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IDDM is positively associated with HLA-DQA10301-DQB10302 (DQ8) and DQA10501-DQB10201 (DQ2) and negatively associated with DQA10102-DQB10602 (DQ6). The aim of the present study was to analyze the importance of several polymorphic residues and domains of DQ? and DQ?, in addition to residue 52 DQ? and residue 57 DQ?, with regard to susceptibility or resistance in new-onset 0- to 15-year-old Swedish children with IDDM ( n 425 ) and matched controls ( n 367 ). HLA genotyping identified several polymorphic residues of the DQ? and DQ? to be either positively or negatively associated with IDDM, including Arg 52 DQ? and Asp 57 DQ?. Leu 69 DQ? was positively (OR 7.02, P< 0.0001 ), Ala 69 DQ? was negatively (OR 0.22, P< 0.0001 ), Gln 47 DQ? was positively (OR 5.8, P< 0.0001 ), Cys 47 DQ? was positively (OR 2.2, P< 0.0001 ), Lys 47 DQ? was negatively (OR 0.47, P< 0.005 ), and Arg 47 DQ? was negatively (OR 0.22, P< 0.005 ) associated with IDDM. Similarly, residues at 11, 18, 45, 48, 50, 53, 55, 61, 64, 66, 76, and 80 were either positively or negatively associated with IDDM. Likewise, for DQ?, Leu 53 DQ? was positively (OR 11.01, P< 0.0001 ), Gln 53 DQ? was negatively (OR 0.22, P< 0.0005 ), Arg 70 DQ? was positively (OR 11.01, P< 0.0001 ), and Gly 70 DQ? was negatively (OR 0.19, P< 0.0001 ) associated like other residues at 71, 74, 84, 85, 86, 89, and 90 DQ? with IDDM. Certain domains in the DQ?, RFTIL (at DQ? positions 52, 61, 64, 66, and 69), were present in 95 of patients compared to 69 of controls (OR 9.01, Pc< 0.0001 ), and DQ? domain GR (at DQ? positions 45 and 70) was present in 95 of patients and 68 of controls (OR 8.68, P< 0.0001 ), which correlated better than the individual amino acid residues with IDDM. A combination of the DQ? and DQ? chain domains was present in 94 of patients compared to 60 of controls (OR 10.6, P< 0.001 ). In conclusion, domains in the DQ?, DQ?, or both in the DQ molecule explain susceptibility or resistance to IDDM better than individual amino acid residues of DQA1 and DQB1.

Predictors of diabetic nephropathy are only partly known. The role of glomerular hyperfiltration is much discussed. We have studied the cumulative incidence of micro and macroalbuminuria and the predictive value of glomerular filtration rate (GFR) and screening value of albumin excretion rate (AER) in type-1 diabetes.

Hyperglycaemia and increased variability of blood glucose in pubertal children with type 1 diabetes may be related to increased growth hormone (GH) secretion and insulin resistance. The role of changes in insulin-like growth factor-I (IGF-I) bioavailability for the glycaemic control in these patients has not been completely elucidated. In particular, the possible role of increased IGF binding protein-3 (IGFBP-3) proteolysis reported in other insulin resistant states awaits further characterization. The aims of this study were to assess if hyperglycaemia in children with type 1 diabetes was associated with changes in free dissociable IGF-I (fdIGF-I) and IGF binding protein-3 protease activity (IGFBP-3-PA) and if increased insulin resistance during puberty was associated with changes in IGFBP-3-PA in healthy and diabetic children. In diabetic boys in the period of maximal linear growth (Tanner stage 3, n= 5), the mean level and the variability of IGFBP-3-PA, determined every second hour throughout 24 h, were significantly higher both compared to postpubertal diabetic boys (n= 6;P= 0.003 and P= 0.001, respectively), and to age matched healthy boys (n= 4;P= 0.006 and P= 0.03). We speculate that the elevated levels of IGFBP-3-PA in Tanner 3 diabetic boys are related to deteriorated glucose homeostasis and that it may be a compensatory mechanism to attenuate the decrease in fdIGF-I in order to partly restore insulin sensitivity and glycemic control.

Aims/hypothesis. To investigate the influence of angiotensin converting enzyme inhibitors and beta blockers on the progression of early diabetic glomerulopathy. Methods. Thirteen patients with Type I (insulin-dependent) diabetes mellitus (mean age 18.8 years) with microalbuminuria 31 (19–160) μg/min were randomised to treatment with enalapril (group 1, n= 7) or metoprolol (group 2, n= 6). Renal biopsies were taken before and after 38 (36–48) months of treatment. Albumin excretion rate, blood pressure and HbA1 cwere measured every third month. A reference group without antihypertensive treatment (group 3, n= 9), with similar age, diabetes duration and degree of microalbuminuria as group 1 and 2, had baseline and follow-up renal biopsies taken previously with an interval of 26–34 months, analysed at the same laboratory. Glomerular structures were measured by stereological methods. Results. Measurements of basement membrane thickness, mesangial and matrix volume fractions were similar among groups at baseline. Structural variables were only increased in group 3 at follow-up. Delta values in basement membrane thickness and diabetic glomerulopathy index per 24 months were lower in group 1 and 2 than in group 3 (p< 0.05). Microalbuminuria returned to normal in group 1 and 2 only. Decreased albumin excretion rate tended to inversely correlate with increased basement membrane thickness (p= 0.08) and diabetic glomerulopathy index (p= 0.05). Mean HbA1 cwas similar between groups. Mean diastolic blood pressure was lower in group 1 and 2 than in group 3 (p< 0.01). Mean HbA1 cand mean diastolic blood pressure correlated to changes in basement membrane thickness, mesangial volume fraction and diabetic glomerulopathy index (p <0.05). Conclusion/interpretation. Contrary to findings in the group without antihypertensive treatment, no progression of glomerulopathy was seen in those treated with enalapril or metoprolol. [Diabetologia (1999) 42: 589–595]Aims/hypothesis. To investigate the influence of angiotensin converting enzyme inhibitors and beta blockers on the progression of early diabetic glomerulopathy. Methods. Thirteen patients with Type I (insulin-dependent) diabetes mellitus (mean age 18.8 years) with microalbuminuria 31 (19–160) μg/min were randomised to treatment with enalapril (group 1, n= 7) or metoprolol (group 2, n= 6). Renal biopsies were taken before and after 38 (36–48) months of treatment. Albumin excretion rate, blood pressure and HbA1 cwere measured every third month. A reference group without antihypertensive treatment (group 3, n= 9), with similar age, diabetes duration and degree of microalbuminuria as group 1 and 2, had baseline and follow-up renal biopsies taken previously with an interval of 26–34 months, analysed at the same laboratory. Glomerular structures were measured by stereological methods. Results. Measurements of basement membrane thickness, mesangial and matrix volume fractions were similar among groups at baseline. Structural variables were only increased in group 3 at follow-up. Delta values in basement membrane thickness and diabetic glomerulopathy index per 24 months were lower in group 1 and 2 than in group 3 (p< 0.05). Microalbuminuria returned to normal in group 1 and 2 only. Decreased albumin excretion rate tended to inversely correlate with increased basement membrane thickness (p= 0.08) and diabetic glomerulopathy index (p= 0.05). Mean HbA1 cwas similar between groups. Mean diastolic blood pressure was lower in group 1 and 2 than in group 3 (p< 0.01). Mean HbA1 cand mean diastolic blood pressure correlated to changes in basement membrane thickness, mesangial volume fraction and diabetic glomerulopathy index (p <0.05). Conclusion/interpretation. Contrary to findings in the group without antihypertensive treatment, no progression of glomerulopathy was seen in those treated with enalapril or metoprolol. [Diabetologia (1999) 42: 589–595]

Vision-threatening diabetic retinopathy can be prevented if it is diagnosed before becoming too advanced. Since diabetic retinopathy has been reported to occur only rarely before the end of pubertal development, children and adolescents are seldom included in screening programmes. We invited 780 children and adolescents with insulin-dependent diabetes mellitus diagnosed before the age of 15.0 years (disease duration of < 12 years) and who were older than 9.0 years at the time of examination from eight regions of Sweden. Retinal examination was performed with stereoscopic fundus photograph. The photograph were rated according to a modified Airlie House classification. The dropouts (223/780, 28.6 %) were significantly older and with a longer duration of diabetes than the examined children (p< 0.001 and 0.001, respectively). Photographs from 557 patients aged (median [interquartile range]:14.6 [12.4–17.0]) years and with a diabetes duration of 8.0 (5.5–9.9) years were evaluated. Retinopathy was demonstrated in 81 patients (14.5 %):66 with background retinopathy, 2 with microaneurysms and hard exudates, 12 with preproliferative retinopathy, 1 with proliferative retinopathy. Preproliferative retinopathy was diagnosed in a 12.8-year-old girl in pubertal stage 3 and an 11.8-year-old boy in pubertal stage 2, and proliferative retinopathy was found in a 21.5-year-old girl. Retinopathy was demonstrated in 6 % and 18 % of patients in pubertal stages 1 and 5, respectively. The overall prevalence of retinopathy in this population may even be higher since the dropouts were older and had a longer duration of diabetes. Since background and preproliferative retinopathy were found in children before puberty, we recommend including children and adolescents in screening programmes for diabetic retinopathy from the age of 10 years. [Diabetologia (1997) 40: 307–310]Vision-threatening diabetic retinopathy can be prevented if it is diagnosed before becoming too advanced. Since diabetic retinopathy has been reported to occur only rarely before the end of pubertal development, children and adolescents are seldom included in screening programmes. We invited 780 children and adolescents with insulin-dependent diabetes mellitus diagnosed before the age of 15.0 years (disease duration of < 12 years) and who were older than 9.0 years at the time of examination from eight regions of Sweden. Retinal examination was performed with stereoscopic fundus photograph. The photograph were rated according to a modified Airlie House classification. The dropouts (223/780, 28.6 %) were significantly older and with a longer duration of diabetes than the examined children (p< 0.001 and 0.001, respectively). Photographs from 557 patients aged (median [interquartile range]:14.6 [12.4–17.0]) years and with a diabetes duration of 8.0 (5.5–9.9) years were evaluated. Retinopathy was demonstrated in 81 patients (14.5 %):66 with background retinopathy, 2 with microaneurysms and hard exudates, 12 with preproliferative retinopathy, 1 with proliferative retinopathy. Preproliferative retinopathy was diagnosed in a 12.8-year-old girl in pubertal stage 3 and an 11.8-year-old boy in pubertal stage 2, and proliferative retinopathy was found in a 21.5-year-old girl. Retinopathy was demonstrated in 6 % and 18 % of patients in pubertal stages 1 and 5, respectively. The overall prevalence of retinopathy in this population may even be higher since the dropouts were older and had a longer duration of diabetes. Since background and preproliferative retinopathy were found in children before puberty, we recommend including children and adolescents in screening programmes for diabetic retinopathy from the age of 10 years. [Diabetologia (1997) 40: 307–310]

Extract: Cerebral blood flow (CBF) was measured by means of 141Celabeled microspheres in infant (20-day-old) and adult (3-month-old) rats, anesthetised with Na-5-ethyl-5-(l-methylpropyl)2-thio-barbituric acid. Cerebral arteriovenous differences of acetoacetate, D-ß-hydroxybutyrate, glucose, lactate, and oxygen and brain DNA content were determined in other groups of similarly treated infant and adult animals fed or starved for 48 or 72 hr.The mean CBF values of 0.48 ± 0.04 and 0.62 ± 0.07 ml/(g × min), ± SEM, in infant and adult animals, respectively, were not significantly different. CBF was unaffected by starvation.At any given arterial concentration the cerebral arteriovenous difference of acetoacetate was significantly higher in infant than adult rats. The same was true for D-ß-hydroxybutyrate at arterial concentrations above 1 mmol/liter. There was an approximately linear relationship between arterial concentration of acetoacetate and its cerebral arteriovenous difference in both infant and adult rats. A similar relationship was found for D-ß-hydroxybutyrate only in infant animals.In the fed state, the cerebral uptake of glucose and ketone bodies (micromoles per (mg DNA × min)) was not different in infant and adult rats. During starvation, cerebral uptake of ketone bodies expressed as micromoles per (mg DNA × min) was higher in infant than adult rats, indicating a higher rate of utilization of ketone bodies per cell in these animals. For glucose, no such difference was found in either fed or starved groups (Table 3). The average percentage of the total cerebral uptake of substrates (micromoles per min) accounted for by ketone bodies increased in both infant and adult rats during starvation. This percentage value was clearly higher in infant than adult rats during starvation. After 72 hr of starvation the values were 38.8% and 15.2% in infant and adult rats, respectively (Fig. 3).Calculated cerebral metabolic rate for oxygen (CMRO2), assuming complete oxidation of glucose and ketone bodies and expressed as micromoles per (mg DNA × min), was similar in fed and starved rats of both age groups (Table 3), indicating that ketone bodies serve as an alternative substrate for glucose during starvation. Calculated CMRO2for glucose plus ketone bodies was similar to the measured CMRO2in adult rats both in the fed and the starved groups. For infant rats, calculated CMRO2for glucose plus ketone bodies was higher than measured CMRO2, indicating that in this age group a portion of substrate was used for synthesis or storage rather than for complete oxidation.Speculation: The present study supports the concept that during the period of maximum myelination in rat brain, when the need of substrate for synthesis of lipid and protein is great, the infant rat brain is adapted to a higher utilization of D-ß-hydroxybutyrate and acetoacetate than later on in life. Thus, during starvation when glucose supply is limited but acetoacetate and D-ß-hydroxybutyrate are available, the synthesis of myelin could be preserved.

The postnatal development of the activity of D-β-hydroxybutyrate dehydrogenase in brain mitochondria was studied in rats with experimentally induced intrauterine growth retardation as compared to normal littermates. Variances in weight of the newborn animals were greater between than within litters, therefore the paired t test was used when analyzing possible differences between intrauterine growth retarded (IUGR) animals and controls. IUGR animals remained smaller as estimated by length and weight than their normal littermates up to the age of 60 days. Brain weight was reduced in newborn and 5-day-old IUGR rats but the brain-body ratio was increased from birth up to 60 days of age. At 20 days of age, when the activity of the enzyme reached a peak value, the growth retarded animals had a significantly lower activity of D-β-hydroxybutyrate dehydrogenase as compared to controls. Plasma glucose concentrations were significantly lower in newborn and 10-day-old IUGR rats as compared to controls. Plasma concentrations of .D-β-hydroxybutyrate and acetoacetate were higher during the suckling period than after weaning, but there were no differences between the growth retarded animals and their normal littermates.

Using a case-control design we have studied whether antibodies to cow's milk proteins are risk determinants for childhood-onset Type 1 (insulin-dependent) diabetes mellitus independent of early exposure to cow's milk formula and islet cell antibodies. Sera from 116 recentonset diabetic children and 112 age- and sex- matched control children were analysed for cow's milk protein IgA, IgG and IgM antibodies, β-lactoglobulin IgA and IgM antibodies and islet cell antibodies. The titres were compared to questionnaire data on duration of breast-feeding and introduction of formula feeding. Most antibody levels tended to be increased among diabetic compared to control children. This was statistically significant for cow's milk protein IgA antibodies (p<0.001) and β-ltoglobulin IgA antibodies (p<0.01) as well as for islet cell antibody-positivity which was found among 92% of the diabetic and 3% of control children. The differences in cow's milk protein antibodies as well as β-lactoglobulin antibodies were more pronounced among children with an early onset of Type 1 diabetes. Breast-feeding duration was significantly inversely related to the log of β-Mactoglobulin IgG (r= −0.16, p= 0.04) and the log of cow's milk protein IgA antibodies (r = −0.17, p<0.001). A positive correlation was found between formula feeding and the logarithm of β-lactoglobulin IgG antibodies (r= 0.22, p= 0.01) and the log of cow's milk protein IgA antibodies (r= 0.16, p= 0.04). In a multiple logistic regression analysis it was found that IgA antibodies to β-lactoglobulin and cow's milk protein were significantly related to the risk of Type 1 diabetes independent of islet cell antibodies. When introducing formula feeding before the age of 4 months as a variable in the regression it was shown that islet cell antibodies and β-lactoglobulin IgA antibodies were still significantly and independently related to an increased risk of diabetes whereas cow's milk protein IgA antibodies did not add further to the regression. It is concluded that β-lactoglobulin IgA antibodies are significantly associated with an increased risk of diabetes at a young age independent of islet cell antibody-status and of an early weaning to cow's milk formula. In genetically susceptible children early exposure to β-actoglobulin might be one trigger in the autoimmune process leading to development of Type 1 diabetes.

Most studies evaluating immune markers for prediction of Type 1 (insulin-dependent) diabetes mellitus have focused on first degree relatives, although only 10 % of newly-diagnosed patients have an affected first degree relative. The Swedish Childhood Diabetes Register identifies 99 % of all diabetic children at diagnosis. In this population-based study, islet cell antibodies and insulin autoantibodies in 0–14-year-old Swedish consecutively-diagnosed patients and control subjects were analysed to define their sensitivity and specificity. Over 16 months (1986–1987), 515 Swedish children developed diabetes. Plasma samples were obtained from 494 (96 %) patients, and 420 matched control children. Among patients, the frequency of islet cell antibodies was 84 % (415 of 494), insulin autoantibodies 43 % (145 of 334); 40 % (135 of 334) were positive for both and 88 % (294 of 334) were positive for one or both. Among control children, 3 % (14 of 420) had islet cell antibodies, 1 % (4 of 390) insulin autoantibodies, and 4 % (16 of 390) had either autoantibody marker. The predictive value of finding a patient with the disease was only 7% since 4 % of the control children were antibody-positive and the cumulative incidence rate up to 15 years of age is 0.38 %. None of the autoantibody-positive (n= 21) or negative control children developed diabetes during 3 to 5 years of follow-up. Longitudinal investigations of islet cell or insulin-autoantibody-positive healthy children are necessary to accurately determine the conversion rate from marker positivity to disease onset.

The nationwide Swedish Childhood Diabetes Registry, which ascertains 99% of recent-onset Type 1 (insulin-dependent) diabetic children (0–14 years) in Sweden, was linked with the Swedish Medical Birth Registry. A matched case-control study was carried out analysing about 20 perinatal variables concerning mother and child. A total of 2757 infants who became diabetic during the period 1978–1988 were analysed. For each case infant three control children were randomly selected from among all infants born in the same year and at the same delivery unit as the case infant. The following statistically significant risk factors were identified for Type 1 diabetes with an onset before 15 years of age: maternal diabetes (OR=3.90), maternal age above 35 (OR=1.36), maternal non-smoking (OR=1.54), pre-ec-lamptic toxaemia (OR=1.19), caesarian section (OR=1.32), and maternal-child blood group incompatibility (OR=1.61). When the analysis was restricted to Type 1 diabetes with an onset before the age of 5 years, most odds ratios were increased — for blood group incompatibility OR=3.86 (95% confidence interval 1.54–9.65). Icterus without blood group incompatibility was not a significant risk factor. When each risk factor was analysed after standardization for all other risk factors, the odds ratios remained significantly increased. Scrutiny of medical records for cases and control children with a diagnosis of blood group incompatibility verified the diagnosis in close to 90% of children. The more severe cases needing phototherapy and/or blood transfusion were found to have a greater risk than milder cases. In conclusion, an early immunological event due to maternal-child blood group incompatibility, known to be associated with neonatal Beta-cell dysfunction, represents an increased risk for Type 1 diabetes in young children. Other stressful perinatal events may also be risk factors for Type 1 diabetes.

The effect of fetal insulin injection on body weight and carcass lipid and nitrogen content was studied in four groups of rat fetuses. In each litter, one fetus in each horn was randomly chosen for treatment with either insulin injection, saline injection, insulin solvent injection or sham operation. Injections were given subcutaneously to the fetuses on days 18½, 19½ and 20½ of gestation. The experimental model and the statistical evaluation took into consideration the influence of the fetal position in the uterine horn as well as the variability of fetal size between different litters. Using this experimental model we found that insulin injections to the fetal rat had no effect on body weight and body composition.

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 HbA1cwere 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 μg/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 Hb A1cwas 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 HbA1cgreater 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 HbA1cnor 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 HbA1cwas the only independent predictor (p= 0.02). Six patients had an onset of microalbuminuria before 5 years of diabetes. In this group age, age at onset and yearly mean HbA1clevels did not differ from normoalbuminuric children at the same duration. We conclude that one-fourth of diabetic youth under the age of 21 years develop microalbuminuria within 14 years of diagnosis. Some patients have an early onset of microalbuminuria, not necessarily related to hyperglycaemia, while in later onset cases early hyperglycaemia is strongly related to subsequent microalbuminuria.

Insulin release and growth are intimately connected. The aim of the present study was to investigate height and weight in diabetic children from birth to onset of Type 1 (insulin-dependent) diabetes mellitus compared to that in referent children. Data on height and weight were collected from mailed questionnaires and from growth records obtained from the child health clinics and schools in 337 recentonset diabetic children, 0–14 years old, and from 517 age-, sex-, and geographically matched referent children. A total of 9002 paired height and weight observations were collected. The anthropometric development of the children was expressed as standard deviation scores using the National Center for Health Statistics/Centers for Disease Control (NCHS/CDC) growth reference material. On the average, the diabetic children were consistently taller than the referent children, a finding more pronounced among the boys. The diabetic boys were significantly taller from 7 to 1 years before the clinical onset of the disease, regardless of age at onset. A similar tendency was found for the girls. When mean height from 5 to 1 years before onset was used as a possible risk factor for diabetes, a linearly increasing trend in the odds ratio was found for diabetes in boys (odds ratio = 1.0; 1.57; 2.46 for height standard deviation score values <0; 0–1 and > 1, respectively; p=0.002 for trend). A similar, but statistically not significant, tendency was found for girls (odds ratio = 1.0; 1.44; 1.43). As regards height increment from birth similar trends in odds ratios were found. Weight-for-height was similar among diabetic and referent children of both sexes. We conclude that diabetic boys tend to be taller and grow faster than referent boys for several years preceding the disease. A similar, but not statistically significant tendency was found among diabetic girls. Our findings indicate that rapid linear growth is a risk factor for Type 1 diabetes in childhood, and may be either a promoter of Type 1 diabetes or else a marker of a physiological mechanism that affects both growth and the pathogenesis of Type 1 diabetes.

This study is part of a nationwide case-referent study. All recent-onset Type 1 (insulin-dependent) diabetic children aged 0–14 years in Sweden were invited to participate. Referent subjects matched for age-, sex- and geographical distribution were selected. In all, 338 patients and 528 referent subjects took part. Life events during the last year prior to clinical onset of Type 1 diabetes were recorded on a questionnaire. The total frequency of life events did not differ between diabetic and referent children. However, qualitatively the life events reported by diabetic children revealed a tendency to increased severity. Events related specifically to actual or threatened losses within the family — events that may affect children differently in different age groups — were reported with a significantly higher frequency by diabetic patients than by referent subjects, aged 5–9 years. The relative risk that such events in fact comprise a risk factor for Type 1 diabetes was 1.82 (95% confidence limits 1.09, 3.03). The relative risk was significantly increased even when standardized for possible confounding factors such as age, sex and indices of social status of the family. We conclude that stressful life events, related to actual or threatened losses within the family, occurring in the vulnerable age group of 5–9 years, are associated with the onset of childhood Type 1 diabetes. Such stressful events may in fact be a risk factor for the disease.

In a nationwide incident case-referent study stepwise univariate analysis has revealed several risk determinants for childhood diabetes mellitus. In a multivariate analysis we have determined the set of risk determinants that would independently predict childhood Type 1 (insulin-dependent) diabetes. Possible interactions between the risk determinants and differences in risk profiles with different ages at onset were also examined. Reported familial insulin-treated and non-insulin-treated diabetes were significant risk factors in all age groups, as was also a low frequency of milk intake. The frequency of infections and a high intake of foods rich in nitrosamine tended to interact (OR 11.8, p=0.053) indicating a synergistic effect. A Cox regression analysis revealed that stressful life events during the last year was the only variable that tended to affect the age at onset (p=0.055). This indicated that psychological stress may rather precipitate than induce Type 1 diabetes. A short breast-feeding duration (OR=3.81), and an increased body height (OR=3.82) contributed significantly to the predictive model in only the youngest age group (0–4 years). An increased frequency of infections in the year preceding onset (OR=2.15) and no vaccination against measles (OR=3.33) contributed significantly to the model only in the age group 5–9 years. Various nutrients had different impacts on the risk of developing Type 1 diabetes in different age groups. It is concluded that in the genetically susceptible child, risk factors which are associated with eating habits, frequency of infections, vaccination status, growth pattern and severe psychological stress affect the risk of developing diabetes independently of each other. The set of risk determinants varies with the age at onset. A high frequency of infections and a high frequency of nitrosamine-rich food intake seem to have a synergistic effect on the risk of developing diabetes in childhood.

In a nationwide incident case referent study we have evaluated vaccinations, early and recent infections and the use of medicines as possible risk determinants for Type 1 (insulin-dependent) diabetes mellitus in childhood. A total of 339 recently onset diabetic and 528 referent children, age 0–14 years, were included. Information about infections was collected from a mailed questionnaire and about vaccinations from childhood health care centres and schools. When vaccinations were considered as possible risk factors for diabetes, a significant decrease in relative risk estimated as odds ratio (OR) was noted for measles vaccination (OR=0.69; 95% confidence limits 0.48–0.98). For vaccination against tuberculosis, smallpox, tetanus, whooping cough, rubella and mumps no significant effect on OR for diabetes was found. The odds ratios for Type 1 diabetes for children exposed to 0, 1–2 or over 2 infections during the last year before diagnosis of diabetes revealed a linear increase (OR = 1.0,1.96 and 2.55 for 0, 1–2 and over 2 infections, respectively). The trend was still significant when standardized for possible confounders such as age and sex of the children, maternal age and education and intake of antibiotics and analgetics. In conclusion, a protective effect of measles vaccination for Type 1 diabetes in childhood is indicated as well as a possible causal relationship between the onset of the disease and the total load of recent infections.

Using the Swedish childhood diabetes register, a nationwide, case-referent study was performed from September 1, 1985 to August 31, 1986. Based on the information from a mailed questionnaire sent to all incident diabetic children and for each diabetic child — two referent children matched according to age, sex, and county, we have analysed perinatal events and aspects of the social environment as possible risk factors for Type 1 (insulin-dependent) diabetes in childhood. A significantly larger proportion of the mothers of the diabetic children were older than 40 years compared to those of the referent children (33% and 24%, p=0.01 respectively). A smaller percentage of mothers of the diabetic children had a high educational level compared to mothers of referent children (10% and 15%, p=0.03 respectively) and 39% of the fathers of the diabetic children were manual workers compared to 31% of the fathers of referent children (p=0.03). Perinatal events did not differ between diabetic and referent children. In children 0–6 years, the duration of breast-feeding was significantly shorter in diabetic children than among referent children (median duration for diabetic children 5 months compared to 6 months for referent children p=0.03). When considering the presence of Type 1 diabetes among relatives, maternal age over 40 years, low educational level of the mother, and the father being a manual worker as risk factors, the presence of 1 to 4 of any of these risk factors increased the relative risk for Type 1 diabetes cumulatively from 1.2–7.5. In conclusion, breast-feeding habits and probably other factors dependent on maternal age and the social status of the family may further increase the risk for Type 1 diabetes in genetically susceptible individuals.

From July 1, 1977 to July 1, 1986, 3,503 incident cases of Type 1 (insulin-dependent) diabetes mellitus were registered in the Swedish childhood diabetes study. Using data from this register and from a case-referent study, including all incident Type 1 diabetic children in Sweden during one year and, for each patient, two referent children matched according to age, sex and county, we have studied the associations between Type 1 diabetes and familial Type 1 and Type 2 (non-insulin-dependent) diabetes, thyroid, adrenal, allergic, rheumatic, heart and bowel disease. The mean annual incidence per 100,000 during the nine year period was 25.1 for boys and 23.5 for girls. In 8.5% of the patients, one parent had Type 1 diabetes, 73% of whom were fathers. Fifty-six of the patients (1.7%) had a parent with Type 2 diabetes. The prevalence of parental Type 1 diabetes tended to be higher in patients with younger age at onset; whereas, the opposite was found for patients with parental Type 2 diabetes. In the case-referent study, the age-adjusted odds ratio for Type 1 diabetes when a first and/or second degree relative had Type 1 diabetes was 5.5 (95% confidence limits 4.0–7.7), and in accordance with the findings of the case register, the odds ratio tended to be highest in patients with the youngest age at onset. Season at onset of the patients was not associated with parental Type 1 diabetes. The odds ratio for Type 1 diabetes was significantly increased 3.3 (95% confidence limits: 2.3–4.6) when Type 2 diabetes was reported in relatives (three generations). Odds ratios were also significantly increased (p(0.05) when thyroid or rheumatic diseases were reported among relatives. It is concluded that although the majority of incident Type 1 diabetic children lack family history, parental Type 1 diabetes may influence the age at onset of the disease but has no effect on sex distribution of these children. An increased risk for Type 1 diabetes in children is also indicated when Type 2 diabetes, (non-insulin-treated) thyroid or rheumatic disease is reported in relatives.

The influence of different protein intake on renal function was studied in 16 Type 1 (insulin-dependent) diabetic patients, aged 15–23 years, with onset of diabetes before puberty and with a duration of diabetes between 5 and 20 years. The glomerular filtration rate, renal plasma flow, albumin excretion rate, and blood pressure were examined in a cross-over randomised order after 10 days on isocaloric diets with either 10% (i.e. 0.9±0.06 g·kg−1·day−1) or 20% (1.9±0.1 g·kg−1·day−1) of the calories as protein, the latter being equal to the recommended diet. Dietary compliance was evaluated using fractional phosphate excretion and overnight urea excretion. Glomerular filtration rate was lower after the low-protein diet compared to the usual protein diet (p<0.001). Patients with glomerular filtration rate above +2 SD of the normal mean on the usual protein diet (n=6) exhibited the steepest fall in glomerular filtration rate with a mean decrease of 20ml/min compared to 7 ml/min in those with initially normal glomerular filtration (p=0.01). Filtration fraction tended to decrease on low protein diet, more so in initially hyperfiltering patients (p=0.09). Renal plasma flow remained unchanged. In patients with elevated glomerular filtration rate on usual protein diet, albumin excretion rate and systolic, but not diastolic blood pressure, were decreased on low protein diet (p=0.03 and p=0.01, respectively) but not in initially normal-filtering patients. Mean blood glucose and serum fructosamine were unchanged on both diets. In conclusion, low protein diet decreases glomerular filtration rate independently of glycaemic control in young Type 1 diabetic patients and more so in hyperfiltering patients. This decline in glomerular filtration rate is accompanied by a decrease in albumin excretion rate and systolic blood pressure in hyper-filtering patients.

The pattern of fall in B-cell function measured as plasma and 24 h urinary C-peptide excretion, as well as levels of islet cell antibodies, insulin antibodies and metabolic parameters, were followed for two years in 39 children aged 1–17 years prospectively from clinical onset of Type 1 (insulin-dependent) diabetes. At onset 32/36 patients had measurable plasma C-peptide (median 0.13 nmol/l). Maximum values of fasting and postprandial plasma C-peptide were reached at a median duration of three months. Thereafter both plasma and urinary C-peptide declined linearly. The median value of the rate of fall in postprandial plasma C-peptide was 0.019 nmol·1−1·month−1. Age at onset was positively correlated to the maximum value of postprandial plasma C-peptide in each patient (rs=0.57, p=0.0001) and throughout the observation time positively correlated to fasting and postprandial C-peptide and to the 24 h urinary C-peptide excretion (rsrange 0.35–0.70, p=0.03–0.0001). The rate of fall of postprandial C-peptide was unrelated to age at onset and was strikingly parallel in different age groups. Islet cell antibodies were present in 87% of the patients at onset and decreased to 38% at 24 months. Islet cell antibody litres were not correlated to age at onset or to plasma or urinary C-peptide at any single observation. However, islet cell antibody negative patients had significantly higher (p<0.05) postprandial plasma C-peptide values at 1, 9, and 12 months of duration, compared to islet cell antibody positive patients. Insulin antibodies and metabolic state at onset did not influence the C-peptide values. It is concluded that age at onset is the most important variable in predicting the duration and magnitude of endogenous insulin secretion during the first two years of Type 1 diabetes in children.

Sera from 40 Swedish children diagnosed as having Type 1 (insulin-dependent) diabetes mellitus during a one year period along with 40 age and geographically matched control subjects were tested for antibodies to a Mr-64000 islet protein by immunoprecipitation of 35S-methionine-labelled rat islet amphiphilic proteins. Of the 40 diabetic patients, 29 (73%) were found to be positive whereas all 40 control subjects were negative. Samples were also tested for titres of islet cell cytoplasmic antibodies by indirect immunofluorescence on frozen sections of human pancreas. In the diabetic group, 30 of the 40 patients (75%) were positive for islet cell cytoplasmic antibodies compared with 2 of the 40 control subjects (5%). A comparison of levels of antibodies to the Mr-64000 protein with islet cell cytoplasmic antibodies revealed a weak (rs=0.46), but significant (p<0.01) correlation between the two tests. There was no effect of age or sex on levels of antibodies to the Mr-64000 protein. These results in population-based diabetic children and control subjects demonstrate a high frequency of antibodies to the Mr-64000 protein at the time of clinical onset.