Combined vitamin D, ibuprofen and glutamic acid decarboxylase-alum treatment in recent onset Type I diabetes: lessons from the DIABGAD randomized pilot trial.

AIM: Double-blind placebo-controlled intervention using glutamic acid decarboxylase (GAD)-alum, vitamin D and Ibuprofen in recent onset Type I diabetes (T1D). METHODS: 64 patients (T1D since <4 months, age 10-17.99, fasting sC-peptide ≥0.12 nmol/l, GADA-positive) were randomized into Day(D) 1-90 400 mg/day Ibuprofen, D1-450 vitamin D 2000 IU/day, D15, 45 sc. 20 µg GAD-alum; as A but placebo instead of Ibuprofen; as B but 40 µg GAD-alum D15, 45; placebo. RESULTS: Treatment was safe and tolerable. No C-peptide preservation was observed. We observed a linear correlation of baseline C-peptide, HbA1c and insulin/per kilogram/24 h with change in C-peptide AUC at 15 months (r = -0.776, p < 0.0001). CONCLUSION: Ibuprofen, vitamin D + GAD-alum did not preserve C-peptide. Treatment efficacy was influenced by baseline clinical and immunological factors and vitamin D concentration. Clinical Trial Registration: NCT01785108 (ClinicalTrials.gov).

The Incidence of Childhood Thyrotoxicosis Is Increasing in Both Girls and Boys in Sweden.

BACKGROUND: We found an increase in the incidence rate (IR) of childhood thyrotoxicosis (CT) during the 1990s in central Sweden. The optimal treatment method for CT is a subject that is still debated upon. OBJECTIVES: To investigate whether the increase in IR of CT in Sweden persists and to study the treatment outcome. METHOD: Children <16 years of age diagnosed with CT during 2000-2009 and living in 1 of 5 counties in central Sweden were identified retrospectively using hospital registers. Data on clinical and biochemical characteristics and outcomes of treatment were collected from medical records. The corresponding data from 1990 to 1999 were pooled with the new data. RESULTS: In total, 113 children were diagnosed with CT during 1990-2009 in the study area. The overall IR was 2.2/100,000 person-years (95% CI 1.2-2.5/100,000 person-years). The IR was significantly higher during 2000-2009 than during 1990-1999 (2.8/100,000 [2.2-3.6] vs. 1.6/100,000 person-years [1.2-2.2], p = 0.006). The increase was significant for both sexes. Seventy percent of the patients who completed the planned initial treatment with antithyroid drugs (ATDs) and were not lost to follow-up relapsed within 3 years. Boys tended to relapse earlier than girls (6.0 months after drug withdrawal [95% CI 1.9-10.0] vs. 12.0 months [95% CI 6.8-17.3], p = 0.074). CONCLUSIONS: The IR of CT is increasing in both girls and boys. Relapse rate after withdrawal of ATD treatment is 70%. Boys tend to relapse earlier than girls, and this needs to be further investigated.

Expression of genes involved in inflammation and growth - does sampling site in human full-term placenta matter?

Objective To investigate the placental gene expression of substances in the inflammatory cascade and growth factors at nine different well-defined sampling sites in full-term placentas from 12 normal weight healthy non-smoking women with an uncomplicated singleton pregnancy. Methods All placentas (six girls and six boys) were delivered vaginally. Quantitative real-time polymerase chain reaction was used to analyze toll receptor-2 and -4, interleukin-6 and -8, tumor necrosis factor-α, leptin, ghrelin, insulin-like growth factor-1 and -2, hepatocyte growth factor, hepatocyte growth factor receptor and insulin receptor (IR). Results The leptin gene and the IR gene showed higher expression in lateral regions near the chorionic plate compared to central regions near the basal plate (P = 0.028 and P = 0.041, respectively). Conclusion Our results suggest that the sampling site may influence the gene expression for leptin and IR in placental tissue obtained from full-term normal pregnancies. We speculate that this may be due to differences in placental structure and perfusion and may be important when future studies are designed.

Placental ghrelin and leptin expression and cord blood ghrelin, adiponectin, leptin, and C-peptide levels in severe maternal obesity.

PURPOSE: The purpose of this study is to investigate placental ghrelin and leptin expression as well as cord blood ghrelin and adiponectin levels in maternal obesity and associations between placental ghrelin expression, cord blood ghrelin levels and maternal and infant variables. MATERIALS AND METHODS: Placental ghrelin and leptin expression were analyzed by RT-PCR in 32 severely obese and 32 matched normal-weight women. Cord blood ghrelin, adiponectin, leptin, and C-peptide concentrations were analyzed by ELISA. RESULTS: Neither ghrelin nor leptin expression and neither cord blood ghrelin nor adiponectin levels differed between the groups. Placental ghrelin expression was associated with BMI at delivery in the obese women (r = 0.424, p = .016) and in the infants born to normal-weight women with their weight z-scores at six (r = -0.642, p = .010), nine (r = -0.441, p = .015), and 12 months of age (r = -0.402, p = .028). CONCLUSIONS: Placental ghrelin and leptin expression as well as cord blood ghrelin and adiponectin levels do not seem to be altered in severe maternal obesity. Placenta-derived ghrelin may influence the infants' postnatal weight gain, but possibly only when the mother has normal weight.

Targets and teamwork: Understanding differences in pediatric diabetes centers treatment outcomes.

OBJECTIVE: The reason for center differences in metabolic control of childhood diabetes is still unknown. We sought to determine to what extent the targets, expectations, and goals that diabetes care professionals have for their patients is a determinant of center differences in metabolic outcomes. RESEARCH DESIGN AND METHODS: Children, under the age of 11 with type 1 diabetes and their parents treated at the study centers participated. Clinical, medical, and demographic data were obtained, along with blood sample for centralized assay. Parents and all members of the diabetes care team completed questionnaires on treatment targets for hemoglobin A1c (HbA1c) and recommended frequency of blood glucose monitoring. RESULTS: Totally 1113 (53% male) children (mean age 8.0 ± 2.1 years) from 18 centers in 17 countries, along with parents and 113 health-care professionals, participated. There were substantial differences in mean HbA1c between centers ranging from 7.3 ± 0.8% (53 mmol/mol ± 8.7) to 8.9 ± 1.1% (74 mmol/mol ± 12.0). Centers with lower mean HbA1c had (1) parents who reported lower targets for their children, (2) health-care professionals that reported lower targets and more frequent testing, and (3) teams with less disagreement about recommended targets. Multiple regression analysis indicated that teams reporting higher HbA1c targets and more target disagreement had parents reporting higher treatment targets. This seemed to partially account for center differences in Hb1Ac. CONCLUSIONS: The diabetes care teams' cohesiveness and perspectives on treatment targets, expectations, and recommendations have an influence on parental targets, contributing to the differences in pediatric diabetes center outcomes.

"Mission Impossible"; the Mothering of a Child With Type 1 Diabetes - From the Perspective of Mothers Experiencing Burnout.

PURPOSE: To explore how mothers experiencing burnout describe their mothering of a child with type 1 diabetes mellitus (T1DM), with a focus on their experienced need for control and self-esteem. METHODS: This study used a qualitative, descriptive design and aimed to reveal the experience of mothering a child with diabetes when experiencing burnout. Twenty-one mothers of children with T1DM who were experiencing burnout participated in this study. Data were collected via semi-structured interviews, and content analysis was performed. RESULTS: The main results (latent content of the data) were interpreted in one theme, Mission impossible, an inner feeling derived from an extremely challenging experience of mothering, encompassing involuntary responsibility and constant evaluation. Two sub-themes emerged: Forced to provide extraordinary mothering and Constant evaluation of the mothering. CONCLUSIONS: In addition to monitoring the health of the child with T1DM, it is important for clinicians to pay attention to how mothers experience their daily life in order to support those who are at risk of developing burnout, as well as those who are experiencing burnout. The wellbeing of the mother could influence the wellbeing of the child, as well as the entire family. Further research on perceived parental responsibility, gender differences, psychosocial factors, and burnout is needed. PRACTICE IMPLICATIONS: Knowledge and understanding of how mothers suffering from burnout experience mothering a child with diabetes could help nurses, social workers, psychologists and counselors conducting pediatric diabetes care become more attentive to the mother's situation and have procedures for counseling interventions.

Clinical and Immunological Characteristics of Autoimmune Addison Disease: A Nationwide Swedish Multicenter Study.

Context: Studies of the clinical and immunological features of autoimmune Addison disease (AAD) are needed to understand the disease burden and increased mortality. Objective: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles, and cardiovascular risk factors. Design, Setting, and Participants: A cross-sectional, population-based study that included 660 AAD patients from the Swedish Addison Registry (2008-2014). When analyzing the cardiovascular risk factors, 3594 individuals from the population-based survey in Northern Sweden, MONICA (monitoring of trends and determinants of cardiovascular disease), served as controls. Main Outcome Measures: The endpoints were the prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined. Results: The proportion of 21-hydroxylase autoantibody-positive patients was 83%, and 62% of patients had ≥1 associated autoimmune diseases, more frequently coexisting in females (P < 0.0001). AAD patients had a lower body mass index (P < 0.0001) and prevalence of hypertension (P = 0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of the patients, with a mean dose of 28.1 ± 8.5 mg/d. The mean hydrocortisone equivalent dose normalized to the body surface was 14.8 ± 4.4 mg/m2/d. A greater hydrocortisone equivalent dose was associated with a greater incidence of hypertension (P = 0.046). Conclusions: Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients did not have an increased prevalence of overweight, hypertension, type 2 diabetes mellitus, or hyperlipidemia. However, high glucocorticoid replacement doses could be a risk factor for hypertension.

National Swedish study of immigrant children with type 1 diabetes showed impaired metabolic control after three years of treatment.

AIM: This study examined the clinical status and socio-demographic conditions of children with type 1 diabetes at baseline and after three years of treatment, comparing those born to immigrant parents and Swedish parents. METHODS: This observational nationwide population-based cohort study used prospectively collected registry data from Swediabkids, the National Quality Registry for Paediatric Diabetes in Sweden from 2000 to 2010. Of the 13 415 children with type 1 diabetes, there were 879 born to immigrant parents. We selected three children born to Swedish parents from the same registry for each immigrant child matching them by gender, age and year of diabetes onset (n = 2627; with 10 control children missing probably due to the matching procedure). RESULTS: Immigrant children had a higher median glycated haemoglobin level (HbA1c) than their Swedish peers, but there was no difference in the frequency of hypoglycaemia or ketoacidosis between the two cohorts. A linear regression model with HbA1c as a dependent variable showed that insulin units per kilogram of body weight were the main reason for inferior metabolic control. CONCLUSION: Children with type 1 diabetes born to immigrant parents had inferior metabolic control three years after disease onset compared to children with Swedish born parents. Social family support and educational coping programmes are needed to improve treatment outcomes in immigrants with diabetes.

Group intervention for burnout in parents of chronically ill children - a small-scale study.

BACKGROUND: Long-term stress leading to burnout symptoms is prevalent in parents of chronically ill children. The aim of the study was to evaluate the effect of a group intervention by measuring changes in self-rated clinical burnout and performance-based self-esteem. In addition, the parental perceptions of the acceptability of the intervention were explored. METHODS: Previously, we have explored the prevalence of clinical burnout in parents of patients 1-18 years with type 1 diabetes mellitus (T1DM) and inflammatory bowel disease (IBD) in the county of Örebro. All parents who exhibited clinical burnout symptoms in accordance with the Shirom-Melamed Burnout Questionnaire (SMBQ) were then invited to participate in a group intervention, which was evaluated in the present small-scale study. The group intervention consisted of eight sessions over a 12-week period, including education about behaviour, cognition and symptoms associated with burnout, intending to help the parents to develop adequate strategies for coping with and reducing stress. We evaluated the effect of the intervention in terms of self-rated clinical burnout and performance-based self-esteem (PBSE). In addition, the acceptability of the intervention was evaluated by analyses of recruitment and retention and self-reports from parents. RESULTS: Sixteen parents (13 of children with TIDM and three of children with IBD) out of 104 reporting clinical burnout participated in the intervention. All participants completed the intervention, and the mean attendance rate at all sessions was 90%. Parents' subjective evaluations were mainly positive, and SMBQ (p = 0.01) and PBSE scale (p = 0.04) measurements were significantly reduced, which effects remained 6 months after completion of the intervention. CONCLUSIONS: Despite the small-scale study, we consider that this intervention for parents with clinical burnout was appreciated and well accepted. The significant reduction in clinical burnout symptoms requires further evaluation in randomised controlled studies based on larger groups of parents.

Randomized controlled study in pregnancy on treatment of marked hyperglycemia that is short of overt diabetes.

INTRODUCTION: A randomized multicenter study was conducted in the Stockholm-Örebro areas in Sweden to evaluate how treatment aiming at normoglycemia affects fetal growth, pregnancy and neonatal outcome in pregnant women with severe hyperglycemia. MATERIAL AND METHODS: Pregnant women with hyperglycemia defined as fasting capillary plasma glucose <7.0 mmol/L and a two-hour plasma glucose value ≥10.0 and <12.2 mmol/L following a 75-g oral glucose tolerance test (OGTT) diagnosed before 34 weeks of gestation were randomized to treatment (n = 33) or controls (n = 36). Women assigned to the control group were blinded for the OGTT results and received routine care. The therapeutic goal was fasting plasma glucose 4-5 mmol/L, and <6.5 mmol/L after a meal. Primary outcomes were size at birth and number of large-for-gestational age (>90th percentile) neonates. Secondary outcomes were pregnancy complications, neonatal morbidity and glycemic control. RESULTS: The planned number of participating women was not reached. There was a significantly reduced rate of large-for-gestational age neonates, 21 vs. 47%, P < 0.05. Group differences in pregnancy complications and neonatal morbidity were not detected because of limited statistical power. In total, 66.7% of the women in the intervention group received insulin. Of all measured plasma glucose values, 64.1% were in the target range, 7.2% in the hypoglycemic range and 28.7% above target values. There were no cases of severe hypoglycemia. CONCLUSIONS: Aiming for normalized glycemia in a pregnancy complicated by severe hyperglycemia reduces fetal growth but is associated with an increased rate of mild hypoglycemia.

Placental gene expression of inflammatory markers and growth factors--a case control study of obese and normal weight women.

OBJECTIVE: To survey the placental gene expression of inflammatory markers and growth factors in non-smoking obese women with an uncomplicated pregnancy without associated morbidity and delivery at term compared with normal weight women. METHODS: Placental tissue samples from 32 obese women (body mass index, BMI≥35.0 kg/m2) were compared with samples from 94 normal weight women (BMI 18.5-25.0 kg/m2) matched for age (±1 year), gestational age (±3 days), parity and mode of delivery. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to analyse toll receptor-2 and -4, interleukin-6 and -8, tumour necrosis factor-α, leptin, adiponectin, insulin-like growth factor-1 and -2, hepatocyte growth factor, hepatocyte growth factor receptor and insulin receptor. RESULTS: There was no significant difference in gene expression in placental tissue samples from obese and normal weight women. CONCLUSION: We found no difference in the occurrence of inflammatory marker and growth factor mRNA levels in placental tissue samples from a large group of obese women without associated morbidity and with healthy infants compared to a closely matched control group of healthy normal weight women. Compared with the previous studies, this anomalous finding may be explained by the absence of associated morbidity in the obese women in our study.

Growth hormone dose-dependent pubertal growth: a randomized trial in short children with low growth hormone secretion.

BACKGROUND/AIMS: Growth hormone (GH) treatment regimens do not account for the pubertal increase in endogenous GH secretion. This study assessed whether increasing the GH dose and/or frequency of administration improves pubertal height gain and adult height (AH) in children with low GH secretion during stimulation tests, i.e. idiopathic isolated GH deficiency. METHODS: A multicenter, randomized, clinical trial (No. 88-177) followed 111 children (96 boys) at study start from onset of puberty to AH who had received GH 33 µg/kg/day for ≥1 year. They were randomized to receive 67 µg/kg/day (GH(67)) given as one (GH(67×1); n = 35) or two daily injections (GH(33×2); n = 36), or to remain on a single 33 µg/kg/day dose (GH(33×1); n = 40). Growth was assessed as heightSDSgain for prepubertal, pubertal and total periods, as well as AHSDS versus the population and the midparental height. RESULTS: Pubertal heightSDSgain was greater for patients receiving a high dose (GH(67), 0.73) than a low dose (GH(33×1), 0.41, p < 0.05). AHSDS was greater on GH(67) (GH(67×1), -0.84; GH(33×2), -0.83) than GH(33) (-1.25, p < 0.05), and heightSDSgain was greater on GH(67) than GH(33) (2.04 and 1.56, respectively; p < 0.01). All groups reached their target heightSDS. CONCLUSION: Pubertal heightSDSgain and AHSDS were dose dependent, with greater growth being observed for the GH(67) than the GH(33) randomization group; however, there were no differences between the once- and twice-daily GH(67) regimens. © 2014 S. Karger AG, Basel.

Metabolic outcomes in young children with type 1 diabetes differ between treatment centers: the Hvidoere Study in Young Children 2009.

OBJECTIVE: To investigate whether center differences in glycemic control are present in prepubertal children <11 yr with type 1 diabetes mellitus. RESEARCH DESIGN AND METHODS: This cross-sectional study involved 18 pediatric centers worldwide. All children, <11 y with a diabetes duration ≥12 months were invited to participate. Case Record Forms included information on clinical characteristics, insulin regimens, diabetic ketoacidosis (DKA), severe hypoglycemia, language difficulties, and comorbidities. Hemoglobin A1c (HbA1c) was measured centrally by liquid chromatography (DCCT aligned, range: 4.4-6.3%; IFFC: 25-45 mmol/mol). RESULTS: A total of 1133 children participated (mean age: 8.0 ± 2.1 y; females: 47.5%, mean diabetes duration: 3.8 ± 2.1 y). HbA1c (overall mean: 8.0 ± 1.0%; range: 7.3-8.9%) and severe hypoglycemia frequency (mean 21.7 events per 100 patient-years), but not DKA, differed significantly between centers (p < 0.001 resp. p = 0.179). Language difficulties showed a negative relationship with HbA1c (8.3 ± 1.2% vs. 8.0 ± 1.0%; p = 0.036). Frequency of blood glucose monitoring demonstrated a significant but weak association with HbA1c (r = -0.17; p < 0.0001). Although significant different HbA1c levels were obtained with diverse insulin regimens (range: 7.3-8.5%; p < 0.001), center differences remained after adjusting for insulin regimen (p < 0.001). Differences between insulin regimens were no longer significant after adjusting for center effect (p = 0.199). CONCLUSIONS: Center differences in metabolic outcomes are present in children <11 yr, irrespective of diabetes duration, age, or gender. The incidence of severe hypoglycemia is lower than in adolescents despite achieving better glycemic control. Insulin regimens show a significant relationship with HbA1c but do not explain center differences. Each center's effectiveness in using specific treatment strategies remains the key factor for outcome.

GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus.

BACKGROUND: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes. METHODS: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels. RESULTS: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences. CONCLUSIONS: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period. (Funded by Diamyd Medical and the Swedish Child Diabetes Foundation; ClinicalTrials.gov number, NCT00723411.).

East Africans in Sweden have a high risk for type 1 diabetes.

OBJECTIVE: To investigate the prevalence of type 1 diabetes in children with an origin in Sub-Saharan Africa in Sweden. RESEARCH DESIGN AND METHODS: Nationwide register study based on retrieved prescriptions of insulin during 2009 in children aged 0-18 years. The study population consisted of 35,756 children in families with an origin in Sub-Saharan Africa and 1,666,051 children with native Swedish parents. RESULTS: The odds ratio (OR) for insulin medication in Swedish-born children in families originating in East Africa was 1.29 (95% CI 1.02-1.63) compared with offspring of native Swedish parents, after adjustment for age and sex, and less common in children who themselves were born in East Africa: 0.50 (0.34-0.73). Offspring of parents from other parts of Sub-Saharan Africa had a comparatively low risk for insulin medication. CONCLUSIONS: This study indicates that Swedish-born children with an origin in East Africa have a high risk of type 1 diabetes.

Being born in Sweden increases the risk for type 1 diabetes - a study of migration of children to Sweden as a natural experiment.

AIM: To investigate whether the age of first exposure to a high-incidence country like Sweden determines the risk of T1DM in children with an origin in a low incidence region of the world. METHODS: Register study in a Swedish study population in the age 6-25 years in three categories of residents with an origin in low incidence regions of T1DM (Eastern Europe, East Asia, South Asia and Latin America); 24,252 international adoptees; 47,986 immigrants and 40,971 Swedish-born with two foreign-born parents and a comparison group of 1,770,092 children with Swedish-born parents. Retrieval of a prescription of insulin during 2006 was used as an indicator of T1DM and analysed with logistic regression. RESULTS: The odds ratios (OR) for T1DM were lower than the Swedish majority population for residents with an origin in the four low incidence regions. Being Swedish-born implied a higher risk for T1DM in the four low incidence study groups compared with the internationally adopted with an OR of 1.68 (CI 1.03-2.73). CONCLUSIONS: Being born in Sweden increases the risk for T1DM in children with an origin in low incidence countries. This may imply that exposures in utero or very early infancy are important risk factors for T1DM.

Parental burnout in relation to sociodemographic, psychosocial and personality factors as well as disease duration and glycaemic control in children with Type 1 diabetes mellitus.

AIM: To examine associations between burnout and sociodemographic, psychosocial, personality and medical factors in parents of children with Type 1 Diabetes Mellitus (T1DM). METHODS: A total of 252 parents of children with T1DM participated in a population-based study. We used self-report questionnaires to assess symptoms of burnout and background factors. RESULTS: Psychosocial background factors were significantly associated with burnout in parents, whereas there were no associations between sociodemographic or medical factors and burnout. For both genders, parental burnout was associated with low social support, lack of leisure time, financial concerns and a perception that the child's disease affects everyday life. Low self-esteem and high need for control were risk factors for maternal burnout. CONCLUSION: In the screening of risk factors for long-term stress in parents of children with T1DM, we should recognize parents' attitudes as well as situational psychosocial issues. In clinics, we need to pay attention to the day-to-day life circumstances in the support of these parents. Certain factors were associated with the risk for burnout only for mothers, which warrant further investigation of gender aspects. Continued research about the causal relationship between the parental responsibility, psychosocial factors and burnout is warranted.

The PTPN22 C1858T gene variant is associated with proinsulin in new-onset type 1 diabetes.

BACKGROUND: The protein tyrosine phosphatase nonreceptor type 2 (PTPN22) has been established as a type 1 diabetes susceptibility gene. A recent study found the C1858T variant of this gene to be associated with lower residual fasting C-peptide levels and poorer glycemic control in patients with type 1 diabetes. We investigated the association of the C1858T variant with residual beta-cell function (as assessed by stimulated C-peptide, proinsulin and insulin dose-adjusted HbA1c), glycemic control, daily insulin requirements, diabetic ketoacidosis (DKA) and diabetes-related autoantibodies (IA-2A, GADA, ICA, ZnT8Ab) in children during the first year after diagnosis of type 1 diabetes. METHODS: The C1858T variant was genotyped in an international cohort of children (n = 257 patients) with newly diagnosed type 1 diabetes during 12 months after onset. We investigated the association of this variant with liquid-meal stimulated beta-cell function (proinsulin and C-peptide) and antibody status 1, 6 and 12 months after onset. In addition HbA1c and daily insulin requirements were determined 1, 3, 6, 9 and 12 months after diagnosis. DKA was defined at disease onset. RESULTS: A repeated measurement model of all time points showed the stimulated proinsulin level is significantly higher (22%, p = 0.03) for the T allele carriers the first year after onset. We also found a significant positive association between proinsulin and IA levels (est.: 1.12, p = 0.002), which did not influence the association between PTPN22 and proinsulin (est.: 1.28, p = 0.03). CONCLUSIONS: The T allele of the C1858T variant is positively associated with proinsulin levels during the first 12 months in newly diagnosed type 1 diabetes children.

Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies.

BACKGROUND: To investigate disease progression the first 12 months after diagnosis in children with type 1 diabetes negative (AAB negative) for pancreatic autoantibodies [islet cell autoantibodies(ICA), glutamic acid decarboxylase antibodies (GADA) and insulinoma-associated antigen-2 antibodies (IA-2A)]. Furthermore the study aimed at determining whether mutations in KCNJ11, ABCC8, HNF1A, HNF4A or INS are common in AAB negative diabetes. MATERIALS AND METHODS: In 261 newly diagnosed children with type 1 diabetes, we measured residual ß-cell function, ICA, GADA, and IA-2A at 1, 6 and 12 months after diagnosis. The genes KCNJ11, ABCC8, HNF1A, HNF4A and INS were sequenced in subjects AAB negative at diagnosis. We expressed recombinant K-ATP channels in Xenopus oocytes to analyse the functional effects of an ABCC8 mutation. RESULTS: Twenty-four patients (9.1%) tested AAB negative after one month. Patients, who were AAB-negative throughout the 12-month period, had higher residual ß-cell function (P = 0.002), lower blood glucose (P = 0.004), received less insulin (P = 0.05) and had lower HbA1c (P = 0.02) 12 months after diagnosis. One patient had a heterozygous mutation leading to the substitution of arginine at residue 1530 of SUR1 (ABCC8) by cysteine. Functional analyses of recombinant K-ATP channels showed that R1530C markedly reduced the sensitivity of the K-ATP channel to inhibition by MgATP. Morover, the channel was highly sensitive to sulphonylureas. However, there was no effect of sulfonylurea treatment after four weeks on 1.0-1.2 mg/kg/24 h glibenclamide. CONCLUSION: GAD, IA-2A, and ICA negative children with new onset type 1 diabetes have slower disease progression as assessed by residual beta-cell function and improved glycemic control 12 months after diagnosis. One out of 24 had a mutation in ABCC8, suggesting that screening of ABCC8 should be considered in patients with AAB negative type 1 diabetes.

Gastrointestinal symptoms in adolescents with type 1 diabetes.

OBJECTIVE: To compare the prevalence of gastrointestinal (GI) symptoms in adolescents with and without type 1 diabetes (T1DM) and to relate the symptoms in patients to demographic, socioeconomic, diabetes-specific variables, and food habits. METHOD: In a population-based, cross-sectional setting, 173 adolescents with T1DM and 160 matched controls completed a questionnaire. Moreover, 13 patients and 1 control were excluded due to having a GI disorder. RESULTS: Moreover, 75% of patients and 77% of controls reported at least one GI symptom (ns). More girls than boys reported symptoms. Reflux episodes were more prevalent in patients with poorer socioeconomic status. Poor appetite, loss of weight, an uncomfortable feeling of fullness, swallowing difficulties, and nausea were more prevalent in patients smoking daily compared with patients not smoking daily. Vomiting was more prevalent in patients with duration of diabetes >7 yr, and patients with reflux episodes had higher glycated hemoglobin (HbA1c). Belching and early satiety were more prevalent in patients with an irregular meal pattern. CONCLUSIONS: GI symptoms in adolescents are common, but the prevalence is not increased in those with T1DM. GI symptoms in adolescents with T1DM are associated with female sex, poorer socioeconomic status, daily cigarette smoking, longer duration of diabetes, poorer metabolic control, and an irregular meal pattern.