Plasma lipid species at type 1 diabetes onset predict residual beta-cell function after 6 months.

INTRODUCTION: The identification of metabolomic dysregulation appears promising for the prediction of type 1 diabetes and may also reveal metabolic pathways leading to beta-cell destruction. Recent studies indicate that regulation of multiple phospholipids precede the presence of autoantigens in the development of type 1 diabetes. OBJECTIVES: We hypothesize that lipid biomarkers in plasma from children with recent onset type 1 diabetes will reflect their remaining beta-cell function and predict future changes in beta-cell function. METHODS: We performed targeted lipidomic profiling by electrospray ionization tandem mass spectrometry to acquire comparative measures of 354 lipid species covering 25 lipid classes and subclasses in plasma samples from 123 patients < 17 years of age followed prospectively at 1, 3, 6 and 12 months after diagnosis. Lipidomic profiles were analysed using liner regression to investigate the relationship between plasma lipids and meal stimulated C-peptide levels at each time point. P-values were corrected for multiple comparisons by the method of Benjamini and Hochberg. RESULTS: Linear regression analysis showed that the relative levels of cholesteryl ester, diacylglycerol and triacylglycerol at 1 month were associated to the change in c-peptide levels from 1 to 6 months (corrected p-values of 4.06E-03, 1.72E-02 and 1.72E02, respectively). Medium chain saturated and monounsaturated fatty acids were the major constituents of the di- and triacylglycerol species suggesting a link with increased lipogenesis. CONCLUSION: These observations support the hypothesis of lipid disturbances as explanatory factors for residual beta-cell function in children with new onset type 1 diabetes.

High Neonatal Blood Iron Content Is Associated with the Risk of Childhood Type 1 Diabetes Mellitus.

(1) Background: Iron requirement increases during pregnancy and iron supplementation is therefore recommended in many countries. However, excessive iron intake may lead to destruction of pancreatic ß-cells. Therefore, we aim to test if higher neonatal iron content in blood is associated with the risk of developing type 1 diabetes mellitus (T1D) in childhood; (2) Methods: A case-control study was conducted, including 199 children diagnosed with T1D before the age of 16 years from 1991 to 2005 and 199 controls matched on date of birth. Information on confounders was available in 181 cases and 154 controls. Iron was measured on a neonatal single dried blood spot sample and was analyzed by laser ablation inductively coupled plasma mass spectrometry. Multivariate logistic regression was used to evaluate if iron content in whole blood was associated with the risk of T1D; (3) Results: A doubling of iron content increased the odds of developing T1D more than two-fold (odds ratio (95% CI), 2.55 (1.04; 6.24)). Iron content increased with maternal age (p = 0.04) and girls had higher content than boys (p = 0.01); (4) Conclusions: Higher neonatal iron content associates to an increased risk of developing T1D before the age of 16 years. Iron supplementation during early childhood needs further investigation, including the causes of high iron in neonates.

Levels of adiponectin and leptin at onset of type 1 diabetes have changed over time in children and adolescents.

Adiponectin and leptin are proteins secreted by the adipose tissue and have an influence on insulin sensitivity and on inflammatory markers. Altered levels could play a part in the pathogenesis of type 1 diabetes mellitus. We determined adiponectin and leptin levels over a nine-year period in children with type 1 diabetes mellitus (T1D) in relation to the increasing incidence of T1D, and studied the impact of patient status, age, gender and body mass index (BMI). Data were derived from a population-based registry of diabetic children (DanDiabKids) from 1997 to 2005. Children with newly diagnosed T1D (n = 482) were included, and healthy siblings (n = 479) were chosen as a control group. Leptin levels were significantly higher in recent years (in both patients and siblings), whereas for adiponectin, the levels were lower in recent years in the patient group. Leptin levels were lower in children with T1D (RR 0.74, p = 0.003) and in males (RR 0.52, p < 0.001) and increasing with age in both groups. For adiponectin, there was a negative association between level and age in patients. Both adipokines showed a significant correlation with BMI and lower levels in children with blood samples taken within the first 2 days after initiation of insulin treatment. There has been a change in leptin and adiponectin levels in children with or without T1D from 1997 to 2005. This is not explained by changes in BMI and may reflect changes in other factors like diet or physical activity.

Prevalence of celiac disease autoimmunity in children with type 1 diabetes: regional variations across the Øresund strait between Denmark and southernmost Sweden.

OBJECTIVES: The aim was to determine the prevalence of celiac disease autoimmunity in children with type 1 diabetes (T1D) diagnosed in Denmark and Sweden. METHODS: A total of 662 Swedish children with T1D were matched with 1080 Danish children with T1D and 309 healthy children from Sweden and 283 from Denmark served as controls. Sera were analyzed for the presence of IgA and IgG (IgAG) autoantibodies against deamidated gliadin peptide (DGP) and tissue transglutaminase (tTG) with enzyme-linked immunosorbent assay (ELISA) and IgG-tTG separately in a radioligand binding assay (RBA). Human leukocyte antigen (HLA)-DQB1 and DQA1 genotyping were determined in the T1D cohorts. RESULTS: In the Swedish T1D cohort, 17.2% (114/662) were IgAG-DGP/tTG positive compared with 11.7% (126/1080) in the Danish T1D cohort (p = 0.001) and with 9.4% (29/309) Swedish (p = 0.001) and 5.7% (16/283) Danish (p = 0.003) controls. In the Swedish T1D cohort, both levels of IgAG-DGP/tTG and IgG-tTG were higher compared with the levels in the Danish T1D (p < 0.001). In the control group, 2.8% of the Danish children were positive for both IgAG-DGP/tTG and IgG-tTG, compared to 0.3% of the Swedish. Presence of HLA-DQ2 was equally distributed among 89 children with T1D positive for both IgAG-DGP/tTG and IgG-tTG. CONCLUSION: The discrepancy in levels of IgAG-DGP/tTG and IgG-tTG between Swedish and Danish T1D cohorts was independent of HLA and suggests that regional variations in comorbidity of celiac disease in T1D is caused by difference in exposure to environmental factors.

Differences in MBL levels between juvenile patients newly diagnosed with type 1 diabetes and their healthy siblings.

The incidence of type 1 diabetes (T1D) has during the last few decades been increasing in children and juveniles. Multi-factorial courses combining genetic disposition and environmental factors might be in play, and through the years, there has been a mounting interest in the innate immune system's role in the development of T1D. The aim of this study was to determine mannose binding lectin (MBL) levels in newly diagnosed children with T1D (n=481) over a period of 10 years (1997-2005) and to compare these levels with corresponding levels in their healthy siblings (n=479). Furthermore, the aims were to evaluate if MBL-levels in patients and siblings were influenced by season, age autoimmunity and/or changed over time. The study found that MBL levels differed between patients and their healthy siblings when adjusted for age, gender, season and period. More patients than siblings had MBL levels above 0.8 µg/ml, associated with high producing MBL genotypes, and the elevated MBL levels were associated with high levels of four T1D related cytokines (IL-1ß, IL-12, IL-18 and TNF-α). MBL levels increased during the study period and siblings had seasonal variance in concentrations with the lowest level during wintertime (Dec-Feb). In conclusion, more patients than siblings had a high MBL level, and high levels of MBL were related to high levels of T1D specific cytokines, supporting a role of the innate immune system and MBL on the risk of developing T1D.

Complex multi-block analysis identifies new immunologic and genetic disease progression patterns associated with the residual ß-cell function 1 year after diagnosis of type 1 diabetes.

The purpose of the present study is to explore the progression of type 1 diabetes (T1D) in Danish children 12 months after diagnosis using Latent Factor Modelling. We include three data blocks of dynamic paraclinical biomarkers, baseline clinical characteristics and genetic profiles of diabetes related SNPs in the analyses. This method identified a model explaining 21.6% of the total variation in the data set. The model consists of two components: (1) A pattern of declining residual ß-cell function positively associated with young age, presence of diabetic ketoacidosis and long duration of disease symptoms (P = 0.0004), and with risk alleles of WFS1, CDKN2A/2B and RNLS (P = 0.006). (2) A second pattern of high ZnT8 autoantibody levels and low postprandial glucagon levels associated with risk alleles of IFIH1, TCF2, TAF5L, IL2RA and PTPN2 and protective alleles of ERBB3 gene (P = 0.0005). These results demonstrate that Latent Factor Modelling can identify associating patterns in clinical prospective data--future functional studies will be needed to clarify the relevance of these patterns.

Do eating behaviors in the general population account for country variance in glycemic control among adolescents with diabetes: the Hvidoere Study Group and the Health Behaviour in School-Aged Children study.

BACKGROUND: The Hvidoere Study Group (HSG) has demonstrated major differences in glycemic control between pediatric diabetes centers which remain largely unexplained. This study investigates whether these differences are partly attributable to healthy eating norms in the background population. METHODS: The study involved adolescents from 18 countries from (i) the Health Behaviour in School-Aged Children study (HBSC) and (ii) the HSG. There were 94 387 participants from representative HBSC samples of 11-, 13- and 15-yr-olds and 1483 11- to 15-yr-old adolescents with diabetes from the HSG. The frequency of intake of fruit, vegetables, sweets, sugary soft drinks, and daily breakfast was compared between the two groups. The glycemic control of the adolescents in the HSG cohort was determined by measuring glycated hemoglobin (HbA1c). RESULTS: Across countries in the HSBC survey, there was substantial variation in prevalence of healthy eating behavior and even greater variation between adolescents from the HSG centers. In all countries more adolescents with diabetes reported healthy eating behavior compared to national norms. In individuals healthy eating behavior had a significant effect on the individual level HbA1c. There was no significant correlation between the frequencies of these healthy eating behaviors at (i) the national level and (ii) diabetes center level and the center mean HbA1c. CONCLUSIONS: Although individual healthy eating behavior is associated with better glycemic control at the individual level, such eating behavior does not explain the center differences in HbA1c. Similarly, the reported healthy eating norm of the background populations does not explain the variation in glycemic control among centers.

Few differences in cytokines between patients newly diagnosed with type 1 diabetes and their healthy siblings.

The cause of the worldwide increase in type 1 diabetes (T1D) is largely unknown. T cells are thought to play a role in disease progression. In contemporary research over the last decade, age- and gender-specific serum levels as well as changes of Th1 and Th2-related cytokines are not well described. From a population-based register of children diagnosed from 1997 to 2005 this study explores eight different cytokines at time of diagnosis. Only TGF-ß and IL-18 showed higher levels in patients compared to siblings in an adjusted model (p<0.01); whereas the other seven cytokines were not significantly different. IL-1ß, IL-18, IL-12, IL-10 and IL-4 were significantly higher among the youngest children and males had significantly lower levels of IL-10 and IL-12 but higher levels of TNF-α. During the nine-year study all of the cytokines increased except TGF-ß, which showed a slight decrease over time. The cytokine levels tended to be highest during summer and were most pronounced for IL-1ß and TNF-α. In conclusion, serum levels of known ß-cell cytotoxic cytokines were indifferent in patients and siblings, while gender, age and season appear to exert some influence on the serum level and need to be explored further. The influence of time on systemic levels cannot be ignored and may reflect decay or environmental impact on the immune system.

High levels of immunoglobulin E and a continuous increase in immunoglobulin G and immunoglobulin M by age in children with newly diagnosed type 1 diabetes.

The incidence of type 1 diabetes (T1D) is increasing, either because of environmental factors accelerating onset of the disease or because of inducement of autoimmune diabetes in children who previously were at lower risk. High levels of immunoglobulin (Ig), specifically, IgM and IgA, and a low level of IgG were reported in adult patients; however no studies have analyzed the increasing incidence in relation to Ig levels. Our aim was to describe Ig in children newly diagnosed with diabetes and in their healthy siblings. Children with T1D expressed significantly lower IgG (p < 0.01) and higher IgA levels (p = 0.045), whereas no differences in IgE or IgM (p > 0.5) levels were found. Age-specific levels were unchanged over a 9-year period. In patients and siblings IgG, IgA and IgE increased by age (p < 0.001); which was in contrast to IgM (p > 0.05). The continued increase in IgG levels by age indicates that adult levels are reached later than in previously studied cohorts, thereby indicating a slower maturation of the immune system.

Intrafamilial Variability of Early-Onset Diabetes due to an INS Mutation.

Aim. The objective of this study was to describe the clinical characteristics of two siblings and their father carrying a C95Y mutation in the insulin (INS) gene. Methods/Results. A Danish patient, his sister, and his father were identified to carry the C95Y mutation in the preproinsulin molecule causing permanent neonatal diabetes. All three were diagnosed before 29 weeks of age, were born at term with near-normal birth weight, and were negative for GAD, ICA, IA-2, and IAA autoantibodies. The daily insulin requirement the first six months after diagnosis was <0.5 U kg(-1) day(-1) for both children. The father, insulin treated for over 40 years, has bilateral preproliferative retinopathy. Conclusions. These three cases further confirm the essential features of diabetes caused by INS mutations with proteotoxic effect. We conclude that patients with similar features must be investigated for mutations of INS gene.

Evaluation of a type 1 diabetes serum cohort by SELDI-TOF MS protein profiling.

Proteomics analysis of serum from patients with type 1 diabetes (T1D) may lead to novel biomarkers for prediction of disease and for patient monitoring. However, the serum proteome is highly sensitive to sample processing and before proteomics biomarker research serum cohorts should preferably be examined for potential bias between sample groups. SELDI-TOF MS protein profiling was used for preliminary evaluation of a biological-bank with 766 serum samples from 270 patients with T1D, collected at 18 different paediatric centers representing 15 countries in Europe and Japan over 2 years (2000-2002). Samples collected 1 (n = 270), 6 (n = 248), and 12 (n = 248) months after T1D diagnosis were grouped across centers and compared. The serum protein profiles varied with collection site and day of analysis; however, markers of sample processing were not systematically different between samples collected at different times after diagnosis. Three members of the apolipoprotein family increased with time in patient serum collected 1, 6, and 12 months after diagnosis (ANOVA, p<0.001). These results support the use of this serum cohort for further proteomic studies and illustrate the potential of high-throughput MALDI/SELDI-TOF MS protein profiling for evaluation of serum cohorts before proteomics biomarker research.

[Acute pancreatitis associated with MMR vaccination]. / Akut pancreatitis i tidsmaessig sammenhaeng med MFR-vaccination.

A 12-year-old girl got abdominal pain three weeks after having received the second vaccination against MMR. MRCP showed dilatation of ductus choledochus and edema of caput pancreaticus. No stone was to be seen and the P-calcium level was normal. Hepatitis A virus, Ebstein-Barr virus, cytomegalovirus, enterovirus, serum col hemaggutinins, Yersinia and cystic fibrosis were all negative. Pancreatitis is seen with endemic parotitis and we suggest that MMR vaccination may have a causal connection with the above case.