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Aim To determine the natural history and psychosocial predictors of disturbed eating behaviour in girls with Type 1 diabetes (T1D) over a 1-year period. Methods One hundred and six girls with T1D, 9–13 years of age at Time 1, completed a Children's Eating Disorder Examination (cEDE) interview at Time 1 and again 1 year later (Time 2). Potential Time 1 predictors of Time 2 disturbed eating behaviour were body mass index (BMI), self-esteem, depressive symptoms, attachment to parents, and parental eating attitudes. Glycated haemoglobin (HbA1c) was measured. Results Disturbed eating behaviour was reported by 14% (15/106) of girls at Time 1, and 17% (18/106) at Time 2, and persisted in 8/15 girls over 1 year. Lower self-esteem, higher BMI and more disturbed maternal eating attitudes at Time 1 accounted for 35% of the variance in Time 2 cEDE score, while higher BMI and more disturbed attachment to one's mother predicted new-onset disturbed eating behaviour at Time 2. Glycaemic control was not associated with or predicted by disturbed eating behaviour. Conclusions There was only moderate stability in disturbed eating behaviour status over a 1-year period. In this preliminary study, disturbed eating behaviour was associated with and, to a lesser degree, predicted by physical, psychological and family factors. Although the long-term clinical course of the mild disturbances identified is not known, prevention and early intervention efforts in this high-risk medical group should begin in the pre-teen years, and should probably target multiple factors in order to prevent the persistence and worsening of disturbed eating behaviour and its medical sequelae.

To evaluate the incidence of abnormal intracranial findings in children with central precocious puberty, 62 children (51 girls, 11 boys) were examined by computerized tomography and/or magnetic resonance imaging (MRI) of the brain. Forty-four had normal examinations; 18 (11 girls, 7 boys) showed intracranial pathologies, including hamartoma of the tuber cinereum (8 cases), parenchymal loss (3 cases), hypothalamic-chiasmatic lesions (2 cases), lesions of the corpus callosum (2 cases), suprasellar cyst (1 case), and pineal cyst and mesiotemporal sclerosis (1 case each). Based on the correlation between the clinical and the imaging results of this series, the authors recommend MRI as the imaging method of choice in the investigation of precocious puberty.

Patients with the highest albumin:creatinine ratio within the normal range are at an increased risk for developing microalbuminuria. The mechanistic basis for this is unknown, but may be related to renal inflammation. Our goal was to characterize the urinary excretion of cytokines/chemokines in normoalbuminuric adolescents with Type 1 diabetes to determine whether higher range normoalbuminuria is associated with evidence of renal inflammation.Forty-two urinary cytokines/chemokines were measured in subjects who were screened for the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial. Urinary cytokines/chemokines were compared across low (n = 50), middle (n = 50) or high (n = 50) albumin:creatinine ratio tertile groups.At baseline, participants in the upper tertile were younger and had shorter diabetes duration compared with the other groups. Other clinical characteristics were similar. Urinary levels of interleukin 6, interleukin 8, platelet-derived growth factor-AA and RANTES differed across albumin:creatinine ratio tertiles, with higher values in patients in the middle and high tertiles compared with the lower tertile (ANCOVA P ≤ 0.01).Within the normal albumin:creatinine ratio range, higher urinary albumin excretion is associated with elevated urinary levels of inflammatory markers. Ultimately, this may provide mechanistic insights into disease pathophysiology and stratify the risk of nephropathy in Type 1 diabetes.

To review and synthesize the published evidence on the possible association between childhood obesity and the subsequent risk of Type 1 diabetes.The PubMed database was systematically searched for studies using childhood obesity, BMI or %weight-for-height as the exposure variable and subsequent Type 1 diabetes as the outcome. Studies were only included if assessment of obesity preceded the diagnosis of Type 1 diabetes.Eight case-control studies and one cohort study were included, comprising a total of 2658 cases. Of these nine studies, seven reported a significant association between childhood obesity, BMI or %weight-for-height and increased risk for Type 1 diabetes. Meta-analysis of the four studies that reported childhood obesity as a categorical exposure produced a pooled odds ratio of 2.03 (95% CI 1.46-2.80) for subsequent Type 1 diabetes; however, in those studies, age at obesity assessment varied from age 1 to 12 years. A dose-response relationship was supported by a continuous association between childhood BMI and subsequent Type 1 diabetes in a meta-analysis of five studies (pooled odds ratio 1.25 (95%CI 1.04-1.51) per 1 sd higher BMI).There is overall evidence for an association between childhood obesity, or higher BMI, and increased risk of subsequent Type 1 diabetes. Several theories have been proposed for a causal relationship. Reduction in Type 1 diabetes should be considered as a potential additional benefit of preventing childhood obesity.

Insulin regimens and metabolic control in children and adolescents with Type 1 diabetes mellitus were evaluated in a cross-sectional, non-population-based investigation, involving 22 paediatric departments, from 18 countries in Europe, Japan, and North America. Blood samples and information were collected from 2873 children from March to August 1995. HbA1c was determined once and analysed centrally (normal range 4.4-6.3%, mean 5.4%). Year of birth, sex, duration of diabetes, height, body weight, number of daily insulin injections, types and doses of insulin were recorded. Average HbA1c in children under 11 years was 8.3 +/- 1.3% (mean +/- SD) compared with 8.9 +/- 1.8% in those aged 12-18 years. The average insulin dose per kg body weight was almost constant (0.65 U kg(-1) 24 h(-1)) in children aged 2-9 years for both sexes, but there was a sharp increase during the pubertal years, particularly in girls. The increase in BMI of children with diabetes was much faster during adolescence compared to healthy children, especially in females. Sixty per cent of the children (n = 1707) used two daily insulin injections while 37% (n = 1071) used three or more. Of those on two or three injections daily, 37% used pre-mixed insulins, either alone or in combination with short- and intermediate-acting insulin. Pre-adolescent children on pre-mixed insulin showed similar HbA1c levels to those on a combination of short- and long-acting insulins, whereas in adolescents significantly better HbA1c values were achieved with individual combinations. Very young children were treated with a higher proportion of long-acting insulin. Among adolescent boys, lower HbA1c was related to use of more short-acting insulin. This association was not found in girls. We conclude that numerous insulin injection regimens are currently used in paediatric diabetes centres around the world, with an increasing tendency towards intensive diabetes management, particularly in older adolescents. Nevertheless, the goal of near normoglycaemia is achieved in only a few.

Disordered eating attitudes and behavior are common and persistent in adolescent and young adult females with type 1 diabetes, and are associated with impaired metabolic control and a higher risk of diabetes-related complications. Specific aspects of diabetes and its management, e.g. weight gain associated with initiation of insulin treatment or improved metabolic control, and dietary restraint, may trigger the body dissatisfaction and drive for thinness that accompany eating disturbances. Health care providers should be aware of the possible association between eating disturbances and diabetes, and also of the types of behavior, particularly insulin omission for weight loss, that are common in these young women. Therapy will depend on the severity of the eating disturbance. Group psychoeducation, incorporating a nondeprivational approach to eating, may prove effective, especially in those with milder degrees of eating and weight psychopathology.

Apparent mineralocorticoid excess (AME) is a genetic disorder causing pre- and postnatal growth failure, juvenile hypertension, hypokalemic metabolic alkalosis, and hyporeninemic hypoaldosteronism due to a deficiency of 11 beta-hydroxysteroid dehydrogenase type 2 enzyme activity (11 beta HSD2). The 11 beta HSD2 enzyme is responsible for the conversion of cortisol to the inactive metabolite cortisone and therefore protects the mineralocorticoid receptors from cortisol intoxication. Several homozygous mutations are associated with this potentially fatal disease. We have examined the phenotype, biochemical features, and genotype of 14 patients with AME. All of the patients had characteristic signs of a severe 11 beta HSD2 defect. Birth weights were significantly lower than those of their unaffected sibs. The patients were short, underweight, and hypertensive for age. Variable damage of one or more organs (kidneys, retina, heart, and central nervous system) was found in all of the patients except one. The follow-up studies of end-organ damage after 2-13 yr of treatment in six patients demonstrated significant improvement in all patients. The urinary metabolites of cortisol demonstrated an abnormal ratio with predominance of cortisol metabolites, i.e. tetrahydrocortisol plus 5 alpha-tetrahydrocortisol/tetrahydrocortisone was 6.7-33, whereas the normal ratio is 1.0. Infusion of [11-3H]cortisol resulted in little release of tritiated water, indicating the failure of the conversion of cortisol to cortisone. Thirteen mutations in the HSD11B2 gene have been previously published, and we report three new genetic mutations in two patients, one of whom was previously unreported. All of the patients had homozygous defects except one, who was a compound heterozygote. Our first case had one of the most severe mutations, resulting in the truncation of the enzyme 11 beta HSD2, and died at the age of 16 yr while receiving treatment. Three patients with identical homozygous mutations from different families had varying degrees of severity of clinical and biochemical features. Due to the small number of patients with identical mutations, it is difficult to correlate genotype with phenotype. In some cases, early and vigilant treatment of AME patients may prevent or improve the morbidity and mortality of end-organ damage such as renal or cardiovascular damage and retinopathy. The outcome of treatment in more patients may establish the efficacy of treatment.

An automated "high-pressure" liquid-chromatographic assay for hemoglobin A1c is described. We use a 45-min incubation in acetate buffer (pH 5.5) to eliminate labile glycated hemoglobins. In this automated system conventional modules are used but it incorporates a solvent-switching valve to select either of two buffers, which differ in pH and NaCl concentration. The chromatographic column contains "polyCAT" (a weak cation-exchanger, polyaspartic acid linked to silica). Run time is 14 min per sample. The method is precise and results correlate well with those by other ion-exchange procedures.

We measured insulin antibody binding in 2 groups of patients: Study 1, 32 children with newly diagnosed IDDM before onset of insulin therapy, and, in 20 of these, 10 days, 1, 3, and 6 months after beginning therapy; and Study 2, 35 children with long-standing IDDM, 20 of whom had free insulin concentrations measured before, and for 2 hours following subcutaneous injection of 0.25 U/kg regular insulin. Almost 35% of new onset subjects had insulin antibody binding above control levels. In those studied prospectively, binding increased significantly with time. Pre-treatment binding did not correlate with later insulin antibody binding nor metabolic control. In Study 1 we have confirmed previous studies showing abnormally high insulin antibody binding in children with IDDM pre-treatment. We have been unable to demonstrate a relationship between this binding and that found 6 months after initiation of therapy. In Study 2, we have shown that insulin antibody binding is not related to either the level of metabolic control or the rate of rise of free insulin levels in children with IDDM.

We report four children with marked short stature, hepatomegaly, and delayed adolescence. Initial funduscopy demonstrated only occasional microaneurysms in two children and a single intraretinal hemorrhage in another. Improved control required large increases in insulin dosage. Growth rate improved significantly and hepatomegaly regressed. Puberty progressed rapidly in two older patients with poor final height. Paradoxically, with improved control, retinopathy progressed rapidly. One child with proliferative retinopathy in both eyes developed vitreous hemorrhage and blindness in one eye. Two required pan retinal photocoagulation with no further progression of their retinopathy. These rapidly progressive retinal changes remain unexplained. We advise caution when correcting metabolic derangements of diabetic patients who have been poorly controlled for a prolonged period.

We studied residual beta-cell function in 84 children with IDDM to assess (1) relationship between basal and stimulated C-peptide concentrations; (2) reproducibility of testing (Group 1, n = 20); (3) the effect of exogenous insulin on test interpretation (Group II, n = 20); and (4) impact on metabolic control. Sustacal (a mixed liquid meal) was utilized as the test stimulus. In C-peptide positive subjects (n = 44) there was a strong correlation between basal and peak C-peptide concentrations (r = 0.88, p less than 0.001). In Group 1 subjects, Sustacal proved to be a highly reproducible test stimulus producing identical results on two tests 7-14 days apart. The results of the tests were not affected by the administration of subcutaneous regular insulin prior to the second test in Group II. Peak C-peptide correlated inversely with HbA1, insulin dose, and disease duration (r = -0.29, -0.40, and -0.33 respectively, p less than 0.05) and positively with age (r = 0.34, p less than 0.05). We conclude that Sustacal is a highly reproducible stimulus to residual beta-cell function in IDDM and is not affected by exogenous insulin. This residual insulin secretion has a small but significant effect on glycemic control.

Growth and pubertal development were studied in 122 children aged 13.4 +/- 2.9 yr (mean +/- SD) with IDDM of 6.1 +/- 3.8 yr duration. Height and weight, pubertal status, insulin dose (u/kg), frequency of insulin administration and HbA1 were measured every 3 months for a minimum period of 1 yr for each child. The mean and distribution of height and height velocity percentiles were normal for boys and girls. The mean weight percentile for boys was increased (62 +/- 27, p less than 0.01), but was normal for girls. The mean and distribution of weight velocity percentiles were normal for both sexes. The mean and distribution of age of onset of Tanner 2 in both boys (11.9 +/- 1.4 yr) and girls (11.2 +/- 1.3) was normal, as was the age of menarche (13.2 +/- 1.2 yr). The mean HbA1 level was 11.1 +/- 2.0% (normal less than 7.5%). There was no correlation of mean HbA1 levels (calculated from 4 or more measurements for each child) with height velocity or with weight velocity percentiles or with mean height or weight percentiles. These results indicate that diabetic control, as reflected by HbA1 levels, was not a major determinant of growth in this group of children with IDDM, who displayed normal growth patterns and pubertal development despite a wide range of HbA1 levels. Normal growth may not reflect optimal metabolic control but "average" control.

Environmental "triggers" (including viruses, toxins and dietary factors) have been implicated in the pathogenesis of insulin-dependent diabetes mellitus. Data have suggested a possible role for cow's milk protein (CMP) as a trigger of diabetes. To study this further, 86 BB rats were divided into 2 groups during the weaning period (days 13-25): Group A received rat chow without CMP; Group B, rat chow with 1% CMP added. Each group was subdivided afterwards into 2: Groups A1 and B1 received chow without CMP; Groups A2 and B2, chow with CMP. Animals weaned with chow containing CMP (B1 and B2) had a higher incidence of diabetes (66%) than those weaned without (A1 and A2; 29%, p less than 0.001). The incidence in both B1 and B2 was significantly greater than in either A1 or A2 (p less than 0.05). The highest incidence of diabetes occurred in male rats weaned on rat chow with CMP (90%), the incidence being significantly higher than female rats weaned with (43%) or without CMP (18%) and males weaned without CMP (39%). Thus, it appears that (a) the presence of cow's milk protein in the diet increases the incidence of diabetes in the BB rat; (b) the critical time for exposure to CMP appears to be the weaning period; and (c) male rats appear to be more susceptible to the development of diabetes than female rats, when exposed to this trigger. This supports the hypothesis that dietary triggers may play an important role in the expression of diabetes in the susceptible host and that its prevalent action occurs early in life.

Thyroid function was systematically evaluated in 15 consecutive children (mean age 13.7 years, range 0.5 to 19.5 years) before and serially during treatment with amiodarone (Cordarone), a potent antiarrhythmic agent. Amiodarone is known to affect thyroid homeostasis by competitive inhibition of 5'-monodeiodinase, which converts L-thyroxine (T4) to triiodothyronine (T3) and reverse T3 (rT3) to 3,3'-diodothyronine (T2), and also by the direct effects of its high iodine content (37% by weight). Clinical and/or biochemical evidence of hypothyroidism occurred in three patients, two of whom required treatment with L-thyroxine. An additional patient had persistent hyperthyroxinemia but no clinical evidence of hyperthyroidism. Results from the patients who remained euthyroid showed characteristic alterations in serum thyroid function tests. These included significant increases in serum T4, rT3, basal thyroid-stimulating hormone and thyroid-stimulating hormone response to thyrotropin-releasing hormone testing. These changes were considered to be compensatory adjustments by the pituitary-thyroid axis to competitive inhibition of 5'-monodeiodinase by the amiodarone. Routine screening of thyroid function is needed to allow early detection of hypothyroidism when these compensations fail to occur.

An unselected sample of 46 female adolescents with insulin-dependent diabetes mellitus (IDDM) for more than one year were assessed systematically for the presence of anorexia nervosa and bulimia. These disorders and their partial syndromes were found in 19.5% of this population. Anorexia nervosa and bulimia diagnosed on the basis of DSM-III criteria were each found in 6.5% of the population representing approximately a 6-fold and 2-fold increase respectively in the expected prevalence for similar nondiabetic individuals. Bulimic symptoms were associated with poor metabolic control as reflected in blood levels of glycosylated hemoglobin (HbAl). These findings have important implications both for the pathogenesis of anorexia nervosa and bulimia and for the management of some cases of IDDM with unstable metabolic control.

One hundred consecutive cases of simple febrile seizures in childhood were studied. Seventeen of these children had had more than one seizure during the febrile episode, but none of the patients had a further seizure after treatment with simple antipyretic measures. Thus it appears unnecessary to give anticonvulsants to prevent early recurrence of simple febrile seizures.