The cumulative incidence of childhood diabetes mellitus in Sweden unaffected by BCG-vaccination.
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Adolescent↗
Biomedical subjects
G Dahlquist
Publications and source records attributed to G Dahlquist.
Effects of the second HLA-DQ haplotype on the association with childhood insulin-dependent diabetes mellitus.
Analysis of HLA-DQ molecules in a large study comprising 425 consecutively diagnosed Swedish Caucasians with IDDM and 367 age, sex and geographically matched controls confirms previous observations that: (a) DQB1*0302-DQA1*0301 confer susceptibility in a dominant manner, except when they are associated with DQB1*0602-DQA1*0102; (b) DQB1*0501-DQA1*0201 does not confer susceptibility to IDDM in either homozygous or heterozygous combinations with any other DQ molecules except when it is in association with DQB1*0302-DQA1*0301; (c) heterozygous combinations of DQB1*0302-DQA1*0301 and DQB1*0501-DQA1*0201 confer the highest risk to IDDM; (d) in DQ2 positive patients being negative for DQ8 in second haplotype (n = 58) the susceptibility may be explained by DR, since all these patients were DR3 positive, or by unknown factors between DQ and DR and (e) DQB1*0602-DQA1*0102 confers protection in a dominant manner. This large study does not confirm the positive association previously observed in Norwegians between the DQ8/DQ4 genotype and IDDM, as this genotype was not significantly associated with IDDM in Swedish patients. The new findings in this study include (a) that DQ8/DQ6 (DQB1*0604-DQA1*0102) was associated with IDDM in Swedish patients and (b) analysis of individual amino acids in DQB1 chain does not fully explain susceptibility to IDDM.
Adolescent↗
Short-term mortality in childhood onset insulin-dependent diabetes mellitus: a high frequency of unexpected deaths in bed.
Mortality and the causes of death have been studied in a population-based cohort of 4919 childhood onset IDDM cases. Enrolment began in 1977 and at the time of study there had been a maximum duration of disease of 13.5 years, with a total of 33,721 person years at risk. Survival status was ascertained by linkage to the Swedish Cause-of-Death register. Death certificates, autopsy protocols, and hospital records were scrutinized for classification of causes of deaths. Twenty males and 13 females with IDDM died before the age of 28.5 years. This corresponds to a Standardized Mortality Rate for age of 262% (95% confidence limits, 172-400) for the boys and 384% (95% confidence limits, 232-635) for girls. Seven patients died of ketoacidosis, four at onset of diabetes. Nine cases were found 'dead in bed', having been seen apparently healthy 1-2 days before death. One of these cases had signs of cerebral haemorrhages at autopsy and another one had signs of bite marks in the mouth, but otherwise all autopsies were normal and no evidence of alcohol or other intoxication was found. In a well-educated population with good access to inexpensive diabetes care, there is still a two- to threefold excess mortality among young onset insulin-dependent diabetic individuals including a high frequency of unexplained deaths in bed.
Adolescent↗
Determinants of blood glucose variability in adolescents with insulin-dependent diabetes mellitus.
Metabolic control and blood glucose variability in children with insulin-dependent diabetes mellitus (IDDM) during and after puberty were studied. Seventy-two children (43M, 29F), aged 10-19 years, with a 2-16-year duration of IDDM participated in the study. Fourteen of the patients were prepubertal (Tanner stage 1), 27 pubertal (Tanner 2-4) and 31 postpubertal (Tanner 5). They performed self-monitoring of blood glucose (SMBG) five times daily, every 2 days for 4 weeks. The SD (SDbg) for all values in each patient was calculated as a measure of blood glucose variability. Weight-length index, linear growth velocity and Tanner stage were recorded. Hemoglobin (Hb)A1c, alkaline phosphatase and sex hormone levels in serum were analyzed. Subjectively experienced hypoglycemic episodes were recorded. HbA1c levels showed no relation to Tanner stage. SDbg was lower in stage 5 than in stages 2-4 (p = 0.02). There was no significant correlation between HbA1c and SDbg, but the variability was significantly lower in individuals with mean blood glucose in the lower quartile compared with those in the upper three quartiles (p < 0.001). Alkaline phosphatase concentration, as a measure of growth velocity, was the main independent determinant of SDbg (r = 0.35, p < 0.005). There was an inverse correlation between levels of sex hormones and SDbg. We conclude that blood glucose variability is lower after than during puberty. This variability seems to be related to linear growth velocity or its biochemical marker.
Adolescent↗
IgA bovine serum albumin antibodies are increased in newly diagnosed patients with insulin-dependent diabetes mellitus, but the increase is not an independent risk factor for diabetes.
We studied the significance of antibodies to bovine serum albumin (BSA) as a risk factor for insulin-dependent diabetes mellitus (IDDM) in a case-control setting. IgA and IgG antibodies to BSA and ovalbumin were measured from sera of 104 patients with newly diagnosed IDDM and of 111 matched controls by enzyme-linked immunosorbent assay. Patients with diabetes had significantly higher levels of IgA antibodies to BSA (p = 0.003); IgG antibodies also tended to be higher (p = 0.08). Levels of IgA antibodies to ovalbumin were similar in the patients and controls, but IgG antibodies were higher in controls (p = 0.02). When antibodies to BSA, beta-lactoglobulin, whole cow's milk and islet cell antibodies were studied as risk determinants of IDDM in a multivariate, logistic regression analysis, IgA antibodies to beta-lactoglobulin and to cow's milk were independently associated with the risk (p = 0.037 and 0.048, respectively), while antibodies to BSA were not a significant risk factor. The results question the role of BSA as a cross-reacting antigen with pancreatic beta-cell surface proteins in the aetiology of IDDM.
Animals↗
Population analysis of protection by HLA-DR and DQ genes from insulin-dependent diabetes mellitus in Swedish children with insulin-dependent diabetes and controls.
A negative association between insulin-dependent diabetes mellitus (IDDM) and HLA-DR, DQA1 or DQB1 was found in a large population-based investigation of childhood-onset patients (more than 420 patients) and controls (more than 340 controls) from Sweden. The relative risk was decreased for several haplotypes that were negatively associated with IDDM: DR15-DQA1*0102-DQB1*0602, DR7-DQA1*0201-DQB1*0303, DR14-DQA1*0101-DQB1*0503, DR11-DQA1*0501-DQB1*0301, DR13-DQA1*0103-DQB1*0603 and DR4-DQA1*0301-DQB1*0301. In a relative predispositional effect (RPE) analysis, however, only the DR15-DQA1*0102-DQB1*0602 haplotype was significantly decreased, which suggests that the major protective effect for IDDM is carried by this haplotype. This was supported by the observation that all genotypes which were negatively associated with IDDM, except DR7/13, included at least one allele from the DR15-DQA1*0102-DQB1*0602 haplotype. Relative predispositional effect (RPE) analysis of genotypes showed further that the DR15-DQA1*0102-DQB1*0602 haplotype was also negatively associated with IDDM when combined with any other haplotype, whether negatively or positively associated with IDDM. This supports previous suggestions that DR15-DQA1*0102-DQB1*0602 acts dominantly. However, both the stratification and the predispositional allele test failed to distinguish the negative association between IDDM and DR15 from that of DQB1*0602. On the other hand, these tests indicated that DQA1*0102 was not likely to explain the negative association between IDDM and the DR15-DQA1*0102-DQB1*0602 haplotype. We conclude that the major protective effect for IDDM in the population of Swedish children is conferred by the DR15-DQA1*0102-DQB1*0602 haplotype in a dominant fashion, the DQB1*0602 allele being the allele most likely to be responsible for the protective effect of this haplotype, although an effect of the DR15 allele could not be excluded.
Adolescent↗
Glutamate decarboxylase-, insulin-, and islet cell-antibodies and HLA typing to detect diabetes in a general population-based study of Swedish children.
Most autoimmune diabetes occurs in those without a diabetic relative, but few cases are identifiable prospectively. To model general population prediction, 491 consecutive newly diabetic children from all of Sweden were tested for autoantibodies to glutamate decarboxylase (GAD65ab), insulin (IAA), and islet cells (ICA), and for HLA-DQ genotypes by PCR; 415 matched control children were tested in parallel. GAD65ab sensitivity/specificity was 70/96%, versus 84/96% for ICA, 56/97% for IAA, 93/93% (any positive), 39/99.7% (all positive), and 41/99.7% (GAD65ab plus IAA). The latter's 25% predictive value was not improved by requiring concomitant high-risk HLA genotypes. GAD65ab were associated with DQA1*0501/B1*0201 (DQ2; P = 0.007) but not DQA1*0301/B1*0302 (DQ8), and IAA with DQA1*0301/B1*0302 (DQ8; P = 0.03) but not DQA1*0501/B1*0201 (DQ2). GAD65ab were more prevalent in females than males (79 vs. 63%; P < 0.0001) but did not vary with onset age nor season. Combining the three antibody assays yielded sufficient sensitivity for screening. GADab were relatively sensitive/specific for diabetes, but even with HLA marker combinations yielded predictive values insufficient for early immunointervention in the low-prevalence general population.
Adolescent↗
Polymorphic amino acid variations in HLA-DQ are associated with systematic physical property changes and occurrence of IDDM. Members of the Swedish Childhood Diabetes Study.
The association between human leukocyte antigen (HLA) and insulin-dependent diabetes was studied in a large population-based investigation using genotyping of 425 new-onset patients, 0-14 years of age, and 367 matched control subjects. As many as 97% of patients compared with 75% of control subjects were positive for one or several of DQA1*0301, DQA1*0501, DQB1*0302, or DQB1*0201. Asp-57 DQB was present among 28% of patients, indicating that this residue alone does not confer protection. Combining Asp-57 DQB1 with either Arg-52 DQA1 or Leu-69 DQA1 did not explain susceptibility or protection either. DQA1*0301-DQB1*0302 (DQ8) and DQA1*0301-DQB1*0301 (DQ7) are identical except for four amino acid substitutions in the beta-chain, but DQ8 was positively (odds ratio 8.07; P < 0.001) and DQ7 negatively (odds ratio 0.38; P < 0.001) associated with the disease. Molecular modeling was used to determine whether physiochemical properties such as steric factors and surface electrostatic potentials also differ in a systematic way for various DQ molecules. Amino acids were substituted systematically at the four polymorphic sites, and the solvent-accessible surfaces and electrostatic potentials were computed for each molecule. Dramatic alterations in electrostatic potential were seen for double substitutions at position 45 (G45E) and 57 (A57D) of DQB1. The variation of physicochemical properties due to polymorphic substitutions may be significant to the mechanism of HLA-DQ association with insulin-dependent diabetes, via the effect these property variations have on peptide antigen binding selectivity and subsequent interactions with specific T-cell receptors.
Adolescent↗
Psychological stress and the onset of IDDM in children.
OBJECTIVE: The purpose of the study was to determine whether psychosocial stress during different life periods could be a risk factor in the etiology/pathogenesis of insulin-dependent diabetes mellitus (IDDM) in children. RESEARCH DESIGN AND METHODS: In a population-based sample of 67 case patients 0-14 years of age and 61 matched healthy control subjects, life events during the entire lifespan before the onset of IDDM were recorded as well as measures of child behavior before onset, social support, and family function. RESULTS: Negative life events occurring during the first 2 years of life, life events with difficult adaptation, child behavioral deviances, and a more chaotic family function were more common in the case group. A stepwise logistic regression indicated that negative life events in the first 2 years increased the risk of IDDM and that premorbid child behavior as well as dysfunctional hierarchical family pattern affect the risk. CONCLUSIONS: Stress early in life may increase the risk for IDDM, presumably by affecting the autoimmune process. To confirm these results, it is necessary to make a truly prospective study.
Case-Control Studies↗
[Starting a new Swedish registry of diabetes is a waste of resources!].
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Diabetes Mellitus, Type 1↗
Childhood onset diabetes--time trends and climatological factors.
BACKGROUND: Childhood diabetes has been shown to have increased over time, to have a north-south gradient within Sweden and to exhibit seasonal variation. In the present study we have analysed the variation in incidence of childhood diabetes with time, and climatological factors such as mean temperature and sunshine hours. METHODS: The Swedish childhood diabetes register prospectively records all incident cases of diabetes with onset at 0-14 years since 1 July 1977. By 1 January 1993, 5831 cases had been registered. The data set was analysed using Poisson regression modelling and Cox' proportional hazards model. RESULTS: The mean annual incidence rate was 25/100,000. Over the 15 years there was an overall increase with time. When analysing the first 7 years and the last 8 years separately the basal linear increase was a mean 6% per year during the first period but no significant increase was noted during the second period. The increase during the first period was mainly due to an increase in incidence before the age of 10. Significant inverse and independent relationships were found between incidence rate and mean sunshine hours and mean temperature, respectively, when measured monthly in each county. We did not find any association between the climatological factors and age at onset. CONCLUSIONS: The increasing trend in childhood diabetes in Sweden during the past 15 years was mainly due to an increase in incidence in children younger than 10 years of age with onset during the first half of the observation period. During the last 8-year period incidence levelled off. A low mean temperature and a low number of sunshine hours are inversely and independently correlated to the incidence of childhood diabetes which may partly explain the north-south gradient and seasonal variation in the incidence of the disease.
Adolescent↗
Analysis of antibody markers, DRB1, DRB5, DQA1 and DQB1 genes and modeling of DR2 molecules in DR2-positive patients with insulin-dependent diabetes mellitus.
HLA-DR2 is negatively associated with insulin-dependent diabetes mellitus (IDDM). The aim of the present study was to analyze DR2-positive patients among 425 consecutively diagnosed unrelated Swedish children with IDDM and in 367 matched controls. HLA-DRB, -DQA and -DQB were determined by Taq I restriction fragment length polymorphism analysis. Amplification by polymerase chain reaction (PCR) and hybridization with sequence-specific oligonucleotide probes was done for DQA1, DQB1 and DRB1 and DRB5. DR2 was positive in 11/425 patients (3%) and 101/367 (28%) controls (OR 0.07, p < 0.0001). Of the 11 DR2-positive patients, PCR was done in 10, of whom 8 were positive for DRB1*1601-DRB5*0201 compared to 4/96 (4%) controls (OR 92.0: p < 0.001) while the remaining 2 were positive for DRB1*1501-DRB5*0101 compared to 92/96 (96%, OR 0.01; p < 0.001). In 2 patients, a recombination between the haplotypes DQB1*0502-DQA1*0102 (DQ5)-DRB1*1601-DRB5*0201 (DR16 Dw21) and DQB1*0301-DQA1*0501 (DQ7)-DRB1*1602-DRB5*0202 (DR16 Dw22) was observed resulting in the DQB1*0301-DQA1*0501 (DQ7) DRB1*1601-DRB5*0201 (DR16 Dw22) haplotypes. The second haplotype was DR3 DQ2 in 6/11 and DR4 DQ8 in 2/11 DR2-positive patients. In all 3 DQB1*0602-DQA1*0102-DR15-positive patients the second haplotype was DR4-positive. In order to test whether physicochemical properties of the DR2 molecules were associated with IDDM, we constructed three-dimensional models of the peptide binding and T-cell recognition sites (alpha 1 and beta 1 domains) of five subtypes of DR2-DRB1, based on the published DR1 crystal structure. No correlations were observed for DR molecule physicochemical properties and diabetes susceptibility. Islet cell antibodies, insulin autoantibodies and GAD65 antibodies, were measured in DR2-positive patients (n = 11) and controls (n = 101). Despite the presence of the DR2 haplotype the antibody markers were significantly elevated in the patients compared to the controls (GAD65 3/10 patients and 2/101 controls; ICA 7/11 patients and 1/101 controls and IAA 3/11 patients and 0/101 controls). In conclusion, of the five subtypes of DR2, only one, the DRB1*1501, DRB5*0101, DQB1*0602-DQA1*0102 haplotype, was negatively associated with IDDM. DQ may therefore confer more protection from the disease than DR.
Alleles↗
Non-genetic risk determinants for type 1 (insulin-dependent) diabetes mellitus in childhood. Hungarian Childhood Diabetes Epidemiology Study Group.
Using the prospective Hungarian childhood diabetes register, a nationwide case-control study was carried out to investigate the possible role of various non-genetic factors as risk determinants for type 1 diabetes in childhood. A questionnaire (covering family characteristics, social status, fetal and perinatal events, breast-feeding habits, infectious diseases and stressful life events) was sent by mail to all incident diabetic children in 1990 (n = 163) and to two referent children (for each diabetic child), matched for age, sex and county. Diabetic children had a tendency to have mothers > 35 years of age (odds ratio (OR) = 3.52; 95% confidence intervals (CI) 0.74-16.79), a lower proportion of their mothers had higher education (OR = 1.69; 95% CI 0.95-3.0) and these children tended to move home more frequently (OR = 1.99; 95% CI 0.97-4.1). Although the duration of exclusive breast feeding was similar in both groups, the proportion of diabetic children who received no breast milk tended to be higher (OR = 1.76; 95% CI 0.91-3.4). A higher proportion of diabetic children reported non-specific infections (OR = 2.94; 95% CI 1.19-7.21) and the number of stressful life events was higher in diabetic children aged 10-14 years (OR = 3.9; 95% CI 1.14-13.27). As the risk determinants for childhood insulin-dependent diabetes mellitus identified in our low-risk population appear to be similar to those detected in the genetically different, high-risk Swedish population, our study strongly supports an etiological role for these non-genetic risk factors in IDDM.
Adolescent↗
Relationship between early metabolic control and the development of microalbuminuria--a longitudinal study in children with type 1 (insulin-dependent) diabetes mellitus.
The cumulative incidence of microalbuminuria from onset up to 15 years of Type 1 (insulin-dependent) diabetes mellitus and the relative importance of age, duration, blood pressure and metabolic control for subsequent microalbuminuria was studied in 156 children. Urinary albumin excretion and HbA1c were followed at 3-month intervals from onset and systolic and diastolic blood pressure at the same interval from 5 years of diabetes. Persistent microalbuminuria over 20 micrograms/min developed in 17 children. The cumulative incidence by duration was 24.2% at 15 years of diabetes. Eleven patients developed microalbuminuria after more than 5 years. Among these, first 5-year mean HbA1c was 8.4 +/- 1.3% vs 7.2 +/- 1.1% in normoalbuminuric children (p < 0.001). The crude relative risk of developing microalbuminuria with a first 5-year mean HbA1c greater than 7.5% was 4.49 (95% confidence interval 1.13-17.84). The age- and duration-adjusted relative risk was 3.51% (0.90-14.42). The year before transition to microalbuminuria neither mean HbA1c nor yearly mean blood pressures, sex or age at onset of diabetes differed from normoalbuminuric children at the same diabetes duration. Age and duration were higher (p = 0.04). The relative importance of early vs later hyperglycaemia, yearly blood pressures, age, age at onset and duration of diabetes for increased albumin excretion rate after more than 5 years, was shown in a multiple regression analysis where the first 5-year mean HbA1c was the only independent predictor (p = 0.02). Six patients had an onset of microalbuminuria before 5 years of diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Proinsulin levels in newborn siblings of type 1 (insulin-dependent) diabetic children and their mothers.
Elevated proinsulin levels have been observed in healthy first degree relatives of Type 1 (insulin-dependent) diabetic patients. This elevation could reflect a sequele after a previous attack on the beta-cells not necessarily leading to diabetes, or represent a family trait related to the development of diabetes. When cord plasma levels of proinsulin, insulin and C-peptide from 14 newborn siblings of Type 1 diabetic patients were compared with 21 newborn control siblings unrelated to diabetic subjects, no differences were observed. Neither were any differences observed between their mothers at delivery when comparing the same parameters. In cord plasma the proinsulin levels (median and range) were higher than those in plasma from 35 adult fasting women unrelated to diabetic subjects (10, 5-83 pmol/l vs 4, 2-33 pmol/l; p < 0.001) whereas the C-peptide levels (median and range) were lower (0.20, 0.11-0.56 nmol/l vs 0.37, 0.21-0.69 nmol/l; p < 0.001). No differences in insulin levels using a highly specific insulin assay were observed. The results suggest that newborn children have high proinsulin and low C-peptide levels unrelated to heredity of diabetes and that the previously described elevated proinsulin level observed in older first degree relatives of diabetic subjects occurs later in life.
Adult↗
Indomethacin but not metoprolol reduces exercise-induced albumin excretion rate in type 1 diabetic patients with microalbuminuria.
The effects of a single oral dose of indomethacin (1 mg kg-1) metoprolol (1.5 mg kg-1) and placebo on exercise-induced albumin excretion rate (AER) were compared in a randomized, crossover design in 14 normotensive, young Type 1 diabetes patients, nine of them with microalbuminuria (AER > 15 micrograms min-1) and five without microalbuminuria at rest. The albumin excretion rate, blood pressure, heart rate, blood glucose, and plasma concentrations of indomethacin and metoprolol were determined before and after 30 min submaximal physical exercise. In microalbuminuric patients the rise in albumin excretion rate after exercise on indomethacin (7 micrograms min-1) was lower than after placebo (29 micrograms min-1, p < 0.001) whereas the rise in albumin excretion rate with metoprolol during exercise (18 micrograms min-1) did not differ from placebo (p = 0.48), in spite of the expected less marked increase in blood pressure. In normoalbuminuric patients no significant increase in albumin excretion rate was noted by exercise in any of the treatment periods. A tendency to a linear correlation (r = -0.54, p = 0.07) was seen between the plasma concentration of indomethacin and the inhibition of exercise-induced increase in albumin excretion rate. No correlations were observed between exercise-induced changes in albumin excretion rate and systolic blood pressure, heart rate or blood glucose. In conclusion, acute indomethacin treatment, presumably through inhibition of renal prostaglandin synthesis, reduces the exercise-induced rise in albumin excretion rate in Type 1 diabetic patients with microalbuminuria.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Etiological aspects of insulin-dependent diabetes mellitus: an epidemiological perspective.
The mechanism of beta-cell destruction leading to insulin dependent diabetes is probably a cell mediated auto-immune process occurring in genetically susceptible individuals. Since 50-70% of monozygotic twins will not get the disease non-genetic risk factors must play an important role in the etiology of the disease. During the past decade population based epidemiological studies have identified several risk determinants for insulin dependent diabetes. Based on these studies a multifactorial hypothesis of causation is proposed. Some risk determinants (maternal child blood group incompatibility, fetal viral infections, early exposure to cow's milk proteins, a high exposure level of nitrosamines) may independently initiate the autoimmune process by causing the initial damage of the beta-cell, leading to antigen release. Other risk determinants may promote an already ongoing autoimmune destructive process through induction of lymphokine release or by causing an increased work load on the beta-cell. Risk factors that may increase the peripheral need for insulin (infectious diseases, cold environment, a high growth rate and stressful life events) may act as promoters of the beta-cell destruction but also disclose the beta-cell impairment and make the disease clinically overt. Possibilities of different risk profiles in different age groups and of synergism between different risk factors are also discussed.
Autoimmune Diseases↗
[New discoveries on the etiology of type 1 diabetes--an example of molecular epidemiology].
During the past decade the incidence of type 1 diabetes has been on the increase in Sweden, as it has in many other Western countries. The paper consists in a review of new hypothesis as to the pathogenesis of disease, resulting from findings in intensive molecular, genetic, immunological and epidemiological studies. Reversal of the rising trend in the incidence of type 1 diabetes is dependent upon further detailed elucidation of the molecular biology of the genetic and immunological markers of the disease, and their predictive value in population based studies. The currently identified risk factors, which may be initiators or promoters of diabetes pathogenesis, also need to be further elucidated, for which purpose a molecular epidemiological strategy is recommended, as it has already been found to be a successful approach in studies of type 1 diabetes.
Autoimmunity↗