J. M. Court

Diabetes in adolescence

Leicester Royal Infirmary Children’s Hospital, Leicester, UKCorresponding author:John M Court, MD,Albert Road Clinic31 Albert RoadMelbourne, Victoria 3004Australia.Tel: 161 3 92793560;fax: 161 3 92793599;e-mail: johncourt@iprimus.com.auAcknowledgement: Barbara Anderson.Editors of the ISPAD Clinical Practice Consensus Guidelines2006–2007: Kim Donaghue, Ragnar Hanas, GeorgeannaKlingensmith, and Peter Swift.

Double-Blind Controlled Trial of Azathioprine in Children With Newly Diagnosed Type I Diabetes

A double-blind controlled trial of azathioprine (2 mg · kg−1 · day−1) was conducted with 49 patients aged 2–20 yr (mean 10.8 yr) who had newly diagnosed type I (insulin-dependent) diabetes. Patients were randomly assigned to receive either azathioprine (n = 24) or placebo (n = 25) for 12 mo, beginning within the 20 day period after diagnosis. Baseline clinical and metabolic characteristics did not differ between the two groups. No patient experienced complete remission, defined as restoration of normal carbohydrate tolerance without other treatment. Partial remission, defined as good metabolic control (hemoglobin A1c ≤7.9%, preprandial blood glucose ≤8 mM with an insulin dose of <0.5 U. kg−1 · day1), occurred in 10 placebo (40%) and 7 azathioprine (29%) patients at 6 mo and in 4 placebo (16%) and 4 azathioprine (17%) patients at 12 mo (differences not significant). Fasting plasma C-peptide was significantly greater in the azathioprine-treated group at 3 and 6 mo, but this difference was not sustained. C-peptide responses to a standard meal and the frequency of islet cell and insulin antibodies did not differ between the two groups over the 12-mo period. Azathioprine caused no significant side effects. We conclude that in the dosage used, and despite early effects on endogenous insulin secretion, azathioprine alone does not influence the remission phase in children with newly diagnosed type I diabetes.

Hypertension in childhood obesity.

Blood pressure has been measured in 209 children on first consultation when referred to the Obesity Research Clinic. Blood pressure correlated with estimates of obesity made by subscapular‐skinfold thickness, and calculations of per cent body weight as fat. Neither age nor duration of the obesity showed significant correlation with the blood pressure.

Factors predicting residual β-cell function in the first year after diagnosis of childhood type 1 diabetes☆

Twenty-five children aged 2-14 years (mean age 8.39 +/- 0.78 years) were studied prospectively during the first year after the diagnosis of type 1 diabetes. Of their clinical and metabolic features at diagnosis, only age showed a significant independent relationship with endogenous C-peptide production during the first year. Age was correlated with higher values for basal and stimulated plasma C-peptide at 7-14 days after diagnosis, at 6 months and at 12 months. At diagnosis, age was also associated with a higher value for HbA1c and a lower prevalence of insulin antibodies. C-peptide production peaked at 3 months and thereafter declined. Mean HbA1c and insulin requirement were both minimal at 6 months. At diagnosis, there were significant inverse relationships between basal C-peptide production and both insulin dose and HbA1c and between stimulated C-peptide production and HbA1c. Basal and stimulated C-peptide production were inversely related to insulin dose at 6 and 12 months. Stimulated C-peptide was higher at 12 months in children retaining islet cell antibodies. These findings confirm the importance of age as a predictor of residual beta-cell function in type 1 diabetes and indicate that older children present clinically following a slower course of beta cell destruction.

HLA-DQ genotypes are associated with autoimmunity to glutamic acid decarboxylase in insulin-dependent diabetes mellitus patients

This study has investigated the genetic basis of the heterogeneous autoimmune response to glutamic acid decarboxylase (GAD) in 179 Australian patients with IDDM. Antibodies to GAD have been correlated with HLA-DQB1 alleles and genotypes, as determined by sequence-specific oligonucleotide hybridizations after polymerase chain reaction was applied to exon 2 of the DQ beta 1 gene. HLA-DQ2 was significantly increased (p < 0.01) in IDDM patients with antibodies to GAD. Antibodies to GAD were detected in 64% of 72 DQ2.8 patients, in 55% of 29 DQ2.2 or DQ8.8 patients and in 41% of 78 patients with other HLA-DQB1 genotypes. HLA-DQ genotype association with autoimmunity to GAD was statistically significant (p = 0.02) and reflected early formation of antibodies to GAD, rather than an HLA association with persistence of antibodies to GAD, since the genotype effect was more evident (p = 0.02) in those with more recent onset (0-5 years) of IDDM. Also, the HLA-DQ genotype effect was more evident in patients with IDDM onset after the age of 14 years (p = 0.003). Multivariate analysis showed that HLA-DQB1 genotypes had a more significant impact on antibodies to GAD than either duration or age of onset of IDDM. In patients with IDDM in childhood, only a minority had low-risk HLA-DQB1 genotypes (37%) when compared with those with onset in adulthood (62%) (p = 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Effective Treatment of Eating Disorders: Results at Multiple Sites

We report the results of a study based on 1,428 patients with eating disorders treated at 6 clinics. These patients were consecutively referred over 18 years and used inpatient and outpatient treatment. The subjects were diagnosed with anorexia nervosa, bulimia nervosa, or an eating disorder not otherwise specified. Patients practiced a normal eating pattern with computerized feedback technology, they were supplied with external heat, their physical activity was reduced, and their social habits restored to allow them to return to their normal life. The estimated rate of remission for this therapy was 75% after a median of 12.5 months of treatment. A competing event such as the termination of insurance coverage, or failure of the treatment, interfered with outcomes in 16% of the patients, and the other patients remained in treatment. Of those who went in remission, the estimated rate of relapse was 10% over 5 years of follow-up and there was no mortality. These data replicate the outcomes reported in our previous studies and they compare favorably with the poor long-term remission rates, the high rate of relapse, and the high mortality rate reported with standard treatments for eating disorders.

Lymphocytotoxic Antibodies and Histocompatibility Antigens in Juvenile-onset Diabetes Mellitus

Cold-reacting serum lymphocytotoxic antibodies (LCAs) were measured in sera from 230 insulin-dependent juvenile-onset diabetes mellitus (IDDM) patients and from 116 control subjects. LCAs were present in only 4% of control sera compared with 19% in IDDM patients. The most significant determinant of LCAs was time since onset of diabetes; within the first 12 mo, 55% of IDDM sera had LCAs, compared with 25% after one year and 15% after five years of diabetes. LCAs were absent in sera from patients with IDDM for 10 yr or more. Genetic factors were also implicated in susceptibility to occurrence of LCAs. HLA antigen B8 and B18 were associated with an increased risk for LCAs, whereas HLA-B7 was associated with a decreased risk. The relative risk for LCAs in patients positive for HLA-B8 but not B7 was 2.3, compared with 0.0 in HLA-B7/B8 heterozygotes. In contrast, B7 did not provide protection from LCAs in B18/B7 IDDM patients. Properdin factor B (Bf) alleles, which are in linkage disequilibrium with alleles of the HLA-B locus, were also associated with LCAs. IDDM patients with alleles BfS1 or BfF had a prevalence of LCAs of 7%, significantly less than the 39% in Bf-F1S or -F1 patients. LCAs were not identical or closely correlated to pancreatic islet cell antibodies. Our findings indicate genetic heterogeneity in, yet, another autoimmune process in IDDM.

Effects of Maternal Caffeine Ingestion on Neonatal Growth in Rats

When caffeine (1,3,7-trimethylxanthine) was introduced into the diet of rats throughout pregnancy and lactation at levels of consumption of 10 mg/kg/day, offspring of successive pregnancies showed growth reductions. This finding was not accompanied by teratogenic effects. However, following four pregnancies severely reduced offspring growth and neonatal mortality was demonstrated. The birthweights of these offspring were 72.5% of control. This study mimicked the mode of intake and quantities of caffeine consumed in many societies.

The Growth and Development of Fat Cells in Infancy

Summary: Studies on the development of adipose tissue in infancy would seem essential to test the hypothesis that adult fat stores relate to the numbers of fat cells developed during early childhood. Thirty infants aged from 1–28 months and 13 fetuses of approximately 11–16 weeks of gestation obtained at therapeutic abortion and two preterm infants of 28 weeks of gestation were studied. The cells of both fetal and infant adipose tissue were separated from connective tissue and fixed by treatment with osmium tetroxide in buffered collidine using a method modified from Hirsch and Gallian (J. Lipid Res., 9:100 (1968)) for estimation of cell size and number. In fetal and early infancy there are two populations of cells in adipose tissue. Small cells found in tissue before birth and the first months of postnatal life do not contain fat. The larger cells, which are fat containing, represent maturing fat cells. They are cells which include fat cells recognized by previous workers but up to 24.6% were found to be less than 25 μm in diameter. Small cells in the early stages of fat accumulation may make an important contribution to the cell population of fat mass. It is apparent that increasing fat accumulation in the first 6–12 months of life, as demonstrated by increased skinfold thickness measurements, is associated with increasing fat cell size and that this association bears a linear relationship.Speculation: Previously unrecognized cells in fetal and infant fat tissue may represent the precursors of mature adipose cells. Establishment of adipose tissue occurs with the development of such cells and the gradual accumulation of fat within the cell until the age of 6–12 months postnatally.

Lipogenesis in developing human adipose tissue.

De novo lipid synthesis can be demonstrated in human fetal subcutaneous tissue cells which are in the initial stages of liquid accumulation. Lipogenic capacity measured as ability to incorporate acetate into neutral lipid was shown to increase with gestational age. This lipogenic capacity was accompanied by an increased activity of acetyl co-enzyme A carboxylase. Insulin, which is known to activate this enzyme in mature adipose tissue, increased neutral lipid synthesis in fetal subcutaneous tissue. When tissue insulin levels were determined, insulin was found from 16 wk gestation. At this time triglyceride content of the tissue was also increasing. Thus de novo fatty acid synthesis is a means by which the developing adipose cell initiates lipid accumulation.