Development Of Islet Autoimmunity Research Articles

Influenza A virus antibodies show no association with pancreatic islet autoantibodies in children genetically predisposed to type 1 diabetes.

Viral infections have long been considered potential triggers of beta cell autoimmunity and type 1 diabetes. Recent studies have suggested that influenza A virus might increase the risk of type 1 diabetes. The present study evaluates this risk association in prospectively observed children at the time when islet autoimmunity starts and autoantibodies are first detected. IgG class antibodies to influenza A virus were analysed in 95 case children whose antibody screening test turned permanently positive for two or more islet autoantibodies and from 186 autoantibody-negative and non-diabetic control children who were matched for time of birth, sex, date of sampling and HLA-conferred risk of diabetes in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study. Virus antibodies were measured from the first autoantibody-positive sample using an enzyme immunoassay. None of the children had been vaccinated against influenza A. The prevalence of influenza A virus antibodies did not differ between the case and control children (42% vs 38%; p = 0.392) and the median antibody levels were also comparable in the two groups (3.0 vs 3.8 enzyme immunoassay units). A similar result was obtained when case and control children were compared separately in subgroups according to different sex, age and HLA-DQ genotype. However, girls had higher antibody levels than boys among both case and control children (median antibody levels 9.0 vs 2.3 enzyme immunoassay units; p = 0.01). Our results suggest that influenza A infections are not associated with the development of islet autoimmunity in young children with increased genetic susceptibility to type 1 diabetes.

Dietary intake of soluble fiber and risk of islet autoimmunity by 5 y of age: results from the TEDDY study

Deficient soluble fiber intake has been suggested to dysregulate the immune response either directly or through alterations of the microbial composition in the gut. We hypothesized that a high intake of dietary soluble fiber in early childhood decreases the risk of type 1 diabetes (T1D)-associated islet autoimmunity. We analyzed 17,620 food records collected between age 9 and 48 mo from 3358 children from the United States and Germany prospectively followed in the TEDDY (The Environmental Determinants of Diabetes in the Young) study. HRs for the development of any/multiple islet autoantibodies (242 and 151 events, respectively) and T1D (71 events) by soluble fiber intake were calculated in Cox regression models and adjusted for potential confounders. There were no statistically significantly protective associations observed between a high intake of soluble fiber and islet autoimmunity or T1D. For example, the adjusted HRs (95% CIs) for high intake (highest compared with lowest quintile) at age 12 mo were 0.90 (0.55, 1.45) for any islet autoantibody, 1.20 (0.69, 2.11) for multiple islet autoantibodies, and 1.24 (0.57, 2.70) for T1D. In analyzing soluble fiber intake as a time-varying covariate, there were also no short-term associations between soluble fiber intake and islet autoimmunity development, with adjusted HRs of 0.85 (0.51, 1.42) for high intake and development of any islet autoantibody, for example. These results indicate that the intake level of dietary soluble fiber is not associated with islet autoimmunity or T1D in early life.

Impact of Islet Autoimmunity on the Progressive β-Cell Functional Decline in Type 2 Diabetes

OBJECTIVECross-sectional studies have suggested that islet autoimmunity may be more prevalent in type 2 diabetes (T2D) than previously appreciated and may contribute to the progressive decline in β-cell function. In this study, we longitudinally evaluated the effect of islet autoimmune development on the progressive β-cell dysfunction in T2D patients.RESEARCH DESIGN AND METHODSTwenty-three T2D patients negative for islet autoantibodies (GAD antibody and insulinoma-associated protein 2) and islet-specific T cells were evaluated prospectively for up to 36 months. We investigated the percentage of patients who developed islet autoantibodies (Ab+) and/or islet-reactive T cells (T+) and the effect of the islet autoimmunity on fasting and glucagon-stimulated C-peptide responses. We defined positive islet autoimmunity as Ab+ and/or T+ for at least two study visits.RESULTSOf the 23 patients, 6 (26%) remained negative for islet autoimmunity (Ab−T−), 14 (61%) developed Ab+ and/or T+, and 3 (13%) were unclassifiable because they developed islet autoimmunity at only one study visit. Islet Ab+ was observed to be less stable than islet-specific T-cell responses. Development of islet autoimmunity was significantly associated with a more rapid decline in fasting (P < 0.0001) and glucagon-stimulated (P < 0.05) C-peptide responses.CONCLUSIONSThese pilot data suggest that the development of islet autoimmunity in T2D is associated with a significantly more rapid β-cell functional decline.

Early infant growth is associated with the risk of islet autoimmunity in genetically susceptible children.

Islet autoimmunity commonly develops early in infancy. We assessed whether specific parameters of early growth (including weight gain) were associated with the development of islet autoimmunity in children of type 1 diabetes patients, taking individual developmental patterns into account. Growth parameters were estimated in n = 1011 children followed from birth in the prospective BABYDIAB and BABYDIET studies using longitudinal models. Cox proportional hazard models, adjusted for study, sex, gestational age, birth weight percentile, and maternal type 1 diabetes status, were calculated to assess hazard ratios (HR) for islet autoimmunity with corresponding 95% confidence intervals (95% CI) by 2 SD increases in growth parameters. In a subset of n = 170 infants, we investigated whether the growth hormones insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) were in the causal pathway. We found an early age at infant body mass index (BMI) peak to be associated with the development of islet autoimmunity [HR 0.60 (95% CI 0.41-0.87), per 2 SD increase in age]. Islet autoimmunity was also associated with BMI difference between infant BMI peak and childhood BMI rebound [HR 1.52 (95% CI 1.04-2.22)], but not after adjustment for age at infant BMI peak, and not with other parameters such as peak height and weight velocity during infancy. Serum concentrations of IGF-1 and IGFBP-3 at birth, 9 months, and 2 yr, respectively, were not significantly different between children with and without later islet autoimmunity. Variations in early growth rate have subtle effects on the risk of islet autoimmunity with growth hormones unlikely to be in the causal pathway.

Evaluation of the fidelity of immunolabelling obtained with clone 5D8/1, a monoclonal antibody directed against the enteroviral capsid protein, VP1, in human pancreas

Enteroviral infection has been implicated in the development of islet autoimmunity in type 1 diabetes and enteroviral antigen expression has been detected by immunohistochemistry in the pancreatic beta cells of patients with recent-onset type 1 diabetes. However, the immunohistochemical evidence relies heavily on the use of a monoclonal antibody, clone 5D8/1, raised against an enteroviral capsid protein, VP1. Recent data suggest that the clone 5D8/1 may also recognise non-viral antigens; in particular, a component of the mitochondrial ATP synthase (ATP5B) and an isoform of creatine kinase (CKB). Therefore, we evaluated the fidelity of immunolabelling by clone 5D8/1 in the islets of patients with type 1 diabetes. Enteroviral VP1, CKB and ATP5B expression were analysed by western blotting, RT-PCR and immunocytochemistry in a range of cultured cell lines, isolated human islets and human tissue. Clone 5D8/1 labelled CKB, but not ATP5B, on western blots performed under denaturing conditions. In cultured human cell lines, isolated human islets and pancreas sections from patients with type 1 diabetes, the immunolabelling of ATP5B, CKB and VP1 by 5D8/1 was readily distinguishable. Moreover, in a human tissue microarray displaying more than 80 different cells and tissues, only two (stomach and colon; both of which are potential sites of enterovirus infection) were immunopositive when stained with clone 5D8/1. When used under carefully optimised conditions, the immunolabelling pattern detected in sections of human pancreas with clone 5D8/1 did not reflect cross-reactivity with either ATP5B or CKB. Rather, 5D8/1 is likely to be representative of enteroviral antigen expression.

Respiratory Infections in Early Life and the Development of Islet Autoimmunity in Children at Increased Type 1 Diabetes Risk

There is evidence for a role of infections within the pathogenesis of islet autoimmunity and type 1 diabetes mellitus (T1D), but previous studies did not allow assessment of potential critical time windows in this context. To examine whether early, short-term, or cumulative exposures to episodes of infection and fever during the first 3 years of life were associated with the initiation of persistent islet autoimmunity in children at increased T1D risk. Prospective cohort study with daily infection records and regular assessment of islet autoimmunity. Diabetes Research Institute, Munich, Germany. A total of 148 children at high T1D risk with documentation of 1245 infectious events in 90,750 person-days during their first 3 years of life. Hazard ratios (HRs) for seroconversion to persistent islet autoantibodies were assessed in Cox regression models with numbers of respiratory, gastrointestinal, and other infections, adjusting for sex, delivery mode, intervention group, season of birth, and antibiotic use. An increased HR of islet autoantibody seroconversion was associated with respiratory infections during the first 6 months of life (HR = 2.27; 95% CI, 1.32-3.91) and ages 6.0 to 11.9 months (HR = 1.32; 95% CI, 1.08-1.61). During the second year of life, no meaningful effects were detected for any infectious category. A higher number of respiratory infections in the 6 months prior to islet autoantibody seroconversion was also associated with an increased HR (HR = 1.42; 95% CI, 1.12-1.80). Respiratory infections in early childhood are a potential risk factor for the development of T1D.

Early Childhood Infections and the Risk of Islet Autoimmunity

OBJECTIVEType 1 diabetes is a common chronic childhood disease, and the incidence is increasing globally. Childhood infections are considered a potential environmental trigger of type 1 diabetes. Alternatively, improved hygiene and reduced childhood infections could explain the increase in type 1 diabetes in developed countries. The association of reported illnesses during infancy and later development of islet autoimmunity (IA) were examined in the Diabetes Autoimmunity Study in the Young.RESEARCH DESIGN AND METHODSComplete illness interviews through 9 months of age were collected for 1,729 children—1,174 without a family history of type 1 diabetes and 555 with a first-degree relative with type 1 diabetes. Persistent IA was defined as positive antibodies to insulin, glutamic acid decarboxylase, or tyrosine phosphatase on at least two consecutive study visits.RESULTSThere were 109 children with persistent IA among the 1,729 children with illness records. A greater number of gastrointestinal illnesses were associated with an increased risk of IA, but only among children who were exposed to gluten-containing grains (wheat or barley) either <4 months of age (hazard ratio 1.37 [95% CI 1.22–1.55]; P < 0.0001) or ≥7 months of age (1.12 [1.05–1.19]; P = 0.0005) compared with 4–6 months of age (P for interaction = 0.02). There were no associations of upper respiratory symptoms, respiratory illnesses, or fevers with IA.CONCLUSIONSSpecific pathogens such as enteroviruses or rotavirus may increase the risk of IA in the presence of existing inflammation induced by diet.

Children With Islet Autoimmunity and Enterovirus Infection Demonstrate a Distinct Cytokine Profile

Cytokines are upregulated in prediabetes, but their relationship with Enterovirus (EV) infection and development of islet autoimmunity is unknown. Cytokines (n = 65) were measured using Luminex xMAP technology in a nested case-control study of 67 children with a first-degree relative with type 1 diabetes: 27 with islet autoantibodies (Ab+) and 40 age-matched persistently autoantibody negative (Ab−) control subjects. Of 74 samples, 37 (50%) were EV-PCR+ in plasma and/or stool (EV+) and the remainder were negative for EV and other viruses (EV−). Fifteen cytokines, chemokines, and growth factors were elevated (P ≤ 0.01) in Ab+ versus Ab− children (interleukin [IL]-1β, IL-5, IL-7, IL-12(p70), IL-16, IL-17, IL-20, IL-21, IL-28A, tumor necrosis factor-α, chemokine C-C motif ligand [CCL]13, CCL26, chemokine C-X-C motif ligand 5, granulocyte-macrophage colony-stimulating factor, and thrombopoietin); most have proinflammatory effects. In EV+ versus EV− children, IL-10 was higher (P = 0.005), while IL-21 was lower (P = 0.008). Cytokine levels did not differ between Ab+EV+ and Ab+EV− children. Heat maps demonstrated clustering of some proinflammatory cytokines in Ab+ children, suggesting they are coordinately regulated. In conclusion, children with islet autoimmunity demonstrate higher levels of multiple cytokines, consistent with an active inflammatory process in the prediabetic state, which is unrelated to coincident EV infection. Apart from differences in IL-10 and IL-21, EV infection was not associated with a specific cytokine profile.

Lack of Association of Type 2 Diabetes Susceptibility Genotypes and Body Weight on the Development of Islet Autoimmunity and Type 1 Diabetes

AimTo investigate whether type 2 diabetes susceptibility genes and body weight influence the development of islet autoantibodies and the rate of progression to type 1 diabetes.MethodsGenotyping for single nucleotide polymorphisms (SNP) of the type 2 diabetes susceptibility genes CDKAL1, CDKN2A/2B, FTO, HHEX-IDE, HMGA2, IGF2BP2, KCNJ11, KCNQ1, MTNR1B, PPARG, SLC30A8 and TCF7L2 was obtained in 1350 children from parents with type 1 diabetes participating in the BABYDIAB study. Children were prospectively followed from birth for islet autoantibodies and type 1 diabetes. Data on weight and height were obtained at 9 months, 2, 5, 8, 11, and 14 years of age.ResultsNone of type 2 diabetes risk alleles at the CDKAL1, CDKN2A/2B, FTO, HHEX-IDE, HMGA2, IGF2BP2, KCNJ11, KCNQ1, MTNR1B, PPARG and SLC30A8 loci were associated with the development of islet autoantibodies or diabetes. The type 2 diabetes susceptible genotype of TCF7L2 was associated with a lower risk of islet autoantibodies (7% vs. 12% by age of 10 years, P = 0.015, Pcorrected = 0.18). Overweight children at seroconversion did not progress to diabetes faster than non-overweight children (HR: 1.08; 95% CI: 0.48–2.45, P>0.05).ConclusionsThese findings do not support an association of type 2 diabetes risk factors with islet autoimmunity or acceleration of diabetes in children with a family history of type 1 diabetes.

Effects of Non-HLA Gene Polymorphisms on Development of Islet Autoimmunity and Type 1 Diabetes in a Population With High-Risk HLA-DR,DQ Genotypes

We assessed the effects of non-HLA gene polymorphisms on the risk of islet autoimmunity (IA) and progression to type 1 diabetes in the Diabetes Autoimmunity Study in the Young. A total of 1,743 non-Hispanic, white children were included: 861 first-degree relatives and 882 general population children identified as having high-risk HLA-DR/DQ genotypes for type 1 diabetes. Of those, 109 developed IA and 61 progressed to diabetes. Study participants were genotyped for 20 non-HLA polymorphisms, previously confirmed as type 1 diabetes susceptibility loci. PTPN22 and UBASH3A predicted both IA and diabetes in regression models controlling for family history of type 1 diabetes and presence of HLA-DR3/4-DQB1*0302 genotype. In addition, PTPN2 predicted IA whereas INS predicted type 1 diabetes. The final multivariate regression models for both IA and type 1 diabetes included PTPN22, UBASH3A, and INS, in addition to family history of type 1 diabetes and HLA-DR3/4. In general population children, the most frequent combinations including these five significant predictors conferred hazard ratio of up to 13 for IA and >40 for type 1 diabetes. Non-HLA susceptibility alleles may help estimate risk for development of type 1 diabetes in the general population. These findings require replication in different populations.

The fallacy of reduction

The "accelerator hypothesis" has made a significant impact on research into the etiology of type 1 diabetes. Some, but not all prospective studies have confirmed a weak association between insulin resistance and faster progression to diabetes among persons with advanced islet autoimmunity. However, there is hardly any evidence that insulin resistance can cause development of islet autoimmunity, thus be responsible for the ongoing pandemic of type 1 diabetes in children.

Self‐reported lower respiratory tract infections and development of islet autoimmunity in children with the type 1 diabetes high‐risk HLA genotype: the MIDIA study

To test whether self-reported lower respiratory tract infections in early infancy predicted risk for islet autoimmunity in genetically predisposed children. The environmental triggers for type 1 diabetes (MIDIA) study recruited newborns in Norway to identify those with the human leukocyte antigen high-risk genotype DR4-DQ8/DR3-DQ2. Of 46 939 newborns genotyped, 1003 (2.1%) carried the high-risk genotype, of whom 885 children were followed longitudinally with questionnaires and blood samples for autoantibody testing at 3, 6, 9 and 12 months of age, and then annually until 4 years of age. The endpoint (autoimmunity) was defined as positivity for at least one of three autoantibodies (to insulin, glutamic acid decarboxylase (GAD) or protein tyrosine phosphatase-like protein (IA2)) on at least two consecutive samples. The parents responded in the questionnaires, whether the child had had 'pneumonia, bronchitis or respiratory syncytial virus'. Cox proportional hazards regression models with time-dependent covariates were used to estimate hazard ratios for autoimmunity using STATA 10. Forty-two children developed autoimmunity, of whom 15 later developed type 1 diabetes. For 17 of the 42 cases (40%) 'pneumonia, bronchitis or respiratory syncytial virus' was reported (0.5-4 years of age) before or at the onset of autoimmunity. For 187 of the 843 non-cases (22%) 'pneumonia, bronchitis or respiratory syncytial virus' was reported in the same age group. The hazard ratio was 3.4 (p=0.001, 95% confidence interval: 1.6-7.1) for developing autoimmunity. The estimated hazard ratio was only marginally influenced by adjustment for potential confounding factors. No association was found for other infectious self-reported symptoms. Self-reported lower respiratory tract infections were associated with increased risk of islet autoimmunity in early infancy.

Human enterovirus infections in children at increased risk for type 1 diabetes: the Babydiet study

The aim of this study was to examine human enteroviruses (HEVs) and other intestinal viruses derived from children who participated in the Babydiet intervention study and to analyse the findings according to the appearance of islet autoantibodies, dietary intervention, maternal type 1 diabetes and clinical symptoms. In the Babydiet study the influence of first gluten exposure (6 or 12 months) on the development of islet autoimmunity was investigated in 150 children with increased genetic and familial risk for type 1 diabetes. Blood and stool samples were collected at 3 monthly intervals until the age of 3 years and yearly thereafter. Infections and clinical symptoms were recorded daily for the first year. In the present study, 339 stool samples collected from 104 children during the first year of life were analysed for HEVs and a certain proportion of the samples were analysed for other intestinal viruses. HEV was detected in 32 (9.4%) samples from 24 (23.1%) children. Altogether 13 serotypes were identified, with HEV-A species being the most common. Children with gastrointestinal symptoms had norovirus (3/11) and sapovirus (1/11) infections in addition to HEV (1/11). Of the 104 children, 22 developed islet autoantibodies. HEV infections were detected in 18% (4/22) and 24% (20/82) of islet-autoantibody-positive and -negative children, respectively (p = 0.5). The prevalence of HEV was similar in the gluten-exposed groups and in children from mothers with type 1 diabetes or from affected fathers and/or siblings (p = 1.0 and 0.6, respectively). No correlation was found between the presence of HEV in the first year of life and the development of islet autoantibodies. There was no association between HEV infections and dietary intervention, maternal diabetes or clinical symptoms.

Longitudinal study of parechovirus infection in infancy and risk of repeated positivity for multiple islet autoantibodies: the MIDIA study

The objective of this study was to investigate a possible association between human parechovirus infections in early infancy, diagnosed in fecal samples, and the development of islet autoimmunity. In the 'Environmental Triggers of Type 1 Diabetes: The MIDIA study', newborns with the highest genetic risk for type 1 diabetes were identified and followed with regular fecal sampling and questionnaires. A nested case-control study, including 27 children who developed islet autoimmunity (repeatedly positive for two or three autoantibodies) and 53 children matched for age and community of residence was used. Monthly stool samples from these children were analyzed for human parechovirus using a semi-quantitative real-time polymerase chain reaction. There was no significant difference in the prevalence of human parechovirus in stool samples when cases and controls were compared: 13.0 and 11.1%, respectively. There was also not any difference as to the number of infection episodes. In analyses restricted to samples collected 3, 6 or 12 months prior to seroconversion for islet autoantibodies, there was a suggestive association in the shortest time window of 3 months (20.8 vs. 8.8%, odds ratio = 3.2, 95% CI 1.2 - 8.5, uncorrected p = 0.022). No symptoms were associated with human parechovirus infection. A subset of the positive samples (n = 31) were sequenced, suggesting that human parechovirus 1 was the dominant genotype. The present study does not support strong associations between human parechovirus infections and the signs of islet autoimmunity. The weak association of parechovirus present in the last 3 months before development of autoimmunity warrants further investigation.

Height growth velocity, islet autoimmunity and type 1 diabetes development: the Diabetes Autoimmunity Study in the Young.

Larger childhood body size and rapid growth have been associated with increased type 1 diabetes risk. We analysed height, weight, BMI and velocities of growth in height, weight and BMI, for association with development of islet autoimmunity (IA) and type 1 diabetes. Since 1993, the Diabetes Autoimmunity Study in the Young (DAISY) has followed children at increased type 1 diabetes risk, based on HLA-DR, -DQ genotype or family history, for the development of IA and type 1 diabetes. IA was defined as the presence of autoantibodies to insulin, GAD or protein tyrosine phosphatase islet antigen 2 twice in succession, or autoantibody-positive on one visit and diabetic at the next consecutive visit within 1 year. Type 1 diabetes was diagnosed by a physician. Height and weight were collected starting at age 2 years. Of 1,714 DAISY children <11.5 years of age, 143 developed IA and 21 progressed to type 1 diabetes. We conducted Cox proportional hazards analysis to explore growth velocities and size measures for association with IA and type 1 diabetes development. Greater height growth velocity was associated with IA development (HR 1.63, 95% CI 1.31-2.05) and type 1 diabetes development (HR 3.34, 95% CI 1.73-6.42) for a 1 SD difference in velocity. Our study suggests that greater height growth velocity may be involved in the progression from genetic susceptibility to autoimmunity and then to type 1 diabetes in pre-pubertal children.

Dietary Glycemic Index, Development of Islet Autoimmunity, and Subsequent Progression to Type 1 Diabetes in Young Children

Dietary factors may trigger or exacerbate the autoimmune disease process. Our objective was to examine dietary glycemic index (GI) and glycemic load (GL) for association with islet autoimmunity (IA) development, and progression from IA to type 1 diabetes. The Diabetes Autoimmunity Study in the Young follows children at increased genetic type 1 diabetes risk. Diet is collected prospectively via a parent-reported food frequency questionnaire. This was an observational study of children in the Denver area. A total of 1776 Diabetes Autoimmunity Study in the Young children younger than 11.5 yr was included in the study. There were no interventions. IA, defined as the presence of autoantibodies to insulin, glutamic acid decarboxylase, or protein tyrosine phosphatase at two consecutive visits, or the presence of autoantibodies at one visit and diabetic on the next consecutive visit was determined. Type 1 diabetes was diagnosed by a physician. A total of 89 subjects developed IA, and 17 subsequently developed type 1 diabetes during follow-up. Our hypothesis was formulated after data collection. GI and GL were not associated with IA development. More rapid progression to type 1 diabetes in children with IA was associated with higher dietary GI (hazard ratio: 2.20; 95% confidence interval: 1.17-4.15) and marginally associated with GL (hazard ratio: 1.59; 95% confidence interval: 0.96-2.64) at the first IA-positive visit. Higher dietary GI and GL are not associated with IA development, but higher GI is associated with more rapid progression to type 1 diabetes in children with IA, perhaps due to increased demand on the beta-cell to release insulin. Further study is needed to confirm this finding and identify the underlying biological mechanism.

Omega-3 Polyunsaturated Fatty Acid Intake and Islet Autoimmunity in Children at Increased Risk for Type 1 Diabetes

Cod liver oil supplements in infancy have been associated with a decreased risk of type 1 diabetes mellitus in a retrospective study. To examine whether intakes of omega-3 and omega-6 fatty acids are associated with the development of islet autoimmunity (IA) in children. A longitudinal, observational study, the Diabetes Autoimmunity Study in the Young (DAISY), conducted in Denver, Colorado, between January 1994 and November 2006, of 1770 children at increased risk for type 1 diabetes, defined as either possession of a high diabetes risk HLA genotype or having a sibling or parent with type 1 diabetes. The mean age at follow-up was 6.2 years. Islet autoimmunity was assessed in association with reported dietary intake of polyunsaturated fatty acids starting at age 1 year. A case-cohort study (N = 244) was also conducted in which risk of IA by polyunsaturated fatty acid content of erythrocyte membranes (as a percentage of total lipids) was examined. Risk of IA, defined as being positive for insulin, glutamic acid decarboxylase, or insulinoma-associated antigen-2 autoantibodies on 2 consecutive visits and still autoantibody positive or having diabetes at last follow-up visit. Fifty-eight children developed IA. Adjusting for HLA genotype, family history of type 1 diabetes, caloric intake, and omega-6 fatty acid intake, omega-3 fatty acid intake was inversely associated with risk of IA (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.21-0.96; P = .04). The association was strengthened when the definition of the outcome was limited to those positive for 2 or more autoantibodies (HR, 0.23; 95% CI, 0.09-0.58; P = .002). In the case-cohort study, omega-3 fatty acid content of erythrocyte membranes was also inversely associated with IA risk (HR, 0.63; 95% CI, 0.41-0.96; P = .03). Dietary intake of omega-3 fatty acids is associated with reduced risk of IA in children at increased genetic risk for type 1 diabetes.

Perinatal factors and development of islet autoimmunity in early childhood: the diabetes autoimmunity study in the young.

The objective of this study was to test whether maternal age at delivery, child's birth order, cesarean section, complicated delivery, maternal smoking during pregnancy, or neonatal jaundice predict islet autoimmunity in children at genetically increased risk of type 1 diabetes in a birth cohort with blood draws at ages 9, 15, and 24 months and yearly thereafter. Newborns with diabetes-associated human leukocyte antigen genotypes (n = 938) and offspring or siblings of persons with type 1 diabetes (n = 428) from the Denver, Colorado, metropolitan area were examined from January 1994 to February 2003. Information on perinatal factors was collected by using questionnaires soon after the birth. Islet autoimmunity was defined as positivity for > or = 1 autoantibody to glutamic acid decarboxylase65, insulin, or protein tyrosine phosphatase-2/ICA512 at > or = 2 consecutive visits (n = 52; mean follow-up, 3.9 years). Complicated delivery (breech, forceps, vacuum extraction) predicted a higher risk of islet autoimmunity (hazard ratio = 2.10, 95% confidence interval: 1.09, 4.05). Increasing maternal age was related to risk of islet autoimmunity among first-degree relatives of persons with type 1 diabetes (hazard ratios = 3.96 and 8.88 for maternal ages 25-34 and > or = 35 years, respectively, compared with < 25 years; p for trend = 0.008. Other factors evaluated were not related to risk of islet autoimmunity. In conclusion, influences in utero or during delivery may affect the fetal immune system.

Environmental triggers of type 1 diabetes

High risk HLA class II alleles account for 40% of the genetic susceptibility to type 1 diabetes in Caucasians, but the majority of the genetically predisposed do not develop the disease. This supports some environmental modification of the autoimmune destruction of beta cells that precedes type 1 diabetes. Identical twin studies and geographical variation in incidence also argue for a critical role of environmental factors. Attention has been directed to the possible harmful effect of cow's milk protein (or protective effect of breast-feeding) and enteric infections in early life. Natural history studies that follow children at increased risk of type 1 diabetes provide the best opportunity to study environmental triggers. The Australian Baby Diab Study has followed approximately 500 babies from birth who have a first-degree relative with type 1 diabetes. No prospective association between duration of breast-feeding or introduction of cow's milk and the development of islet autoimmunity was found. The same Australian cohort demonstrated a relationship between rotavirus infection and the first appearance or increase in islet antibodies. Enteroviral infection is seen more frequently in prediabetic children and prior to the onset of islet autoimmunity in Finnish cohorts. Environmental factors may interact. Breast milk protects against enteric infections; enteric infections in turn could increase immunity to dietary antigens by increasing intestinal permeability. It is also possible that an alteration in gut mucosal immune function in genetically susceptible individuals underlies any effect of dietary or viral proteins on the development of islet autoimmunity in early life.

Response to Dahlquist

There are important differences between the prospective studies from birth and the case-control studies of type 1 diabetes. First, the prospective studies have been performed on subjects who have relatives with type 1 diabetes and, therefore, have the so-called familial type 1 diabetes, a minority of all type 1 diabetes cases. None of the case-control studies have examined risk factors in individuals having a relative with the disease. A second difference is that prospective studies examine the relationship between environmental factors and the development of islet autoimmunity. This is very important because 1 ) most of the environmental factors examined (breast-feeding, introduction of cow's milk, vaccinations, etc.) are likely to have causative effects early in life and 2 ) as we have previously shown, islet autoantibodies appear early in life; …