Onset Of Type 1 Diabetes Mellitus Research Articles

Development of a novel autoantibody assay for autoimmune gastritis in type 1 diabetic individuals

Autoimmune atrophic body gastritis (ABG) and pernicious anaemia are prototypical, organ-specific autoimmune diseases whose prevalence in the general population is 2.0 vs 2 and 0.15-1%, respectively. The incidence of disease increases with age and is frequently associated with other autoimmune disorders such as type 1 diabetes mellitus (T1DM). Early diagnosis of ABG/pernicious anaemia is essential for the prevention and/or treatment before manifestations of chronic disease become irreversible. Parietal cell autoantibody detection via enzyme-linked immunosorbent assay is currently the most widely used biomarker of disease with diagnosis confirmed by subsequent immunohistochemistry via biopsy. To improve the assay we designed a specific, molecularly defined radioimmunoprecipitation assay for early detection of ABG, targeting its major antigen, the gastric H+/K+ ATPase 4A subunit ATP4A. The major antigenic domain in ATP4A was tested against a panel of sera from new onset patients with T1DM which tested positive for the gold standard T1DM autoantibodies (IAA, IA2A, GAD65A, and ZnT8A). Significant immunoreactivity to ATP4A was measured (25%) while 6% of first-degree relatives of subjects with T1DM who were sero-negative for T1DM autoantigens were positive for ATP4A autoantibodies. ATP4A antibody prevalence increased with age of onset of T1DM, which is atypical of other T1DM autoantibodies. Immunoreactivity to ATP4A, unlike that of T1DM antigens, demonstrates a significant gender bias in newly diagnosed individuals with T1DM. Although the utility of the assay as a biomarker for T1DM is likely limited, it may serve as an improved indicator of ABG.

Japanese Herbal Medicine TJ-48 Prevents Autoimmune Diabetes in NOD Mice

Type 1 diabetes mellitus (T1DM) is mainly caused by CD8(+) cytotoxic T cell infiltration into islets. Recently, the role of regulatory T cells (Tregs) in the prevention of the onset of T1DM was reported. We reported that TJ-48, a common Japanese herbal medicine, decreased Treg population in cancer patients, thus we investigated whether TJ-48 had an influence on T1DM onset using NOD mice. In the TJ-48 group, TJ-48 (2.0g/kg/day) was administered in the drinking water for NOD mice from three weeks of age to 20 weeks of age. Their body weight and fast blood glucose (FBG) were measured every week. Histology (Hematoxylin-Eosin staining) was investigated every month. Lymphocyte profiles were investigated every month with FACS. The results were compared to the age-matched NOD mice control group. FBG of the control group mice showed diabetic status of 66.7% at 18 weeks of age. On the other hand, the TJ-48 group mice showed diabetic status of 16.7% at 18 weeks of age (p = 1.905E-06). There were no significant differences in general conditions or body weight between the two groups. Lymphocyte infiltrations into islets were dramatically suppressed in the TJ-48 group. The effect of TJ-48 on decreasing Tregs was less apparent in the NOD mice model. TJ-48 inhibited lymphocyte infiltrations into islets, which led to preventing the onset of T1DM in NOD mice.

Diabetic Ketoacidosis and Memory Dysfunction in Children with Type 1 Diabetes

We tested the hypothesis that diabetic ketoacidosis (DKA) results in memory deficits typical of hypoxic/ischemic injury because recent studies suggest that cerebral metabolic changes similar to those observed in hypoxic/ischemic cerebral injury are observed in children with DKA, even without symptoms suggesting cerebral injury. Thirty-three children with type 1 diabetes mellitus (T1DM) and a history of DKA and 29 children with T1DM without a history of DKA were enrolled from an academic hospital pediatric endocrinology clinic. These groups were comparable on demographic and disease-related variables. These groups' ability to recall events in association with specific details, the memory function most directly affected by mild hypoxia/ischemia, was compared on 2 tasks (ie, event-color associations and event-spatial position associations). In multivariate analyses controlling for other critical variables, children with DKA history had significantly lower rates of accurate memory on both tasks (mean, 0.34 +/- 0.13 on the color task and 0.57 +/- 0.15 on the spatial task) than did children without DKA history (mean, 0.44 +/- 0.11 and 0.65 +/- 0.18, P < .01). DKA disrupts memory function, underscoring the importance of DKA prevention when T1DM is known and prompt diagnosis of children with new onset of T1DM.

Study of interleukin-10 promoter region polymorphisms (−1082A/G, −819T/C and −592A/C) in type 1 diabetes mellitus in Turkish population

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by progressive destruction of islet β-cells (Atkinson and MacLaren 1994). It apparently arises from T-cell dependent destruction of β-cells in genetically susceptible individuals (Eisenbarth 2005). The cytokines secreted by CD4 T helper type 1 and 2 (Th1 and Th2) cells may play a crucial role in the pathogenesis of T1DM (Almawi et al. 1999). Cytokines can be classified into two groups: Th1 (proinflammatory) cytokines such as TNF-α and interleukin 1, and Th2 (anti-inflammatory) cytokines such as interleukin 10 and interleukin 4 (Keen 2002). Although the exact roles that Th1 and Th2 cells play in IDDM pathogenesis remain to be established, it was suggested that Th1 cytokines promote, whereas Th2 cytokines protect from the diabetes progression (Rapoport et al. 1993; Pennline et al. 1994). It is thought that the onset and progression of T1DM results from an altered balance between Th1 and Th2 cells (Almawi et al. 1999). IL-10 is a pleiotropic Th2 cytokine that is usually considered to have a role in the downregulation of cell mediated and cytotoxic inflammatory responses, thus being a potent anti-inflammatory mediator. It has been suggested that Th2 induced component of anti-β cell immunity is mediated principally by IL-10 (Lee et al. 1994, 1996; Pakala et al. 1997). Approximately 75% of the variation in IL-10 production appears to be genetically determined (Westendorp et al. 1997). The gene encoding IL-10 has been mapped to chromosome 1q. Several polymorphic sites within the promoter region have been described, including two microsatellite polymorphisms and three biallelic polymorphisms at

Annual screening detects celiac disease in children with type 1 diabetes

To investigate the prevalence of celiac disease (CD) in a cohort of type 1 diabetes mellitus (T1DM) children and adolescents at the time of clinical diagnosis and to evaluate the screening procedure and possible role of human leukocyte antigen (HLA)-DQ during a 5-yr follow-up. The study group was a cohort of 300 newly diagnosed T1DM children and youths younger than 20 yr followed for 5 yr at six clinical centers for pediatric diabetes in the region Skåne in Sweden. Immunoglobulin A endomysium antibodies were used to screen the patients annually to be considered for an intestinal biopsy. All patients were analyzed for HLA-DQA1-B1 genotypes. While 0.7% (2/300) already had a diagnosed symptomatic CD, an additional 3% (10/300) had silent CD at the diagnosis of T1DM. During follow-up, another 6% (17/300) developed CD as follows: 10 after 1 yr, 5 after 2 yr, 1 after 3 yr, and 1 after 5 yr. Therefore, the cumulative frequency of CD confirmed by intestinal biopsies was 10% (29/300). HLA genotypes among T1DM patients developing CD were not different from those among patients with T1DM alone. Our study confirmed the low prevalence (0.7%) of diagnosed symptomatic CD at the time of clinical diagnosis but document by screening an increasing prevalence of silent CD during a 5-yr follow-up to reach an overall prevalence of 10%. We suggest that children with T1DM should be screened for CD at the onset of T1DM and annually for a minimum of at least 2 yr. HLA genotypes among T1DM patients developing CD were not different from those among patients with T1DM alone.

Menarcheal timing in intensively treated girls with type 1 diabetes mellitus

Background and aim Previous studies on menarcheal age (MA) in type 1 diabetes mellitus (T1DM) have shown conflicting results about the effects of DM, but most lack a control group. The present study design is peculiar in that it covers a study population of 73 intensively treated menarcheal adolescents with premenarcheal onset of T1DM (Group A), whose MA was compared with that recorded in three control populations: the first one consisting of 280 healthy adolescents, the second one consisting of 20 T1DM adolescents with postmenarcheal DM onset (Group B) and the third one represented by the respective mothers. Methods and results MA of Group A patients was significantly delayed when compared with the respective mothers, healthy controls and Group B patients. By contrast MA of Group B girls was superimposable to the one of both their respective mothers and healthy controls. In Group A MA was strongly related ( p < 0.0005) to HbA1c at the time of menarche and to average HbA1c concentrations during the last years before menarche. In Group A no relationship between patients' and mothers' MAs was found, whilst such a correlation was significant in Group B. Conclusions (a) MA is significantly delayed in girls with premenarcheal presentation of T1DM, even if intensively treated; (b) menarcheal retardation is more severe in the patients with suboptimal metabolic control at the time of menarche; and (c) MA in premenarcheal presenting T1DM is irrespective of maternal MA, age and HbA1c concentrations at DM presentation, body mass index and daily insulin dose at menarche.

Prevalence of Structural Central Nervous System Abnormalities in Early-Onset Type 1 Diabetes Mellitus

To characterize the effects of severe hypoglycemia on the developing brain in children with early-onset type 1 diabetes mellitus (T1DM). Children diagnosed with T1DM before age 6 years were studied. Those with prospectively monitored severe hypoglycemia (coma/seizure; n = 32) were compared with age-matched peers (n = 30) with no history of such events using magnetic resonance imaging. Glycemic control (evaluated based on glycated hemoglobin [HbA(lc)] level), episodes of diabetic ketoacidosis (DKA), and clinical variables were monitored continuously since diagnosis in all subjects. Mean HbA(lc) from diagnosis and the duration of T1DM were similar in those with and without a history of severe hypoglycemia (9.0% +/- 0.9% vs 8.8% +/- 0.9%; 7.2 +/- 2.7 years vs 6.7 +/- 2.3 years). A high prevalence of central nervous system (CNS) structural abnormalities was detected (29%), and mesial temporal sclerosis (MTS) was detected in 16% of the total sample (n = 62). The presence of MTS was not associated with a history of severe hypoglycemia or DKA. Analysis of brain matter volumes suggested relatively less gray matter density in those subjects with a history of severe hypoglycemia. Early age of onset of T1DM per se is associated with a high incidence of CNS abnormalities, particularly MTS, suggesting hippocampal damage. Early-onset severe hypoglycemia may have an effect on gray matter volume.

Relation of Time of Introduction of Cow Milk Protein to an Infant and Risk of Type-1 Diabetes Mellitus

Several studies of infant feeding show a causal relationship between time of introduction of formula containing cow protein and risk of onset of type-1 diabetes mellitus. This paper cites the literature pro and con and discusses lipocalins which might play a role in the pathogensis. beta Lactoglobulin, a major lipocalin protein in bovine milk, is homologous to the human protein glycodelin (PP14), a T cell modulator. Anti-beta lactoglobulin cross-reacts with glycodelin. The newborn intestine does not have complete "closure" and can pass food antigens. Beta lactoglobulin could generate antibody to glycodelin undermining T cell regulation of beta cells.

The Assessment of Autoimmunological Status and Prevalence of Different Forms of Celiac Disease among Children with Type 1 Diabetes Mellitus and Celiac Disease

This study aims to assess the autoimmunological status and forms of celiac disease (CD) among children with type 1 diabetes mellitus (T1DM). The study group comprises 27 patients at the mean age of 12.30 years (±SD 3.12). The measurement of the level of diabetes-specific antibodies and organ-specific antibodies was gained at the T1DM-onset and repeated annually. The following risk factors influencing time of CD diagnosis were analyzed: age, sex, T1DM duration, autoantibodies, and HLA-haplotype. The prevalence of antibodies was GADA-74%, IAA-63%, IA2A-67%, ATA-11%, and ATG-4%. The intestinal biopsy revealed in 19% no changes and in 77% stage 3 (Marsh scale). In most cases, no clinical manifestation of CD was observed. The diagnosis of Hashimoto's disease was made twice. The negative correlation between the age at T1DM-onset and the interval between onset of T1DM and CD (r = −0.35, p < .05) was noted. The high-comorbidity ratio of CD and thyroiditis with T1DM demands regular screening tests especially in the first years after T1DM-onset.

Predicting diabetic ketoacidosis in children by measuring end‐tidal CO2 via non‐invasive nasal capnography

To determine if nasal capnography can be used as a screening tool to predict diabetic ketoacidosis (DKA) in children with Type 1 diabetes mellitus (T1DM) presenting to the emergency department. Cross-sectional, prospective, observational study of children with T1DM who presented to the Emergency Department of Princess Margaret Hospital for Children, Western Australia, over a 12-month period from June 2003 to June 2004. Information on demographic data and T1DM was recorded. Nasal capnography, venous blood gases and urinary analysis were performed on patients. Data were analysed using chi(2) tests and receiver operating characteristic curve analysis. Sensitivities and specificities were calculated at different end-tidal carbon dioxide (ETCO(2)) levels to predict presence of DKA. Fifty-eight patients aged 1-18 years (mean 10.7, SD 4.7) were analysed. Thirty-three (57%) were male and 30 (52%) presented with new onset of T1DM. Of the 58 cases, 15 (26%) had DKA, and 11 of these were new T1DM patients. No patients with an ETCO(2) > 30 mmHg had DKA (sensitivity 1.0, specificity 0.86). Six patients with an ETCO(2) < 30 mmHg did not have DKA. Nasal capnography in conjunction with clinical assessment is predictive of DKA. Further research into this area with larger numbers could help validate ETCO(2) as a screening tool for DKA in the emergency department.

Increasing Ten-Year Burden of Pediatric Type 1 Diabetes Mellitus in Southeastern Wisconsin: Relationship with Body Weight at Diagnosis

Purpose Several studies in Europe have documented the increase in incidence of Type 1 Diabetes Mellitus (T1DM) and the apparent relationship with increase weight at diagnosis. Such data suggests that maintaining a healthy weight throughout childhood may delay the onset of T1DM into adolescents. This is the first study conducted in the Midwest examining this issue. Our objective was to determine if there is an increasing burden of T1DM in specific age cohorts and if increasing body weight is an apparent risk factor for this increase. Methods Retrospective chart review of all 1618 newly diagnosed children and adolescents ( Results An overall, estimated annual incidence, which increased from 18.8 to 40.3/100,000 (p=0.006) over 10 years was observed, with an average yearly cumulative incidence of 2.39%. The increase in incidence was largest in the younger age groups with children ages 0–4, 5–9, and 10–14 having an average yearly increase of 2.4, 2.3, and 3.0% respectively; corresponding to a relative 10-year increase of 25.2, 32.6, and 37.9%, respectively. Age at diagnosis was inversely correlated with weight z-score (p Conclusion The incidence of T1DM increased 2-fold in Southeastern Wisconsin over 10 years. The majority of the increase was in the youngest age groups, which were comparatively the heaviest. Our observations suggest excess weight gain during childhood may be a risk factor for early manifestation of T1DM.

A study and the growth and the development of microvascular complications in patients with type 1 diabetes mellitus

Purpose : Reduced growth and microvascular complications have been recognized as consequences of type 1 diabetes mellitus (T1DM). We assessed the effect of T1DM on growth and factors associated with the development of microvascular complications. Methods : We conducted a retrospective longitudinal evaluation of 154 patients above 16 years of age. We analyzed factors which affect final height standard deviation scores (SDS) and development of microvascular complications. Results : Final height SDS was -0.11±1.15 (-0.26±1.33 in females, 0.04±0.91 in males). Final height SDS was significantly lower than midparental height SDS and height SDS at diagnosis. There was no difference in final height SDS according to age at onset, existence or nonexistence of complications, or average HbA1C. Height SDS at onset of puberty, midparental height SDS and pubertal growth gain affected final height SDS. The number of patients with complications was 37 (24 percent). Microvascular complications developed at a younger age and after longer duration of diabetes in patients with a prepubertal onset of T1DM compared to patients with pubertal onset. Patients with complications had a higher level of average HbA1C than patients without complications. Patients whose microalbuminuria regressed had lower levels of average HbA1C, systolic BP, second 24h urine microalbumin than patients with persistant or progressed microalbuminuria. Conclusion : The results suggest that degrees of glycemic control don't affect final height, but various factors associated with T1DM can impair growth potential. Additionally, the degrees of glycemic control and puberty affect the development of microvascular complications.

Metabolic decompensation in children with type 1 diabetes mellitus associated with increased serum levels of the soluble leptin receptor

Type 1 diabetes mellitus (T1DM) leads to increased serum levels of the soluble leptin receptor (sOB-R) by an as yet unknown cellular mechanism. The aim of our study was to investigate potential metabolic factors that may be associated with the induction of the sOB-R release from its membrane receptor. Twenty-five children (aged between 1.5 and 17.0 years) were studied at the onset of T1DM. Blood samples were collected before (n = 25), during the first 18 h (mean +/- S.D. 11.1 +/- 4.3 h, n = 16) and 92 h (47.5 +/- 22.5 h; n = 14) after beginning insulin therapy. Serum sOB-R and leptin levels were determined by in-house immunoassays. The sOBR-level and the molar sOB-R/leptin ratio were significantly higher before than after starting insulin treatment (P < 0.05). In contrast, leptin levels were significantly lower (P < 0.05) before insulin therapy. The correlation between sOB-R and blood glucose (r = 0.49; P < 0.05), as well as sOB-R with parameters of ketoacidosis, such as pH (r = -0.72), base excess (r = -0.70), and bicarbonate (r = -0.69) (P < 0.0001) at diagnosis of T1DM remained significant during the first 18 h of insulin treatment. Multiple regression analysis revealed that base excess predicted 41.0% (P < 0.001), age 16.4% (P < 0.05), and height SDS 13.9% (P < 0.01) of the sOB-R variance. Metabolic decompensation in children with new onset T1DM is associated with dramatic changes of the leptin axis; serum levels of sOB-R are elevated and of leptin are reduced. The molar excess of sOB-R over leptin (median 11.3) in this condition may contribute to leptin insensitivity. Upregulation of the soluble leptin receptor appears to be a basic mechanism to compensate for intracellular substrate deficiency and energy-deprivation state.

Genetic interaction among three genomic regions creates distinct contributions to early- and late-onset type 1 diabetes mellitus

There are two peaks in the distribution of the age of onset of type 1 diabetes mellitus (T1DM)--the first in early childhood and the second at the time of puberty. Although T1DM results from the interaction of genetic and non-genetic factors, it has not been established which factors contribute to the bimodal distribution. The genetic component of T1DM is in large part related to genes from the human leukocyte antigen (HLA) complex (IDDM1); however, loci from the variable nucleotide tandem repeat (VNTR) region of the insulin (INS) gene (IDDM2) and more recently, the cytotoxic T-lymphocyte-associated protein-4 region (CTLA4, IDDM12) have also been implicated. Therefore, we examined the potential interaction between these loci through the influence of the age of onset of T1DM in diabetic and control Caucasian individuals. We discovered that younger individuals with HLA-DRB1*0301/DRB1*04 and INS I/I genotypes exhibited increased susceptibility to T1DM, whereas the interaction of INS I/I and CTLA4 G/G genotypes was more common in older children with T1DM. Combining the age of onset of T1DM with specific genotypes may operate to produce a single disease through different underlying causes.

Rate of hypoglycaemia and insulin dosage in children during the initial therapy of type 1 diabetes mellitus

Hypoglycaemia is a major side-effect of insulin treatment. It is known that young children with type 1 diabetes mellitus (T1DM) show a higher risk of hypoglycaemia than older children. This study was performed to analyse the incidence of hypoglycaemia within the first 14 days (day 1-day 14) of insulin treatment in children at the onset of T1DM and to evaluate the influence of age and insulin dosage. The Paediatric Quality Initiative (DPV), including data from 121 centres in Germany and Austria, provided anonymous data of 1,680 patients (age 0.7-18.8 years; 799 girls) at the onset of T1DM. Hypoglycaemia was defined as a blood glucose level (BG) <2.8 mmol/l (50 mg/dl). The hypoglycaemia rate rose continuously from day 2 (4.8%) to day 5 (11.2%) and then remained stable between 8.7%-11.2% until day 14. The hypoglycaemia rate was higher in younger than in older children (P <0.0001). Multiple regression analysis revealed an influence of age (P <0.0001), insulin dosage (P = 0.0034), and route of initial treatment (P = 0.0052) on the hypoglycaemia rate. From day 2 to day 14, the insulin dosage itself was higher in females than in males (P = 0.0147), in patients with high HbA1c (P = 0.0001), high BG (P <0.0001), or low pH (P <0.0001). There was no influence of age on the insulin dosage. During the first 14 days after onset of type 1 diabetes mellitus, young children, intravenous-treated patients and patients receiving a high insulin dosage are at particular risk of developing hypoglycaemia. In order to avoid hypoglycaemia, blood glucose should be measured frequently and the insulin dosage should be carefully adjusted. Low blood glucose levels should be treated promptly.

Association of a functional 17beta-estradiol sensitive IL6-174G/C promoter polymorphism with early-onset type 1 diabetes in females.

The type 1 diabetes mellitus (T1DM) candidate gene SNP IL6-174G/C was genotyped in 253 Danish T1DM families (1129 individuals). TDT analysis demonstrated linkage in the presence of association between the IL6-174C allele and T1DM in the 416 T1DM offspring, P(tdt)=0.04. Gender conditioned TDT analyses revealed that linkage and association with T1DM were present in females exclusively; P(tdt)=6.5 x 10(-4) and P(tdt)=2.4 x 10(-4), respectively. Random transmission of the IL6-174C/G alleles was found in T1DM males, non-T1DM males and non-T1DM females; all P(tdt)>/=0.37. Heterogeneity analyses (T1DM versus non-T1DM females) excluded preferential meiotic segregation in females, P=4.6 x 10(-3), and demonstrated differences in the transmission patterns between female and male T1DM offspring, P=5.1 x 10(-3). The IL6-174 CC genotype was associated with younger age at onset of T1DM in females (P=0.002). The impact of 17beta-estradiol (E(2)) on the IL6-174G/C variants was investigated by reporter studies. The PMA stimulated activity of the T1DM risk IL6-174C variant exceeded that of the T1DM protective IL6-174G variant by approximately 70% in the absence of E(2) (P(c)=0.004), but not with E(2) present (P(c)=0.12). The PMA stimulated activity of the IL6-174G variant was repressed without E(2) present, but was derepressed by addition of E(2), P(c)=0.024. In contrast, the PMA stimulated IL6-174C activity was unaffected by E(2) as were the constitutive activities of the IL6-174G/C variants. In conclusion, higher IL6 promoter activity may confer risk to T1DM in very young females. This excess risk is negated with increasing age, possibly by the increasing E(2) levels in puberty.

MHC class I chain-related gene alleles 5 and 5.1 are transmitted more frequently to type 1 diabetes offspring in HBDI families.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by autoimmune destruction of pancreatic beta cells. Genetic and environmental factors contribute in this disease. There is evidence that MHC class I chain-related gene (MIC-A) plays a role in the susceptibility to this and other autoimmune diseases. There are five alleles of the MIC-A gene, which consist of different repetitions of GCT. In particular, MIC-A alleles 5 and 5.1 (the former with five repetitions of GCT, the latter with five repetitions and one additional insertion of nucleotide G) have been found to be associated with susceptibility to and age at onset of T1DM. The aim of our study was to analyze the transmission of these MIC-A alleles to T1DM-affected offsprings in HBDI families. These are multiplex families with affected offsprings and unaffected parents. DNA samples were amplified for MIC-A using fluorescence-labeled primers and analyzed on an ABI prism DNA sequencer. The transmission of alleles was then analyzed using pedigrees of families also obtained from HBDI. We analyzed 78 families and found that MIC-A alleles 5 and 5.1 are present and transmitted more frequently than expected. Heterozygotic parents for MIC-A alleles 5 and 5.1 were excluded from the study. Our results suggest that MIC-A alleles 5 and 5.1 are associated with susceptibility to T1DM in family studies.