严重低血糖.发生轻中度低血糖的次数亦显著减少(t=13.31,P<0.001).结论 应用基础加餐时胰岛素治疗儿童T1DM可使患儿获得较好的血糖控制,同时减少低血糖发生,而胰岛素用量并无增加,并可改善患儿的治疗满意度及生活质量.     

2型糖尿病儿童8例临床分析及综合治疗随访

目的探讨2型糖尿病(T2DM)儿童的临床特点及诊治方法。方法对2002年5月-2008年2月本院8例住院T2DM患儿的临床资料进行回顾性分析,包括临床症状、体质量指数、血压、血脂、合并症、家族史、口服葡萄糖耐量试验、胰岛素释放试验。予饮食、运动、行为纠正和药物综合治疗及疗效随访。结果8例中仅1例有典型症状;均为肥胖儿,体质量指数为31.4±2.7;并脂肪肝7例,并原发性高血压、代谢综合征各4例,并高三酰甘油血症、黑棘皮病各3例,并酮症酸中毒1例;4例有肥胖家族史;3例通过饮食、运动和行为纠正治疗2个月后血糖有效控制,1例予胰岛素治疗1周后改为二甲双胍,余服用二甲双胍,2周后血糖有效控制。结论儿童T2DM起病隐匿,肥胖症是其重要危险因素,易并原发性高血压、脂质代谢异常、血管病变及靶器官损伤,需采取饮食、运动和药物治疗、教育及自我监控相结合的综合治疗措施。     

Type 2 diabetes mellitus in European children and adolescents

Aim: The aim of the study was to review the published and unpublished data on type 2 diabetes in European children in order to determine how common this problem is in the dominantly Caucasian population. Methods: The MEDLINE database was searched and a questionnaire was distributed among European Childhood Obesity Group (ECOG) representatives from 16 countries. Results: One hundred and eighty-four children with type 2 diabetes were diagnosed in Europe, 144 of them of Caucasian origin. The majority of them were overweight females and, had positive family history for type 2 diabetes mellitus.

Conclusion: Because of the significant rates of type 2 diabetes in Europe, screening for it in obese children and adolescents is highly recommended.     

Association between Sex,Age, Insulin Regimens and Glycemic Control in Children and Adolescents with Type 1 Diabetes

We examined the association between sex, age, insulin regimens and glycemic control in 133 Japanese children and adolescents, 42 males and 61 females aged 16.8 ± 7.0 yr, with type 1 diabetes mellitus (T1DM). The patients were divided into 5 age groups and were also classified according to the insulin regimen. The annual median HbA1c level in males (7.3 ± 0.2%) was similar to that in females (7.2 ± 0.2%). In regard to the age of the patients, the median HbA1c levels in patients aged 15–19 yr (7.9 ± 0.4%) was significantly higher than those aged 5–9 yr (7.2 ± 0.1%) and those aged 20≤ yr (6.6 ± 0.4%, p<0.05, respectively). On the other hand, there were no significant relationships between the HbA1c values and the insulin regimens. In conclusion, difficulty in management of diabetes due to emotional issues and endocrinological factors during adolescence may play a possible role in the deterioration of diabetes control. On the other hand, the insulin regimen does not seem to have a major impact on the metabolic outcome in young people with T1DM.     

不同血钾水平1型糖尿病175例的临床特征

目的了解不同血钾水平儿童及青少年1型糖尿病临床特征。方法1型糖尿病患者175例根据血钾水平将其分为3组：A组血钾〈4 mmol/L,C组血钾≥5 mmol/L,B组血钾正常（4~5 mmol/L）。对3组性别、年龄、住院时间、伴发呕吐、感染、酮症酸中毒（DKA）的比例及生化指标等临床特征进行观察。分析血钾紊乱和不同临床表现之间的关系及可能原因。结果血钾异常组较易发生代谢紊乱及伴发症状。A组40例,其发生酮症酸中毒及感染比例比B组要高。A组血氯水平最高。C组36例,发生呕吐比例比B组高,其患儿年龄较A组小,C组入院时血糖水平在3组中最高。结论糖尿病发生代谢紊乱和急性并发症时,易并血钾异常,治疗方面应积极纠正血钾紊乱。     

Relatively Small Birth Size and Accelerated Early Growth of Japanese Type 1 Diabetic Children with Younger Onset

We investigated the changes of anthropometrical parameters in Japanese children with type 1 diabetes (T1DM) from birth to the onset of diabetes. One-hundred ninety-nine children (79 males and 120 females) diagnosed between 0–16 yr of age during the period between 1990 and 2003 were the subjects of this study. The subjects were categorized into 3 groups according to onset age (0–5 yr; n=74, 5–10 yr; n=61, 10–16 yr; n=64). At birth, the younger onset (<5) group had significant lower height and weight standard deviation score (SDS) compared with the older onset (5≤) group (p=0.01 and p=0.02, respectively). When the changes in height SDS from birth to onset were compared, height SDS at onset were significantly greater than those at birth in the younger onset group (p<0.001). However, no significant difference was observed in the other groups (p=0.95 and p=0.39). These results suggest that relatively small size at birth and accelerated growth after birth until the onset of diabetes may be a characteristic of Japanese T1DM children with younger onset and may further support the hypothesis that emphasizes accelerated growth and subsequent insulin resistance as a cause of earlier onset of T1DM.     

Role of Counterregulatory Hormones for Glucose Metabolism in Children and Adolescents with Type 1 Diabetes

To elucidate the mechanism of insulin resistance due to insulin counterregulatory hormones (ICRHs) and evaluate ICRH secretion kinetics, ICRH concentrations were measured and correlated with blood glucose levels in 28 type 1 diabetic patients. Blood glucose was measured before bedtime. Early morning urine samples were collected the next morning before insulin injection and breakfast. Fasting blood glucose, cortisol, glucagon and HbA1c levels were measured. Growth hormone (GH), adrenaline, cortisol and C-peptide levels in morning urine samples were measured; SD scores were calculated for urine GH. The laboratory values (mean ± SD) were as follows; HbA1c of 8.1% ± 1.4%; pre-bedtime glucose of 203 ± 105 mg/dl; fasting blood glucose of 145 ± 87 mg/dl; serum cortisol of 21.6 ± 5.5 µg/dl; plasma glucagon of 98 ± 41 pg/ml; urinary GH, 27.2 ± 13.0 ng/gCr; urinary cortisol of 238 ± 197 ng/gCr; and urinary Adrenaline of 22.9 ± 21.0 ng/gCr. The mean urinary GH SD score was increased (+1.01 ± 0.70; p=0.000); the mean plasma glucagon lebel (98 ± 41 pg/ml) was not. Fasting blood glucose was positively correlated with plasma glucagon (R=0.378, p=0.0471) and negatively correlated with urinary cortisol (R=–0.476, p=0.010). Urinary adrenaline correlated positively with urinary GH (R=0.470, p=0.013) and urinary cortisol (R=0.522, p=0.004). In type 1 diabetes, GH, glucagon and cortisol hypersecretion may contribute to insulin resistance, but the mechanism remains unclear.     

Pathogenic Characteristics at Diagnosis in Young Children with Type 1 Diabetes Presenting Prior to 5 Years of Age

We examined pathogenic characteristics in Japanese children with type 1 diabetes presenting before 5 years of age. The subjects were 23 Japanese children, 9 males and 14 females, 1.1–4.8 yr of age at diagnosis. The majority had severe metabolic decompensation accompanied by complete absence of β-cell function at diagnosis. We found a high frequency of preceding viral illness (41.7%) among them. The prevalence of antibodies to GAD and IA-2 at diagnosis in young children were significantly lower than those in older cases diagnosed after 5 yr of age (31.6% vs. 86.3%, 47.1% vs. 82.5%, respectively). These findings suggest that non-autoimmune mechanisms or age-related differences in autoimmunity could be involved in the pathogenesis of diabetes in young children. In regard to diabetes-related HLA-DRB1 and DQB1 alleles, all subjects had high-risk genotypes in both alleles. On the other hand, none of the patients had any of the protective genotypes in either allele. In regard to haplotypes, the frequencies of DRB1*0405-DQB1*0401 and DRB1*0901/ DQB1*0303 were 60.9% and 52.2%, respectively, and both these haplotypes are associated with strong susceptibility to type 1 diabetes. Patients with early-childhood onset may have diabetes-related autoimmunity and genetic backgrounds different from those of patients diagnosed at a later age.     

儿童青少年2型糖尿病的诊断及治疗

随着世界范围肥胖者的增加,2型糖尿病(T2DM)在儿童及青少年中的发病率也明显上升.儿童青少年T2DM的病因也是由遗传、环境等多因素相互作用的结果.重要的危险因素包括肥胖、T2DM家族史、高危种族及胰岛素抵抗表型.为及早诊断及治疗,对具有危险性的儿童应进行T2DM筛查.筛查的指征包括肥胖和其他2个危险因素.儿童青少年T2DM的诊断标准同成人,基于空腹、随机血糖及口服糖耐量试验的标准值.防治T2DM的重要措施是改善生活方式、减低或控制体质量.此外,还可应用二甲双胍和(或)胰岛素.控制高血压及血脂紊乱及监测微血管并发症也很必要.实用儿科临床杂志, 2009, 24(8 ): 638-640     

Treatment for Childhood Type 2 Diabetes

Urine glucose screening at school implemented in Japan is useful for detecting childhood type 2 diabetes at the early stage of the disease. Most patients detected by the screening can improve hyperglycemia and reduce overweight within one to three months by changing lifestyle with diet and exercise. For patients who are unable to alter their lifestyle and for those who have hyperglycemia despite maintaining these changes, a variety of oral hypoglycemic agents, including α-glucosidase inhibitors, sulfonylureas, glitinides, metformin, thiazolidenediones, and insulin are available. Metformin is considered to be the most effective oral agent as monotherapy for Japanese young persons with type 2 diabetes, because most of them are obese with insulin resistance. The approach to insulin therapy in patients with type 2 diabetes often differs from that most frequently used in patients with type 1 diabetes. Adjustment of the dose of insulin at each injection using sliding scales or algorithms is not required in most cases. In some cases, combination therapy with metformin and sulfonylureas or use of insulin is more effective for stabilization of blood glucose values. Therapeutic means for childhood type 2 diabetes should be variable depending on each patient’s characteristics.     

Urinary C-Peptide Excretion at Onset of Insulin Dependent Diabetes Mellitus in Children

ABSTRACT. The 24-hour urinary excretion of C-peptide and the plasma C-peptide concentration were measured at the onset of insulin dependent diabetes mellitus (IDDM) in children. The excretion of C-peptide was twice as high as that found in normal control subjects, whereas the plasma C-peptide values were markedly lower, indicating increased urinary leakage of C-peptide in this phase of the disease. In the diabetic children under seven years of age the mean value of C-peptide excretion was clearly lower than in the older children.     

CLEC16A基因与中国儿童1型糖尿病遗传易感性及临床表现的相关性

目的研究CLEC16A基因与中国儿童1型糖尿病(T1DM)易感性及临床表现的关联。方法提取131例无血缘关系的T1DM患儿(T1DM组,均符合1999年WHOT1DM的诊断标准)及121例无血缘关系的成年健康献血员(健康对照组)的外周血基因组DNA(饱和盐析法),选取CLEC16A基因17个具有单核甘酸多态性(SNPs)的位点,运用飞行质谱技术对CLEC16A基因与中国儿童T1DM遗传易感性及临床表现的相关性进行研究。结果1.在17个CLEC16ASNPs位点多态性中,只有rs12921922和rs12931878位点的等位基因的频率在T1DM组中显著增加,其他等位基因的频率分布在T1DM组与健康对照组中无统计学差异。rs12921922的等位基因为C与T,其中T等位基因的频率在T1DM组为90.8%,健康对照组为85.0%,二组比较有统计学差异(P=0.0440)。rs12931878的等位基因为A与C,其中A等位基因的频率在T1DM组为90.1%,健康对照组为84.0%,二组比较有统计学差异(P=0.0435)。2.CLEC16A易感性基因在中国T1DM患儿不同临床表现分组中的频率分布无统计学差异。结论C...     

Type 2 diabetes in Asian Indian youth

Abstract:  The prevalence of youth-onset type 2 diabetes is increasing worldwide in parallel with the obesity epidemic. In India, the age at onset of type 2 diabetes had traditionally been a decade or two earlier compared with the western population. Hence, it is not surprising that the prevalence of youth-onset type 2 diabetes is rapidly escalating in India not only among the more affluent sections of society but also in the middle and lower socioeconomic groups as well. In India, type 2 diabetes in youth overlaps with monogenic forms of diabetes such as maturity-onset diabetes of the young, fibrocalculous pancreatic diabetes, and malnutrition-modulated diabetes, all of which are ketosis-resistant forms of youth-onset diabetes. Screening of high-risk groups may help in the early detection of youth-onset type 2 diabetes and prevention of its complications. Primary prevention would require a multisectoral approach involving the government and non-governmental agencies with a focus on healthier lifestyles among children.