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.

Beneficial effects of C-peptide on incipient nephropathy and neuropathy in patients with Type 1 diabetes mellitus.

AIMS: Recent studies have indicated that proinsulin C-peptide shows specific binding to cell membrane binding sites and may exert biological effects when administered to patients with Type 1 diabetes mellitus. This study was undertaken to determine if combined treatment with C-peptide and insulin might reduce the level of microalbuminuria in patients with Type 1 diabetes and incipient nephropathy. METHODS: Twenty-one normotensive patients with microalbuminuria were studied for 6 months in a double-blind, randomized, cross-over design. The patients received s.c. injections of either human C-peptide (600 nmol/24 h) or placebo plus their regular insulin regimen for 3 months. RESULTS: Glycaemic control improved slightly during the study and to a similar extent in both treatment groups. Blood pressure was unaltered throughout the study. During the C-peptide treatment period, urinary albumin excretion decreased progressively on average from 58 microg/min (basal) to 34 microg/min (3 months, P < 0.01) and it tended to increase, but not significantly so, during the placebo period. The difference between the two treatment periods was statistically significant (P < 0.01). In the 12 patients with signs of autonomic neuropathy prior to the study, respiratory heart rate variability increased by 21 +/- 9% (P < 0.05) during treatment with C-peptide but was unaltered during placebo. Thermal thresholds were significantly improved during C-peptide treatment in comparison to placebo (n = 6, P < 0.05). CONCLUSION: These results indicate that combined treatment with C-peptide and insulin for 3 months may improve renal function by diminishing urinary albumin excretion and ameliorate autonomic and sensory nerve dysfunction in patients with Type 1 diabetes mellitus.

Morbidity and neurological function of very low birthweight infants from the newborn period to 4 y of age. A prospective study from the south-east region of Sweden.

All 107 infants weighing < or = 1500 g at birth (VLBW) and born alive in the south-east region of Sweden during a 15-month period in 1987-88 were enrolled in a prospective study to determine the prevalence of handicap and to assess neurological function in comparison with controls. Eighty-six (80%) infants survived. Twenty (19%) had intracranial haemorrhages (ICH) assessed by ultrasound examinations in the neonatal period and 2 (2.3%) retinopathy of prematurity stage 3 or more. The VLBW infants who survived had fewer optimal neurological responses than the controls at 40 weeks post-conceptional age. Eighty-two VLBW children were followed to 4 y of age. Three (4%) children had a neurological handicap and 9 (11%) had a moderate neurological deviation. Neither the size of ICH nor neonatal optimality score correlated to neurological outcome at 4 y of age. The VLBW children without neurological handicap or deviation (n = 70) had a delay in psychomotor development in comparison with the controls. Mental development and school performance, in particular language development, will be examined at school age.

Prevalence of diabetic retinopathy in children and adolescents with IDDM. A population-based multicentre study.

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.

Randomised placebo-controlled trial of human recombinant insulin-like growth factor I plus intensive insulin therapy in adolescents with insulin-dependent diabetes mellitus.

BACKGROUND: Good glycaemic control in insulin-dependent diabetes mellitus (IDDM) to prevent complications may be difficult to achieve during adolescence, because abnormalities in production of growth hormone or insulin-like growth-factor-I (IGF-I) can lead to lower insulin sensitivity. Recombinant human IGF-I (rhIGF-I) given as an adjunct to insulin therapy in IDDM, might improve glycaemic control in adolescents; we investigated the effects of the addition of IGF-I in a randomised, double-blind, placebo-controlled trial. METHODS: 53 patients with IDDM (26 male, 27 female) with a median age of 16.1 years (range 10.8-20.6) and diabetes of more than 2 years' duration were randomly assigned subcutaneous rhIGF-I (20 or 40 microg/kg daily [n=18, n=18, respectively]) or placebo (n=17), both in addition to multiple-injection insulin therapy for 24 weeks. The primary endpoint, glycated haemoglobin (HbA1c) and routine biochemistry were measured every 4 weeks. Retinal photographs and glomerular-filtration rates were assessed at base line and at the end of the study. Data were analysed by intention to treat. FINDINGS: With a dose of 40 microg/kg rhIGF-I daily, we found significant reductions in HbA1c compared with placebo (p=0.03), without changes in body-mass index, rate of hypoglycaemia, insulin dose, or circulating concentrations of IGF-binding proteins 1 and 3. The greatest median change in HbA1c of -0.6% (range -2.8 to -1.5%) was seen with rhIGF-I 40 microg/kg at week 12, but was not sustained at week 24. The greatest reductions in HbA1c at week 24 were seen among patients with the greatest changes in IGF-I concentrations (r=-0442, p=0.002). Retinal photographs, renal function (glomerular filtration rate and urinary albumin excretion), and routine biochemistry showed no adverse events. INTERPRETATION: Our data confirm that rhIGF-I as an adjunct to insulin therapy can improve HbA1c values in adolescents with IDDM without overt toxic effects, but they raise questions about whether these effects can be sustained in cases of poor compliance or reduced bioefficacy.

Influence of combined C-peptide and insulin administration on renal function and metabolic control in diabetes type 1.

The possible influence of C-peptide on renal function and metabolic control in patients with type 1 diabetes was examined in a double blind, randomized study. Nine patients received insulin and equimolar amounts of biosynthetic human C-peptide for 1 month (group 1), and nine were given insulin only (group 2). C-Peptide levels in plasma ranged from 0.3-2.6 nmol/L in group 1 during the study, whereas group 2 had undetectable levels. The urinary excretion of albumin in group 1 was 21 +/- 6 micrograms/min before the study and decreased by 40% and 55% after 2 and 4 weeks, respectively (P < 0.05). No change was seen in group 2. The glomerular filtration rate fell by 6% after 2 and 4 weeks (P < 0.05) in group 1, whereas no change was observed in group 2. Fluorescein leakage across the blood-retinal barrier decreased by 30% in group 1 (P < 0.05) and was unaltered in group 2. Hemoglobin-A1c and fructosamine values decreased by 9-16% in group 1 (P < 0.05), but not in group 2. The findings suggest that administration of C-peptide plus insulin, compared to insulin alone, to type 1 diabetic patients may reduce glomerular permeability and improve metabolic control.

Superoxide dismutase in the anterior chamber and the vitreous of diabetic patients.

Total superoxide dismutase (SOD) activity was examined in the anterior humor of 32 diabetic patients and 34 nondiabetic controls during cataract extraction. Median age (95% confidence interval) was 77.5 yr (73.3-81.0) and 79.3 yr (76.0-83.2), respectively. The SOD activity also was examined in posterior vitreous sampled peroperatively in 10 diabetics with proliferative retinopathy and post-mortem in seven diabetic patients and 35 nondiabetic controls. Ages were 57.2 yr (35.0-73.9), 74.4 yr (40.7-83.6), and 73.8 yr (65.0-80.2), respectively. In nondiabetic patients, the total SOD activity was much lower in the anterior chamber, 9.9 U/ml (8.1-12.6), than in the posterior vitreous, 106.3 U/ml (range 65.6-119.0), P < 0.001. We found no difference between the SOD levels in the anterior chamber of nondiabetic controls and diabetic patients, who had 9.6 U/ml (7.6-13.7). The SOD activity in posterior vitreous in diabetic patients sampled peroperatively, 23.9 U/ml (8.9-39.2), P < 0.0001, and post-mortem, 39.5 U/ml (6.5-214.2), P < 0.04, was significantly lower than in the controls sampled post-mortem, 106.3 U/ml (65.6-119.0). Low levels of SOD in the anterior chamber may be involved in cataract development, in diabetic patients and nondiabetic controls. That diabetics had decreased SOD activity in the posterior vitreous points to a possible role of SOD in the complex process of diabetic retinopathy development.

Vitreous fluorophotometry in juvenile diabetics with and without retinopathy in relation to metabolic control: insulin antibodies and c-peptide levels.

Vitreous fluorophotometry was performed in 56 juvenile insulin-dependent diabetic patients aged 9-23 years (median: 16 years), diabetes duration 1-20 years (median: 8 years). Fundus photography showed mild background retinopathy in 5 patients, while 51 patients had no signs of retinopathy. Abnormal leakage into the posterior vitreous body was found in 4/5 patients with background retinopathy and in 24/51 with normal fundi. We found a significantly positive correlation between abnormal leakage and duration of diabetes and HbA1 with Kendall rank-order correlation coefficients T = 0.21 (P = 0.01) and 0.19 (P = 0.02) resp. No significant correlation was found between leakage and age, actual blood glucose level or insulin antibodies expressed as insulin binding capacity of IgG, but a significantly negative correlation between abnormal leakage and low levels of fasting c-peptide/s T = 0.437 P less than 0.001. Kendall partial rank-order correlation analysis showed that c-peptide/s significantly explained the leakage when HbA1 or duration was kept constant. Duration could only explain leakage when HbA1 was fixed but not when c-peptide/s was kept constant. HbA1 could also explain leakage when duration or c-peptide was fixed.

Blood-retinal barriers in juvenile diabetics in relation to early clinical manifestations, HLA-DR types, and metabolic control.

Eighty-seven diabetics 8.5-26 years old (mean +/- SD 15.3 +/- 3.9) and 32 healthy non-diabetic controls 8-27 years old (13.9 +/- 4.3) were included in the study. They had had the disease for 2 months to 19 years (5.8-4.0 years). Seventy-two of the diabetic patients were HLA-DR type, 13 patients had DR 3 alone, 25 DR4, 33 DR 3,4 and 1 patient was neither DR 3 nor 4. The mean fluorescein concentration in the vitreous body 3.5-7 mm from the retinal surface at 60 min after intravenous administration of fluorescein was 15.5 +/- 11.9 ng/ml in the diabetics and 7.2 +/- 3.7 ng/ml in the non-diabetic controls (P less than 0.001). The diabetics still in partial remission had an almost normal blood-retinal barrier (BRB; 7.9 +/- 4.8 ng/ml) while about 55% of the diabetics beyond remission had impaired barrier function. Abnormal leakage was found in some patients who had had diabetes for less than 2 years and also before the onset of puberty. The incidence of abnormal leakage increased with increasing age and duration. There was a positive correlation between fluorescein leakage and the blood glucose level at the onset of diabetes (P less than 0.01). There was no statistically significant relationship between specific HLA-DR types and abnormal leakage. A defect BRB was significantly correlated with poor short-term metabolic controls, expressed as glucosuria index during the last week before examination with vitreous fluorophotometry. Prospective studies will show whether abnormal BRB gradually leads to irreversible retinopathy.

Influence of metabolic control on the blood-retinal barrier in streptozocin diabetic rats.

One hundred and eight male Sprague-Dawley rats weighing 160-225 g were examined with vitreous fluorophotometry (VF). Fifty-five rats were made diabetic with streptozocin (43 with 65 mg/kg and 12 with 90 mg/kg); 53 nondiabetic rats served as controls. Fluorescein (7 mg/kg) was injected IV and VF was performed 60 min later. The diabetic rats had an abnormal blood-retinal barrier (BRB) after 4-7 days duration. The difference between the diabetic and non-diabetic rats was persistent up to 35 days (P < 0.02-0.001). The diabetic rats treated with 90 mg/kg streptozotocin had a more severe diabetes and a higher treated with 65 mg/kg (P < 0.05). The BRB function was normalized in 18 rats treated for 6-7 days with 5-6 IU long-acting insulin (P < 0.02). The results imply that streptozocin-diabetic rats have an abnormal BRB and that this abnormality seems to be related to the diabetic state and to be reversible after insulin treatment.

Effect of insulin treatment on the blood-retinal barrier in rats with streptozocin-induced diabetes.

Eighteen rats were made diabetic with a single intravenous dose of streptozocin; 16 rats served as nondiabetic controls. Fluorescein sodium was injected into the tail vein for fluorophotometry. After insulin therapy, metabolic control was improved in the diabetic animals, but normoglycemia was not achieved. The vitreous fluorescein level in diabetic animals was significantly higher than in controls before insulin treatment, but it decreased after six to seven days of insulin therapy. There was no significant alteration of the fluorescein concentration in the vitreous body of the controls when vitreous fluorophotometry was repeated after six to seven days. The plasma fluorescein concentration was lower in the diabetic than in the nondiabetic animals and unaltered after insulin treatment. The results imply that the dysfunction of the blood-retinal barrier in the diabetic rats is reversible by insulin therapy. It is probably related to the diabetic state and not to a toxic effect of streptozocin.

Vitreous fluorophotometry in juvenile diabetes.

A group of 26 juvenile diabetics, 8-22 years old with a mean duration of diabetes of 7.8 +/- 5.7 years were examined by vitreous fluorophotometry. Eleven non-diabetic healthy individuals, 12-27 years old, served as controls. Vitreous fluorescein concentrations one hour after injection of fluorescein were higher in the diabetics than in the controls indicating an abnormal blood-retinal barrier. In diabetes beyond the partial remission period a pronounced leakage of fluorescein into the vitreous body occurred, while diabetics still in partial remission showed no such abnormal leakage. There were no significant correlations between a defect blood-retinal barrier and duration or age at onset of diabetes. Some diabetic patients showed an abnormal leakage with a duration of diabetes less than 2 years, while some other patients with a duration of more than 16 years did not have an abnormal blood-retinal barrier. The diabetics with defect blood-retinal barrier had a lower glucosuria index during the last year, indicating a more inadequate metabolic control than those patients who had a normal barrier. There was no relation between the actual blood-glucose value during the examination and abnormal leakage. In some diabetics, all beyond partial remission significantly elevated fluorescein concentrations were also found in the anterior parts of the vitreous body, indicating a break-down of the blood-aqueous barrier as well. In conclusion, vitreous fluorophotometry provides information about early, functional and possibly reversible retinal changes in juvenile diabetes. The observation that the blood-retinal barrier remained intact during the remission period supports the hypothesis that normoglycemic metabolic control is of importance for the preservation of a normal blood-retinal barrier function.

Benign meningococcemia in childhood. A report of five cases with clinical and diagnostic remarks.

Five children aged 1/2--10 years with benign meningococcemia are reported. The clinical picture was quite uniform: good general condition, spikes of fever, skin eruptions as maculopapules--sometimes haemorrhagic, appearing in association with febrile periods, and arthralgia (big joints). The diagnosis involves either isolation of meningococci (MC) from blood, demonstration of MC with immunofluorescence in skin eruptions, or a significant elevation of MC antibody titre in connection with typical clinical signs and symptoms. Important differential diagnoses are Henoch-Schönlein syndrome, disseminated gonococcal infection, septicemia of other origins, subacute bacterial endocarditis, viral infections, hypersensitivity reactions and subsepsis allergica. By co-agglutination technique, the causative agent of meningococcemia in 4 of the 5 children was shown to be MC group B. These have some features in common with gonococci, whereby an incorrect diagnosis might be suggested as demonstrated in one of our patients. The question is raised whether MC group B is the main causative agent in benign meningococcemia.