The Better Diabetes Diagnosis (BDD) study - A review of a nationwide prospective cohort study in Sweden.

The incidence of type 1 diabetes (T1D) in Sweden is one of the highest in the world. However, the possibility of other types of diabetes must also be considered. In addition, individuals with T1D constitute a heterogeneous group. A precise classification of diabetes is a prerequisite for optimal outcome. For precise classification, knowledge on the distribution of genetic factors, biochemical markers and clinical features in individuals with new onset of diabetes is needed. The Better Diabetes Diagnosis (BDD), is a nationwide study in Sweden with the primary aim to facilitate a more precise classification and diagnosis of diabetes in order to enable the most adequate treatment for each patient. Secondary aims include identification of risk factors for diabetes-related co-morbidities. Since 2005, data on almost all children and adolescents with newly diagnosed diabetes in Sweden are prospectively collected and including heredity of diabetes, clinical symptoms, levels of C peptide, genetic analyses and detection of autoantibodies. Since 2011, analyses of HLA profile, autoantibodies and C peptide levels are part of clinical routine in Sweden for all pediatric patients with suspected diagnosis of diabetes. In this review, we present the methods and main results of the BDD study so far and discuss future aspects.

Preferences for treatment among adolescents with Type 1 diabetes: a national study using a discrete choice experiment model.

AIM: To test the possibility of using a discrete choice experiment model, on a national level in adolescents with Type 1 diabetes, in order to obtain a better understanding of drivers of and barriers to diabetes self-care. METHODS: A survey instrument was constructed and tested on a small group of the target population: adolescents aged 15 to <18 years with Type 1 diabetes. All individuals in Sweden belonging to this target group (N=2112) were then identified via the Swedish paediatric diabetes quality registry SWEDIABKIDS, and were sent an invitation to answer an online questionnaire. A valid response for the discrete choice experiment analyses was achieved from 431 individuals. RESULTS: The included respondents were not statistically different from non-participants in terms of age and duration of diabetes, but more young women entered the study and the participants had (on average) a significantly lower HbA1c value than the non-participants. Participants regarded as undesirable both non-severe hypoglycaemic events (day and night) and hyperglycaemic events. Avoiding weight gain and even achieving weight loss were the most important aspects among female respondents, who were willing to trade off a substantial level of glycaemic control [13 mmol/mol (1.2%)] to avoid a weight gain of 3 kg. Hypothetical equipment improvements were desired. CONCLUSIONS: The responses may provide useful indications of the aspects that the respondents would prioritize given a real-life dilemma. For treatment effects, stratification along gender lines was important, whereas the treatment administration aspects were stratified according to treatment type because these aspects are closely related.

Seasonality at the clinical onset of type 1 diabetes-Lessons from the SWEET database.

BACKGROUND: Seasonality at the clinical onset of type 1 diabetes (T1D) has been suggested by different studies, however, the results are conflicting. This study aimed to evaluate the presence of seasonality at clinical onset of T1D based on the SWEET database comprising data from 32 different countries. METHODS: The study cohort included 23 603 patients (52% males) recorded in the international multicenter SWEET database (48 centers), with T1D onset ≤20 years, year of onset between 1980 and 2015, gender, year and month of birth and T1D-diagnosis documented. Data were stratified according to four age groups (<5, 5-<10, 10-<15, 15-20 years) at T1D onset, the latitude of European center (Northern ≥50°N and Southern Europe <50°N) and the year of onset ≤ or >2009. RESULTS: Analysis by month revealed significant seasonality with January being the month with the highest and June with the lowest percentage of incident cases (P < .001). Winter, early spring and late autumn months had higher percentage of incident cases compared with late spring and summer months. Stratification by age showed similar seasonality patterns in all four age groups (P ≤ .003 each), but not in children <24 months of age. There was no gender or latitude effect on seasonality pattern, however, the pattern differed by the year of onset (P < .001). Seasonality of diagnosis conformed to a sinusoidal model for all cases, females and males, age groups, northern and southern European countries. CONCLUSIONS: Seasonality at T1D clinical onset is documented by the large SWEET database with no gender or latitude (Europe only) effect except from the year of manifestation.

Health-related quality of life in preschool children with Type 1 diabetes.

AIMS: To describe health-related quality of life in children aged < 7 years with Type 1 diabetes mellitus compared with healthy children of the same age, and to investigate how health-related quality of life was correlated with aspects of insulin treatment and glycaemic control. METHODS: The participants in this study were 24 children with diabetes (12 girls, mean age 4.5 years) and 27 healthy children (14 girls, mean age 4.6 years). All participants completed the Pediatric Quality of Life Inventory 4.0 Generic Core Scales and the participants with diabetes also completed the Pediatric Quality of Life Inventory 3.0 Type 1 Diabetes Module Scales. HbA1c levels were measured in children with diabetes and the plasma glucose meter memories were uploaded. RESULTS: Children aged <7 years with diabetes had lower parent-rated generic health-related quality of life compared with healthy children (score: 80 vs 91; P = 0.003). The difference was largest in children aged < 5 years (score: 79 vs 93; P = 0.004). Among the parents of children with Type 1 diabetes, 22% rated their child's generic health-related quality of life to be at a level of concern (- 1 sd of a general population). Of the children with Type 1 diabetes aged between 5 and 7 years, 40% rated their own generic health-related quality of life at the same level of concern. CONCLUSION: This study shows a significantly lower level of generic health-related quality of life in very young children with diabetes in comparison with healthy children. We suggest screening for health-related quality of life in children of all ages with Type 1 diabetes mellitus.

Diabetes management in Swedish schools: a national survey of attitudes of parents, children, and diabetes teams.

BACKGROUND: Parents of children with type 1 diabetes often raise complaints about self-care support during school time. The aim of this study was to investigate attitudes to diabetes care in school reported by children with type 1 diabetes, their parents, and their diabetes teams. METHODS: Children who had completed preschool class or at least one grade in the 9-yr compulsory school system were invited to participate. Data were collected using separate questionnaires for the children and their parents. In addition, the members of the diabetes team answered a separate questionnaire. All pediatric diabetes centers in Sweden were invited to participate in the study. RESULTS: All Swedish children and adolescents with diabetes are treated at pediatric diabetes centers. Out of 44 eligible centers, 41 were able to participate. The questionnaires were completed by 317 children and adolescents and 323 parents. The mean age was 11.4 ± 2.7 yr and hemoglobin A1c (HbA1c) was 61.8 ± 12.4 mmol/mol (7.8 ± 1.1%). For 57% of the children, there was no member of staff at the school with principal responsibility to support diabetes self-care. A written action plan for hypoglycemia existed for 60% of the children. Twenty-one percent of the parents regularly gave less insulin than they calculated would be needed at breakfast because of fear of hypoglycemia during school time. CONCLUSIONS: Although Sweden has legislation underlining the specific need for diabetes care in school, this nationwide study demonstrates deficiencies in the support of self-care management.

Antibodies to influenza virus A/H1N1 hemagglutinin in Type 1 diabetes children diagnosed before, during and after the SWEDISH A(H1N1)pdm09 vaccination campaign 2009-2010.

We determined A/H1N1-hemagglutinin (HA) antibodies in relation to HLA-DQ genotypes and islet autoantibodies at clinical diagnosis in 1141 incident 0.7-to 18-year-old type 1 diabetes patients diagnosed April 2009-December 2010. Antibodies to (35) S-methionine-labelled A/H1N1 hemagglutinin were determined in a radiobinding assay in patients diagnosed before (n = 325), during (n = 355) and after (n = 461) the October 2009-March 2010 Swedish A(H1N1)pdm09 vaccination campaign, along with HLA-DQ genotypes and autoantibodies against GAD, insulin, IA-2 and ZnT8 transporter. Before vaccination, 0.6% patients had A/H1N1-HA antibodies compared with 40% during and 27% after vaccination (P < 0.0001). In children <3 years of age, A/H1N1-HA antibodies were found only during vaccination. The frequency of A/H1N1-HA antibodies during vaccination decreased after vaccination among the 3 < 6 (P = 0.006) and 13 < 18 (P = 0.001), but not among the 6 < 13-year-olds. HLA-DQ2/8 positive children <3 years decreased from 54% (15/28) before and 68% (19/28) during, to 30% (9/30) after vaccination (P = 0.014). Regardless of age, DQ2/2; 2/X (n = 177) patients had lower frequency (P = 0.020) and levels (P = 0.042) of A/H1N1-HA antibodies compared with non-DQ2/2; 2/X (n = 964) patients. GADA frequency was 50% before, 60% during and 51% after vaccination (P = 0.009). ZnT8QA frequency increased from 30% before to 34% during and 41% after vaccination (P = 0.002). Our findings suggest that young (<3 years) along with DQ2/2; 2/X patients were low responders to Pandemrix(®) . As the proportion of DQ2/8 patients <3 years of age decreased after vaccination and the frequencies of GADA and ZnT8QA were enhanced, it cannot be excluded that the vaccine affected clinical onset of type 1 diabetes.

Children under the age of seven with diabetes are increasing their cardiovascular risk by their food choices.

AIM: Early-onset diabetes increases the risk of cardiovascular disease. This study examined the eating habits of children under 7 years of age with diabetes to see whether their diet increased that risk even further. METHODS: A total of 24 children with type 1 diabetes (mean age 4.5 years) and 27 healthy controls (mean age 4.6 years) participated in this cross-sectional study. Food intake was assessed by two 4-day food records. RESULTS: Children with type 1 diabetes had a higher energy intake from protein (18 vs 15%, p < 0.05) and fat (35 vs 31%, p < 0.05) but lower intake from carbohydrates (47 vs 54%, p < 0.05), than the healthy control group. Intake of saturated fat was higher than recommended in both groups, and consumption of fruit and vegetables was lower than recommended, but similar, in both the diabetes and control groups (191 vs 207 g per day). Total intake of fat was negatively correlated with intake of fruit and vegetables (r = -0.74 p < 0.05) in children with type 1 diabetes. CONCLUSION: Children under 7 years of age with type 1 diabetes eat too much saturated fat and not enough fruit and vegetables. Their diet should be improved to reduce their cardiovascular risk.

Thyroid autoimmunity in relation to islet autoantibodies and HLA-DQ genotype in newly diagnosed type 1 diabetes in children and adolescents.

AIMS/HYPOTHESIS: The aim of this work was to investigate, in children newly diagnosed with type 1 diabetes: (1) the prevalence of autoantibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TGAb); and (2) the association between TPOAb, TGAb or both, with either islet autoantibodies or HLA-DQ genes. METHODS: Blood samples from 2,433 children newly diagnosed with type 1 diabetes were analysed for TPOAb and TGAb in addition to autoantibodies against arginine zinc transporter 8 (ZnT8RA), tryptophan zinc transporter 8 (ZnT8WA), glutamine zinc transporter 8 (ZnT8QA), glutamic acid decarboxylase (GADA), insulin (IAA), insulinoma-associated protein-2 (IA-2A), HLA-DQA-B1 genotypes, thyroid-stimulating hormone (TSH) and free thyroxine (T4). RESULTS: At type 1 diabetes diagnosis, 12% of the children had thyroid autoantibodies (60% were girls; p < 0.0001). GADA was positively associated with TPOAb (p < 0.001) and with TGAb (p < 0.001). In addition, ZnT8A was associated with both TPOAb (p = 0.039) and TGAb (p = 0.015). DQB1*05:01 in any genotype was negatively associated with TPOAb (OR 0.55, 95% CI 0.37, 0.83, p value corrected for multiple comparisons (p c) = 0.012) and possibly with TGAb (OR 0.55, 95% CI 0.35, 0.87, p c = 0.07). Thyroid autoimmunity in children newly diagnosed with type 1 diabetes was rarely (0.45%) associated with onset of clinical thyroid disease based on TSH and free T4. CONCLUSIONS/INTERPRETATION: GADA and ZnT8A increased the risk for thyroid autoimmunity at the time of clinical diagnosis of type 1 diabetes, while HLA-DQB1*05:01 reduced the risk. However, the associations between thyroid autoimmunity and HLA-DQ genotype were weak and did not fully explain the co-occurrence of islet and thyroid autoimmunity.

Triple specificity of ZnT8 autoantibodies in relation to HLA and other islet autoantibodies in childhood and adolescent type 1 diabetes.

OBJECTIVE: To establish the diagnostic sensitivity of and the relationships between autoantibodies to all three Zinc transporter 8 (Zinc transporter 8 autoantibody to either one, two, or all three amino acid variants at position 325, ZnT8A) variants to human leukocyte antigen (HLA)-DQ and to autoantibodies to glutamic acid decarboxylase (GADA), insulinoma-associated protein 2 (IA-2A), and insulin (IAA). METHODS: We analyzed 3165 patients with type 1 diabetes (T1D) in the Better Diabetes Diagnosis study for HLA-DQ genotypes and all six autoantibodies (ZnT8RA, arginine 325 Zinc transporter 8 autoantibody; ZnT8WA, tryptophan 325 Zinc transporter 8 autoantibody; ZnT8QA, glutamine 325 Zinc transporter 8 autoantibody; GADA, IA-2A, and IAA). RESULTS: ZnT8A was found in 65% of the patients and as many as 108 of 3165 (3.4%) had 1-3 ZnT8A alone. None had ZnT8QA alone. Together with GADA (56%), IA-2A (73%), and IAA (33%), 93% of the T1D patients were autoantibody positive. All three ZnT8A were less frequent in children below 2 yr of age (p < 0.0001). All three ZnT8A were associated with DQA1-B1*X-0604 (DQ6.4) and DQA1-B1*03-0302 (DQ8). ZnT8WA and ZnT8QA were negatively associated with DQA1-B1*05-02 (DQ2). CONCLUSIONS: Analysis of ZnT8A increased the diagnostic sensitivity of islet autoantibodies for T1D as only 7% remained islet autoantibody negative. The association between DQ6.4 and all three ZnT8A may be related to ZnT8 antigen presentation by the DQ6.4 heterodimer.

Residual beta cell function at diagnosis of type 1 diabetes in children and adolescents varies with gender and season.

BACKGROUND: There are seasonal variations and gender differences in incidence of type 1 diabetes (T1D), metabolic control and responses to immune interventions at onset of the disease. We hypothesized that there are seasonal and gender differences in residual insulin secretion already at diagnosis of T1D. METHODS: In 2005, a national study, the Better Diabetes Diagnosis, was started to classify all newly diagnosed children and adolescents with diabetes. About 95% (3824/4017) of the patients were classified as T1D, and our analyses are based on the patients with T1D. RESULTS: C-peptide was lower in younger children, 0-10 years of age (0.23 ± 0.20 nmol/L) than in older children, 11-18 years of age (0.34 ± 0.28 nmol/L) (p < 0.000 ). There was a seasonal variation in non-fasting serum C-peptide, significantly correlated to the seasonal variation of diagnosis (p < 0.01). Most children were diagnosed in January, February and March as well as in October when C-peptide was highest, whereas fewer patients were diagnosed in April and May when serum C-peptide was significantly lower (p < 0.01). The seasonal variation of C-peptide was more pronounced in boys than in girls (p < 0.000 and p < 0.01, respectively). Girls had higher C-peptide than boys (p < 0.05), especially in early puberty. CONCLUSIONS: Both seasonal and gender differences in residual beta cell function exist already at diagnosis of T1D. These observations have consequences for treatment and for randomizing patients in immune intervention clinical trials.

Age-dependent variation of genotypes in MHC II transactivator gene (CIITA) in controls and association to type 1 diabetes.

The major histocompatibility complex class II transactivator (CIITA) gene (16p13) has been reported to associate with susceptibility to multiple sclerosis, rheumatoid arthritis and myocardial infarction, recently also to celiac disease at genome-wide level. However, attempts to replicate association have been inconclusive. Previously, we have observed linkage to the CIITA region in Scandinavian type 1 diabetes (T1D) families. Here we analyze five Swedish T1D cohorts and a combined control material from previous studies of CIITA. We investigate how the genotype distribution within the CIITA gene varies depending on age, and the association to T1D. Unexpectedly, we find a significant difference in the genotype distribution for markers in CIITA (rs11074932, P=4 × 10(-5) and rs3087456, P=0.05) with respect to age, in the collected control material. This observation is replicated in an independent cohort material of about 2000 individuals (P=0.006, P=0.007). We also detect association to T1D for both markers, rs11074932 (P=0.004) and rs3087456 (P=0.001), after adjusting for age at sampling. The association remains independent of the adjacent T1D risk gene CLEC16A. Our results indicate an age-dependent variation in CIITA allele frequencies, a finding of relevance for the contrasting outcomes of previously published association studies.

Children younger than 7 years with type 1 diabetes are less physically active than healthy controls.

AIM: To examine if children younger than 7 years with type 1 diabetes are less physically active and spend more time sedentary than healthy children. METHODS: Using a repeated measures case-control study design, physical activity (PA) was measured by continuous combined accelerometer and heart rate registration for 7 days at two time points during 1 year (autumn and spring). PA data were expressed as time spent sedentary, in moderate and vigorous intensity PA and total PA. Differences between groups and gender were analysed with mixed linear regression models. In this study there were 24 children (12 girls) with type 1 diabetes mellitus and 26 (14 girls) healthy controls, all younger than 7 years at inclusion. RESULTS: Children with diabetes were less active overall (p = 0.010) and spent 16 min less in moderate-to-vigorous PA (p = 0.006). The difference in sedentary time (21 min less) between groups was not significant (p = 0.21). Overall PA (12.1 counts/min per day, p = 0.004) and time in moderate and vigorous PA (16.0 min/day, p = 0.002) was significantly higher in boys than in girls. A significant effect of age was observed. CONCLUSION: Physical activity is significantly reduced in young children with type 1 diabetes.

C-peptide in the classification of diabetes in children and adolescents.

AIM: To report C-peptide results in newly diagnosed patients and the relation to clinical diagnosis of diabetes. METHODS: A nation-wide cohort, the Better Diabetes Diagnosis study was used to determine serum C-peptide at diagnosis in 2734 children and adolescents. Clinical data were collected at diagnosis and follow-up. C-peptide was determined in a validated and controlled time-resolved fluoroimmunoassay. RESULTS: The clinical classification of diabetes, before any information on human leukocyte antigen, islet autoantibodies, or C-peptide was received, was type 1 diabetes (T1D) in 93%, type 2 diabetes (T2D) in 1.9%, maturity onset diabetes of the young (MODY) in 0.8%, secondary diabetes (0.6%), while 3.3% could not be classified. In a random, non-fasting serum sample at diagnosis, 56% of the patients had a C-peptide value >0.2 nmol/L. Children classified as T2D had the highest mean C-peptide (1.83 + 1.23 nmol/L) followed by MODY (1.04 ± 0.71 nmol/L) and T1D (0.28 ± 0.25 nmol/L). Only 1/1037 children who had C-peptide <0.2 nmol/L at diagnosis was classified with a type of diabetes other than T1D. Predictive value of C-peptide >1.0 nmol/L for the classification of either T2D or MODY was 0.46 [confidence interval 0.37-0.58]. CONCLUSIONS: More than half of children with newly diagnosed diabetes have clinically important residual beta-cell function. As the clinical diagnosis is not always straightforward, a random C-peptide taken at diagnosis may help to classify diabetes. There is an obvious use for C-peptide determinations to evaluate beta-cell function in children with diabetes.

Low risk HLA-DQ and increased body mass index in newly diagnosed type 1 diabetes children in the Better Diabetes Diagnosis study in Sweden.

OBJECTIVE: Type 1 diabetes and obesity has increased in childhood. We therefore tested the hypothesis that type 1 diabetes human leukocyte antigen DQ (HLA-DQ) risk genotypes may be associated with increased body mass index (BMI). DESIGN: The type 1 diabetes high-risk HLA-DQ A1*05:01-B1*02:01/A1*03:01-B1*03:02 genotype along with lower risk DQ genotypes were determined at the time of clinical onset by PCR and hybridization with allele-specific probes. BMI was determined after diabetes was stabilized. SUBJECTS: A total of 2403 incident type 1 diabetes children below 18 years of age were ascertained in the Swedish national Better Diabetes Diagnosis (BDD) study between May 2005 to September 2009. All children classified with type 1 diabetes, including positivity for at least one islet autoantibody, were investigated. RESULTS: Overall, type 1 diabetes HLA-DQ risk was negatively associated with BMI (P<0.0008). The proportion of the highest risk A1*05:01-B1*02:01/A1*03:01-B1)03:02 genotype decreased with increasing BMI (P<0.0004). However, lower risk type 1 diabetes DQ genotypes were associated with an increased proportion of patients who were overweight or obese (P<0.0001). Indeed, the proportion of patients with the low-risk A1*05:01-B1*02:01/A1*05:01-B1*02:01 genotype increased with increasing BMI (P<0.003). The magnitude of association on the multiplicative scale between the A1*05:01-B1*02:01/A1*05:01-B1*02:01 genotype and increased BMI was significant (P<0.006). The odds ratio in patients with this genotype of being obese was 1.80 (95% confidence interval 1.21-2.61; P<0.006). The increased proportion of overweight type 1 diabetes children with the A1*05:01-B1*02:01 haplotype was most pronounced in children diagnosed between 5 and 9 years of age. CONCLUSIONS: Susceptibility for childhood type 1 diabetes was unexpectedly found to be associated with the A1*05:01-B1*02:01/A1*05:01-B1*02:01 genotype and an increased BMI. These results support the hypothesis that overweight may contribute to the risk of type 1 diabetes in children positive for HLA-DQ A1*05:01-B1*02:01.

Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: The aim of this study was to investigate the safety and efficacy of alum formulated glutamic acid decarboxylase GAD(65) (GAD-alum) treatment of children and adolescents with type 1 diabetes after 4 years of follow-up. METHODS: Seventy children and adolescents aged 10-18 years with recent onset type 1 diabetes participated in a phase II, double-blind, randomised placebo-controlled clinical trial. Patients identified as possible participants attended one of eight clinics in Sweden to receive information about the study and for an eligibility check, including a medical history. Participants were randomised to one of the two treatment groups and received either a subcutaneous injection of 20 µg of GAD-alum or placebo at baseline and 1 month later. The study was blinded to participants and investigators until month 30. The study was unblinded at 15 months to the sponsor and statistician in order to evaluate the data. At follow-up after 30 months there was a significant preservation of residual insulin secretion, as measured by C-peptide, in the group receiving GAD-alum compared with placebo. This was particularly evident in patients with <6 months disease duration at baseline. There were no treatment-related serious adverse events. We have now followed these patients for 4 years. Overall, 59 patients, 29 who had been treated with GAD-alum and 30 who had received placebo, gave their informed consent. RESULTS: One patient in each treatment group experienced an episode of keto-acidosis between months 30 and 48. There were no treatment-related adverse events. The primary efficacy endpoint was the change in fasting C-peptide concentration from baseline to 15 months after the prime injection for all participants per protocol set. In the GAD-alum group fasting C-peptide was 0.332 ± 0.032 nmol/l at day 1 and 0.215 ± 0.031 nmol/l at month 15. The corresponding figures for the placebo group were 0.354 ± 0.039 and 0.184 ± 0.033 nmol/l, respectively. The decline in fasting C-peptide levels between day 1 and month 1, was smaller in the GAD-alum group than the placebo group. The difference between the treatment groups was not statistically significant. In those patients who were treated within 6 months of diabetes diagnosis, fasting C-peptide had decreased significantly less in the GAD-alum group than in the placebo-treated group after 4 years. CONCLUSION/INTERPRETATION: Four years after treatment with GAD-alum, children and adolescents with recent-onset type 1 diabetes continue to show no adverse events and possibly to show clinically relevant preservation of C-peptide. TRIAL REGISTRATION: ClinicalTrials.gov NCT00435981 FUNDING: The study was funded by The Swedish Research Council K2008-55X-20652-01-3, Barndiabetesfonden (The Swedish Child Diabetes Foundation), the Research Council of Southeast Sweden, and an unrestricted grant from Diamyd Medical AB.

Glycaemic control and diabetes care utilization in young adults with Type 1 diabetes.

OBJECTIVES: To explore how glycaemic control in young adults is related to diabetes care utilization during the transition to adult diabetes care and if these variables differ between males and females. METHODS: This is a retrospective, longitudinal design following patients' records from age 18-24 years. Adolescents (n = 104) connected to one paediatric outpatient clinic and referred to six different adult clinics were included. Data were collected regarding gender, age at diagnosis and transfer, yearly glycated haemoglobin (HbA(1c)) and body mass index, severe hypoglycaemia and diabetic ketoacidosis, retinopathy and diabetes care utilization. RESULTS: HbA(1c) decreased over time in females (P = 0.004) but not in males. Less than 10% had HbA(1c) in the recommended range during the study period. The decrease in severe hypoglycaemia and diabetic ketoacidosis was not significant. The prevalence of background retinopathy increased from 5 to 29% during the study period (P < 0.001). Mean transfer age was 19.8 years. The youths visited the paediatric clinic more often than the adult clinic (P < 0.001) and females visited adult care more often than males (P = 0.04). There was a steady decrease in the number of visits/year over time (P < 0. 001). Poor glycaemic control was associated with more visits for both males and females (P = 0.005) in adult care. CONCLUSIONS: As there was no gender difference in the relation between HbA(1c) and the number of visits in adult diabetes care, the higher frequency of visits in adult care for females cannot be solely explained by their glycaemic control. Gender differences regarding diabetes care utilization should be further explored.

Temporal trends of HLA genotype frequencies of type 1 diabetes patients in Sweden from 1986 to 2005 suggest altered risk.

The aim of this study was to compare the frequency of human leukocyte antigen (HLA) genotypes in 1-18-year-old patients with type 1 diabetes newly diagnosed in 1986-1987 (n = 430), 1996-2000 (n = 342) and in 2003-2005 (n = 171). We tested the hypothesis that the HLA DQ genotype distribution changes over time. Swedish type 1 diabetes patients and controls were typed for HLA using polymerase chain reaction amplification and allele specific probes for DQ A1* and B1* alleles. The most common type 1 diabetes HLA DQA1*-B1*genotype 0501-0201/0301-0302 was 36% (153/430) in 1986-1987 and 37% (127/342) in 1996-2000, but decreased to 19% (33/171) in 2003-2005 (P \ 0.0001). The 0501-0201/0501-0201 genotype increased from 1% in 1986-1987 to 7% in 1996-2000 (P = 0.0047) and to 5% in 2003-2005 (P > 0.05). This study in 1-18-year-old Swedish type 1 diabetes patients supports the notion that there is a temporal change in HLA risk.

IA-2 autoantibodies in incident type I diabetes patients are associated with a polyadenylation signal polymorphism in GIMAP5.

In a large case-control study of Swedish incident type I diabetes patients and controls, 0-34 years of age, we tested the hypothesis that the GIMAP5 gene, a key genetic factor for lymphopenia in spontaneous BioBreeding rat diabetes, is associated with type I diabetes; with islet autoantibodies in incident type I diabetes patients or with age at clinical onset in incident type I diabetes patients. Initial scans of allelic association were followed by more detailed logistic regression modeling that adjusted for known type I diabetes risk factors and potential confounding variables. The single nucleotide polymorphism (SNP) rs6598, located in a polyadenylation signal of GIMAP5, was associated with the presence of significant levels of IA-2 autoantibodies in the type I diabetes patients. Patients with the minor allele A of rs6598 had an increased prevalence of IA-2 autoantibody levels compared to patients without the minor allele (OR=2.2; Bonferroni-corrected P=0.003), after adjusting for age at clinical onset (P=8.0 x 10(-13)) and the numbers of HLA-DQ A1*0501-B1*0201 haplotypes (P=2.4 x 10(-5)) and DQ A1*0301-B1*0302 haplotypes (P=0.002). GIMAP5 polymorphism was not associated with type I diabetes or with GAD65 or insulin autoantibodies, ICA, or age at clinical onset in patients. These data suggest that the GIMAP5 gene is associated with islet autoimmunity in type I diabetes and add to recent findings implicating the same SNP in another autoimmune disease.

SUMO4 M55V polymorphism affects susceptibility to type I diabetes in HLA DR3- and DR4-positive Swedish patients.

SUMO4 M55V, located in IDDM5, has been a focus for debate because of its association to type I diabetes (TIDM) in Asians but not in Caucasians. The current study aims to test the significance of M55V association to TIDM in a large cohort of Swedish Caucasians, and to test whether M55V is associated in those carrying human leukocyte antigen (HLA) class II molecules. A total of 673 TIDM patients and 535 age- and sex-matched healthy controls were included in the study. PCR-RFLP was performed to identify the genotype and allele variations. Our data suggest that SUMO4 M55V is not associated with susceptibility to TIDM by itself. When we stratified our patients and controls based on heterozygosity for HLA-DR3/DR4 and SUMO4 genotypes, we found that presence of SUMO4 GG increased further the relative risk conferred by HLA-DR3/DR4 to TIDM, whereas SUMO4 AA decreased the risk. From the current study, we conclude that SUMO4 M55V is associated with TIDM in association with high-risk HLA-DR3 and DR4, but not by itself.