Screening frequency for celiac disease and autoimmune thyroiditis in children and adolescents with type 1 diabetes mellitus--data from a German/Austrian multicentre survey

Objective: Type 1 diabetes mellitus (T1DM) is associated with other autoimmune diseases such as celiac disease (CD) and Hashimoto thyroiditis. The aim of this study was to evaluate the screening frequency for CD and thyroid antibodies in a multicentre survey. Methods: The Diabetes Patienten Verlaufsdokumentationssystem (DPV) initiative is based on standardized, prospective, multicentre documentation in children and adolescents with diabetes. Data from 31 104 patients <18 yr of age (52% males, mean age 13.1 yr) with T1DM from 177 paediatric centres in Germany and Austria from 1995 until 2007 were analysed. Results: Of 31 104 patients, 16 994 patients (55%) were screened at least once for CD. In 1995, 44% of the patients were screened for CD compared with 68.6% in 2006. Annual screening for CD has also increased (11.9% in 1995 compared with 43.6% in 2006). Eleven per cent of the patients had positive antibodies for CD. Patients with positive antibodies were significantly younger at diabetes onset and had a significantly longer duration of diabetes (p < 0.001). Compared with screening for CD, screening for thyroid antibodies was performed more frequently (at least once in 62% of the patients). Fifteen per cent of the patients had positive thyroid antibodies. Screening for thyroid antibodies also increased from 62.6 to 72.9%, and annual screening frequency increased from 15.9 to 48.9%. Conclusion: Screening for associated autoimmune diseases in children with T1DM has increased during the past decade. Eleven per cent of the patients had positive CD‐specific antibodies, and 15% had positive thyroid antibodies. Screening for thyroid antibodies is performed more frequently than screening for CD.     

HLA-DRB1*08 allele may help to distinguish between type 1 diabetes mellitus and type 2 diabetes mellitus in Mexican children

BACKGROUND: It may be difficult to distinguish type 1 diabetes mellitus (T1DM) from type 2 diabetes mellitus (T2DM) in the pediatric population. Autoantibodies may help to differentiate both types of diabetes, but sometimes these are positive in patients with T2DM and negative in patients with T1DM. The human leukocyte antigen (HLA)-DR genotype has been associated with T1DM and with T2DM only in adults and in determined cases. AIM: To determine the differences in HLA class II allele frequencies in Mexican children with T1DM and T2DM. METHODS: We included 72 children with T1DM, 28 children with T2DM, and 99 healthy controls. All were Mexican, and diabetes was diagnosed according to the clinical and laboratory criteria established by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. The HLA-DRB1 typing was performed using polymerase chain reaction-sequence-specific oligonucleotide probe and polymerase chain reaction sequence-specific primers. RESULTS: We found an increased frequency of HLA-DRB1*08 and a decreased frequency of HLA-DRB1*04 in the group with T2DM vs. T1DM [p = 0.0001, odds ratio (OR) = 10.58, 95% confidence interval (CI) = 3-40.8 and p = 0.0006, OR = 0.24, 95% CI = 0.11-0.53, respectively]. No significant differences were found between HLA-DRB1 alleles in T2DM vs. controls. In the group with T1DM, there was a significantly increased frequency of the HLA-DR4 and HLA-DR3 alleles relative to controls (p = 0.0000001, OR = 3.59, 95% CI = 2.2-5.8 and p = 0.00009, OR = 4.66, 95% CI = 2.1-10.3, respectively). CONCLUSION: There are significant differences in the HLA profile in Mexican children with T1DM and T2DM. HLA typing could play a role in the differentiation between both types of diabetes in this population.     

Prevalence of hepatic abnormalities in a cohort of Egyptian children with type 1 diabetes mellitus

El‐Karaksy HM, Anwar G, Esmat G, Mansour S, Sabry M, Helmy H, El‐Hennawy A, Fouad H. Prevalence of hepatic abnormalities in a cohort of Egyptian children with type 1 diabetes mellitus. Background and aim: Children with type 1 diabetes mellitus (T1DM) are frequently investigated for hepatic abnormalities. This study was carried out to report on the prevalence of hepatic abnormalities in diabetic children and adolescents and to highlight the possible etiology and appropriate management. Methods: The study included 692 children (333 were males) with T1DM attending the Diabetes Unit at Cairo University Pediatric Hospital. Their mean age was 9.65 ± 4.18 yr. All children were subjected to clinical examination for hepatomegaly, determination of alanine aminotransferase (ALT) and antibodies to hepatitis C virus (anti‐HCV), and abdominal ultrasonography. All children with clinical, laboratory or ultrasound abnormality were counseled about proper glycemic control and followed up. If abnormalities persisted, more detailed investigations were carried out. HCV RNA was done for anti‐HCV positive children. Results: Sixty (8.7%) were found to have one or more abnormalities: clinical hepatomegaly in 13 (1.9%), elevated ALT in 27 (3.9%), anti‐HCV in 25 (3.6%) and abnormal hepatic ultrasound in 31 (4.5%). Forty percent of anti‐HCV positive children were HCV‐RNA positive. Glycogenic hepatopathy was diagnosed in three cases by liver biopsy. Abnormalities were reversible in 37/60 after proper glycemic control. Conclusion: Although diabetic children are at risk of acquisition of HCV, poor glycemic control is the key factor that predisposes to hepatomegaly, elevated ALT and abnormal ultrasound findings. A 4 to 8‐wk therapeutic trial of proper glycemic control is recommended prior to more invasive diagnostic procedures.     

人白介素18基因启动子多态性与儿童1型糖尿病的相关性研究

目的研究IL-18基因单核苷酸多态性与儿童1型糖尿病（T1DM）的关系。方法应用聚合酶链反应．序列特异性引物（PCR-SSP）和测序的方法,检测118例1型糖尿病患儿和150例正常儿童IL-18基因．137位点C／G和-607位点C／A单核苷酸的多态性。结果①IL-18基因-607位点C／A的-607A等位基因在T1DM和对照组中的发生率分别为41％和53％,差异有统计学意义（P=0．01）,两组间．137位点C／G的等位基因差异无统计学意义（P=0．37）;②IL-18基因．137位点的CC、CG和GG基因型在T1DM和对照组中差异均无统计学意义（P〉0．05）;-607位点的CC基因型T1DM组显著高于正常对照组（P=0．03）,AA基因型T1DM组显著低于正常对照组（P=0．03）;IL-18基因-607位点的CC基因型的新发糖尿病患儿更易发生酮症酸中毒。③IL-18基因的-137G／-607C单体基因型在T1DM和正常对照组间的分布频率差异有统计学意义（P=0．03）。结论IL-18基因-607位点的CC基因型和-137G／-607C单体基因型可能与儿童1型糖尿病的发病有关,而-607位点的AA基因型可能是T1DM的保护性基因型。-607位点的CC基因型与儿童1型糖尿病患者临床表型存在显著的相关性。     

Reducing postprandial hyperglycemia with adjuvant premeal pramlintide and postmeal insulin in children with type 1 diabetes mellitus

Objective:  The purpose of this study was to determine the effect of adjuvant premeal pramlintide with postmeal insulin on postprandial hyperglycemia in children with type 1 diabetes mellitus (T1DM).
Methods:  Eight adolescents with T1DM on intensive insulin therapy participated in an open-label, non-randomized, crossover study, comparing postprandial glucose excursions in study A (prescribed insulin regimen and given premeal) vs. study B (pramlintide + insulin). Prandial insulin dose for study B was decreased by 20% and given postmeal, while pramlintide was given just before the meal. Blood glucose (BG), glucagon, and pramlintide concentrations were measured basally and at timed intervals during a 300-min study period.
Results:  Postprandial incremental BG for the duration of the study was reduced in study B vs. study A with AUC_{(−60 to 300 min)} (area under the curve) at 6600 ± 2371 vs. 20 230 ± 3126 mg/dL/min (367 ± 132 vs. 1124 ± 174 mmol/L/min) (p < 0.001). Glucagon concentration was suppressed for ∼120 min following administration of 30 μg of pramlintide and postmeal insulin (p < 0.003). No severe hypoglycemic episodes were experienced in this study.
Conclusions:  Postprandial hyperglycemia is considerably reduced in adolescents with T1DM when treated with fixed-dose premeal pramlintide, and precisely calculated postmeal insulin, without significant side effects.     

Onset of type 1 diabetes mellitus in two patients with maturity onset diabetes of the young

The association between maturity onset diabetes of the young (MODY) and type 1 diabetes mellitus (T1DM) has been rarely described. We report two patients affected by MODY who developed T1DM. Case 1: a 4-yr-old girl referred for glycosuria presented hemoglobin A1c (HbA1c) of 6.6%. Islet cell antibodies (ICA) and anti-glutamic acid decarboxylase (GADA) were initially negative. As her father, uncle and grandmother showed mild hyperglycemia, they were screened for MODY 2. A novel mutation in glucokinase gene was found in the family. Few months later, her glycemic control worsened consistently and she required insulin treatment. A high titer of GADA and ICA was then detected. Six years afterwards insulin requirement is 0.8 U/kg and HbA1c 6.7%. Case 2: a 15-yr-old boy treated for growth hormone deficiency was found with a blood glucose level of 106 mg/dL. HbA1c was 7.2%, ICA and GADA were negative. Family history was positive for autoimmune diseases and type 2 diabetes mellitus. The patient was investigated for MODY 2 and MODY 3, and a mutation of hepatocyte nuclear factor-1 alpha gene was found. The same mutation was found in the mother who had never been referred for hyperglycemia. After 1 yr, due to an unjustified worsening of the metabolic control, autoimmunity was again investigated and a mild positivity was found. He then required insulin therapy and after 5 yr current HbA1c was 8.2%. The diagnosis of MODY does not exclude the risk of developing T1DM. Therefore autoimmunity should be investigated when ordinary treatments fail and metabolic control unexpectedly worsens.     

Effects of prior hypoglycemia and hyperglycemia on cognition in children with type 1 diabetes mellitus

Objective:  Despite the general consensus that youth with type 1 diabetes mellitus (T1DM) can experience modest cognitive impairment, debate continues over the role of severe hypoglycemia (Hypo) and/or hyperglycemia (Hyper) in producing such impairment. Our aim was to determine how Hypo and Hyper experienced during brain development predict patterns of subsequent cognitive performance in youth with T1DM.
Methods:  We tested youth aged 5–16 yr (T1DM, n = 117; non-diabetic sibling controls, n = 58) on cognitive tasks (verbal and spatial intelligence, verbal and spatial memory, and processing speed). T1DM participants were categorized as having experienced 0, 1–2, or 3 or more (3+) Hypo episodes, as having their first Hypo episode before or after 5 yr of age and as having early (before age 5) or late (after age 5) diabetes onset. Hyper exposure was estimated with median hemoglobin A1c, adjusted for diabetes duration for each subject.
Results:  The group with T1DM had lower estimated verbal intelligence than sibling controls. Within the T1DM group, verbal intelligence was reduced with increased exposure to Hyper, not to Hypo. In contrast, spatial intelligence and delayed recall were reduced only with repeated Hypo, particularly when Hypo episodes occurred before the age of 5 yr. Age of onset did not explain these results.
Conclusions:  Hypo and Hyper have qualitatively different effects on cognitive function in T1DM that depend in part on the timing of exposure during development, independent of onset age. This information extends the known benefits of avoiding both Hypo and chronic Hyper during childhood to include preservation of specific cognitive skills.     

Sibling psychological adjustment to type 1 diabetes mellitus

Objective:  Type 1 diabetes mellitus (T1DM) is a chronic condition whose management affects the whole family, and siblings of children with chronic conditions have been shown to be at higher risk of emotional and behavioural problems. The aims of this study were to investigate sibling adjustment to T1DM using a cross-sectional questionnaire survey design.
Methods:  Forty-one families (48% of those eligible) were recruited from a children's diabetes clinic. From each family, one parent and one sibling of the child with T1DM participated. Parents completed questionnaires measuring sibling adjustment and measures of major life events, social support and parenting stress. Demographic and disease information was obtained from medical records. Siblings completed questionnaires assessing cognitive appraisals and coping strategies. A semi-structured interview was also administered to siblings.
Results:  Siblings were found to be better adjusted than normative data (p < 0.01). Factors associated with poorer sibling adjustment were higher sibling age at diagnosis, higher levels of parenting stress, more difficult sibling temperament, poorer adjustment of the child with T1DM, higher levels of parental distress and more negative sibling perceptions of diabetes and its impact on the family. Results suggest that sibling perceptions of diabetes and parental distress are important predictors of sibling adjustment to T1DM.
Conclusions:  The findings from this study emphasize the relationships between the adjustment of the sibling and that of the child with T1DM and their parents. Many parents worry about how the siblings may cope with the diabetes, but the results of this study are generally reassuring.     

Prevalence of type 1 diabetes mellitus in 6-18-yr-old school children living in Istanbul, Turkey

Akesen E, Turan S, Güran T, Atay Z, Save D, Bereket A. Prevalence of type 1 diabetes mellitus in 6–18‐yr‐old school children living in Istanbul, Turkey. Background: Type 1 diabetes mellitus (T1DM) is among the most common chronic diseases in childhood and the incidence of T1DM is increasing worldwide. There is no actual data regarding the frequency of T1DM in Turkish children. Objectives: We aimed to assess current prevalence of T1DM in 6–18‐yr‐old school children living in Istanbul. Methods: Total number of students and children on insulin treatment were reported by the schools, as the first part of the study. At the second step, the study team visited 203 schools for confirmation of the reported data. Results: One thousand and ninety children in a population of 1 630 751 school children were reported to have T1DM, which made the total prevalence of T1DM 0.67/1000 (95% confidence interval 0.6/1000–0.7/1000). A population of 217 030 children (α = 0.05 and β = 0.20) from 203 schools were screened. The difference between the reported and detected prevalence was 0.032/1000 (215 detected vs. 222 reported, p > 0.05). Comparison of the current data with the prevalence reported in a smaller population in Ankara, Turkey, 16 yr ago, demonstrated that the prevalence of T1DM is higher in the current study (0.46/1000 vs. 0.16/1000, 0.57/1000 vs. 0.34/1000, and 0.92/1000 vs. 0.69/1000 at primary, secondary, and high schools, respectively). Conclusion: This first pediatric T1DM prevalence data in a large pediatric population in Istanbul, Turkey, estimated the prevalence of T1DM as 0.67/1000. This prevalence is 2.5‐fold higher than that reported in Ankara, Turkey, in 1993, suggesting that T1DM prevalence is increasing in Turkey as in the other parts of the world.     

Impaired overnight counterregulatory hormone responses to spontaneous hypoglycemia in children with type 1 diabetes

Abstract:  To assess the changes in counterregulatory hormones overnight after an afternoon of structured exercise or sedentary activity in children with type 1 diabetes mellitus (T1DM), the Diabetes Research in Children Network (DirecNet) studied 50 children (10 to <18 yr) with T1DM in five clinical research centers on two separate days (with and without an afternoon exercise session) using a crossover design. Glucose, epinephrine, norepinephrine, cortisol, growth hormone (GH), and glucagon concentrations were measured hourly overnight. Nocturnal hypoglycemia [plasma glucose concentrations ≤70 mg/dL (3.9 mmol/L)] occurred more frequently on the nights following exercise (56 vs. 36%; p = 0.008). Mean hourly concentrations of most hormones did not differ between sedentary or exercise nights or between nights with or without hypoglycemia. Spontaneous nocturnal hypoglycemia only stimulated small increases in plasma epinephrine and GH concentrations and failed to cause a rise in norepinephrine, cortisol, or glucagon levels in comparison with values during the hour before or after hypoglycemia or other times during those same nights. Counterregulatory hormone responses to spontaneous nocturnal hypoglycemia were markedly decreased regardless of whether there was antecedent afternoon exercise in children with T1DM. Sleep-induced impairments in counterregulatory hormone responses likely contribute to the increased risk of hypoglycemia during the entire overnight period in youth with T1DM.     

Quality of life in children with diabetes and celiac disease: minimal impact of the 'double diagnosis'

Sud S, Marcon M, Assor E, Daneman D and Mahmud FH. Quality of life in children with diabetes and celiac disease: minimal impact of the ‘double diagnosis'. Background: Despite the advent of sensitive testing to detect celiac disease (CD), screening in type 1 diabetes (T1D) remains controversial. Many diabetes clinics are apprehensive about the prospect of introducing a second illness requiring intensive lifestyle changes in patients and families already managing a chronic condition, especially in asymptomatic patients. Objective: To determine the impact of managing CD + T1D on quality of life in families, with attention to the effect of adherence with a gluten‐free diet (GFD) and metabolic control. Patients and Methods: Cross‐sectional assessment using a validated self‐reported quality of life measure: 28 children with biopsy‐proven CD + T1D were compared with 40 subjects with T1D aged 8–18 yr. Parental and child reports were assessed as well as symptoms at the time of CD diagnosis and adherence with a GFD at the quality of life assessment. Results: No significant differences in quality of life were observed between subjects with established CD + T1D and subjects with T1D alone. Parents of children with CD + T1D reported lower social functioning scores than parents of children with T1D (p = 0.03). In the CD + T1D group no differences in quality of life were observed with regard to age at CD diagnosis, CD duration, or on the basis of adherence with a GFD. Conclusions: The additional diagnosis of CD has minimal impact on quality of life in children with T1D; however, parents of CD + T1D children did express greater concern about their child's social functioning.     

Rising incidence of type 1 diabetes mellitus in children and adolescents in Cyprus in 2000-2004

Introduction:  The incidence of type 1 diabetes mellitus (T1DM) has dramatically increased recently in some countries.
Aim:  To ascertain any changes in the incidence of T1DM in our population during the years 1990–2004.
Methodology:  All newly diagnosed cases of T1DM children under the age of 15 yr were registered and relevant information was obtained. Population demographic data based on the most recent census were used for calculations.
Results:  The overall mean annual incidence of T1DM during this 15-yr period was 11.9/100 000 person-years, with a statistically significant increase in the third 5-yr period (14.9/100 000 person-years).
The incidence during the first (1990–1994) and second (1995–1999) 5-yr periods was 10.5/100 000 person-years (p < 0.001). The overall male:female ratio was 0.94. Seasonal distribution for the first and second 5-yr periods revealed a higher incidence during winter and autumn months. Seasonal variation, however, disappears in the third 5-yr period, where no differences were found between the four seasons.
Conclusion:  The incidence of newly diagnosed T1DM cases has increased during 2000–2004. A seasonal variation during the first and second 5-yr periods was no longer observed in the third 5-yr period.     

Incidence of enteropathy-associated T-cell lymphoma in celiac disease: implications for children and adolescents with type 1 diabetes

Abstract: The long-term consequences of screening for celiac disease in diabetic children are not known. Routine screening is not practiced in our pediatric diabetic population. This study of the incidence of the most severe and specific long-term complication of untreated celiac disease, i.e., enteropathy-associated T-cell lymphoma (EATCL) and its association with diabetes, is done in order to justify our strategy not to practice routine screening. In the first phase of this study, a questionnaire was sent to all Swiss pathologists. The second phase consisted of a search in the cancer registry of the canton of Zurich. The incidence of EATCL in the general population of a Swiss region and the theoretical risk for a diabetic patient to develop this type of lymphoma were calculated.
Ten cases of EATCL were found. Five had a long history of malabsorption, three of them since childhood. The mean age of the patients was 61.9 yr. None suffered from diabetes mellitus. The incidence of EATCL was 0.07/100 000 inhabitants/year. The expected risk for EATCL in patients with type 1 diabetes is 12.4/100 000 diabetic patients over a period of 60 yr.
The data suggest that the risk for EATCL is small in diabetic patients. Therefore, we restrict the investigation for celiac disease to patients with typical and atypical symptoms, but do not perform routine screening.