Heparanase and Type 1 Diabetes.

Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing beta cells in pancreatic islets. The degradation of the glycosaminoglycan heparan sulfate (HS) by the endo-ß-D-glycosidase heparanase plays a critical role in multiple stages of the disease process. Heparanase aids (i) migration of inflammatory leukocytes from the vasculature to the islets, (ii) intra-islet invasion by insulitis leukocytes, and (iii) selective destruction of beta cells. These disease stages are marked by the solubilization of HS in the subendothelial basement membrane (BM), HS breakdown in the peri-islet BM, and the degradation of HS inside beta cells, respectively. Significantly, healthy islet beta cells are enriched in highly sulfated HS which is essential for their viability, protection from damage by reactive oxygen species (ROS), beta cell function and differentiation. Consequently, mouse and human beta cells but not glucagon-producing alpha cells (which contain less-sulfated HS) are exquisitely vulnerable to heparanase-mediated damage. In vitro, the death of HS-depleted mouse and human beta cells can be prevented by HS replacement using highly sulfated HS mimetics or analogues. T1D progression in NOD mice and recent-onset T1D in humans correlate with increased expression of heparanase by circulating leukocytes of myeloid origin and heparanase-expressing insulitis leukocytes. Treatment of NOD mice with the heparanase inhibitor and HS replacer, PI-88, significantly reduced T1D incidence by 50%, impaired the development of insulitis and preserved beta cell HS. These outcomes identified heparanase as a novel destructive tool in T1D, distinct from the conventional cytotoxic and apoptosis-inducing mechanisms of autoreactive T cells. In contrast to exogenous catalytically active heparanase, endogenous heparanase may function in HS homeostasis, gene expression and insulin secretion in normal beta cells and immune gene expression in leukocytes. In established diabetes, the interplay between hyperglycemia, local inflammatory cells (e.g. macrophages) and heparanase contributes to secondary micro- and macro-vascular disease. We have identified dual activity heparanase inhibitors/HS replacers as a novel class of therapeutic for preventing T1D progression and potentially for mitigating secondary vascular disease that develops with long-term T1D.

Hereditary pituitary hyperplasia with infantile gigantism.

CONTEXT: We report hereditary pituitary hyperplasia. OBJECTIVE: The objective of the study was to describe the results of the clinical and laboratory analysis of this rare instance of hereditary pituitary hyperplasia. DESIGN: The study is a retrospective analysis of three cases from one family. SETTING: The study was conducted at the National Institutes of Health, a tertiary referral center. PATIENTS: A mother and both her sons had very early-onset gigantism associated with high levels of serum GH and prolactin. INTERVENTIONS: The condition was treated by total hypophysectomy. MAIN OUTCOME MEASURE(S): We performed clinical, pathological, and molecular evaluations, including evaluation basal and provocative endocrine testing, neuroradiological assessment, and assessment of the pituitary tissue by microscopic evaluation, immunohistochemistry, and electron microscopy. RESULTS: All three family members had very early onset of gigantism associated with abnormally high serum levels of GH and prolactin. Serum GHRH levels were not elevated in either of the boys. The clinical, radiographic, surgical, and histological findings indicated mammosomatotroph hyperplasia. The pituitary gland of both boys revealed diffuse mammosomatotroph hyperplasia of the entire pituitary gland without evidence of adenoma. Prolactin and GH were secreted by the same cells within the same secretory granules. Western blot and immunohistochemistry demonstrated expression of GHRH in clusters of cells distributed throughout the hyperplastic pituitary of both boys. CONCLUSIONS: This hereditary condition seems to be a result of embryonic pituitary maldevelopment with retention and expansion of the mammosomatotrophs. The findings suggest that it is caused by paracrine or autocrine pituitary GHRH secretion during pituitary development.

Establishment of pediatric reference intervals on a large cohort of healthy children.

BACKGROUND: Reference intervals are essential in assessing the significance of laboratory results. There have been limited studies generating reference intervals from pediatric populations. We have studied a large cohort of healthy children on 3 separate occasions at 2yearly intervals. METHODS: 852 healthy 8year old children were enrolled in a community-based multidisciplinary longitudinal study investigating how early physical activity contributes to health. The same children came back for reassessment at ages 10 and 12years. Blood samples were analyzed for a total of 37 different chemistries, immunoassays or derived values. RESULTS: Reference intervals were derived for all the analytes for males and females separately. CONCLUSION: Whilst our results are largely in agreement with previously published work, we have shown that for a number of analytes, previously published work is distorted by subclinical disease.

Contrasting longitudinal and cross-sectional relationships between insulin resistance and percentage of body fat, fitness, and physical activity in children-the LOOK study.

BACKGROUND: Knowledge of individual changes in insulin resistance (IR) and longitudinal relationships of IR with lifestyle-associated factors are of important practical significance, but little longitudinal data exist in asymptomatic children. We aimed to determine (a) changes in the homeostatic model of insulin resistance (HOMA-IR) over a 2-yr period and (b) comparisons of longitudinal and cross-sectional relationships between HOMA-IR and lifestyle-related risk factors. METHODS: Our subjects, 241 boys and 257 girls, were assessed at age 8.1 yr (SD 0.35) and again 2 yr later for fasting blood glucose and insulin, dual X-ray absorptiometry-assessed percentage of body fat (%BF), pedometer-assessed physical activity (PA), and cardio-respiratory fitness (CRF) by multistage running test. RESULTS: HOMA-IR was initially 9% greater in girls than boys and 27% greater 2 yr later. There was no evidence of longitudinal relationships between HOMA-IR and %BF in boys or girls, despite significant cross-sectional relationships (p < 0.001). In boys, there was evidence of a longitudinal relationship between HOMA-IR and both PA (p < 0.001) and CRF (p = 0.05). In girls, we found a cross-sectional relationship between HOMA-IR and CRF (p < 0.001). CONCLUSIONS: HOMA-IR increases between 8 and 10 yr of age and to a greater extent in girls. Longitudinal, unlike cross-sectional, relationships do not support the premise that body fat has any impact on HOMA-IR during this period or that PA or CRF changes affect HOMA-IR in girls. These data draw attention to difficulties in interpreting observational studies in young children.

Discordance of international adiposity classifications in Australian boys and girls - the LOOK study.

BACKGROUND: Various charts based on body mass index (BMI) and per cent body fat (%BF) are used to classify childhood body composition but outcomes may vary. AIM: The study investigated variation in incidences of childhood obesity as depicted by four classification charts. SUBJECTS AND METHODS: BMI and DXA-derived %BF were assessed in 741 children. Incidences of overweight and obesity were compared between two BMI charts and two bioelectrical impedance (BIA)-based %BF charts. RESULTS: The International Obesity Task Force (IOTF)-adopted BMI chart designated 21%, 6% (boys), and 26%, 9% (girls) as overweight and obese, respectively. Corresponding figures using the USA CDC BMI chart were 27%, 11% (boys) and 27%, 12% (girls). Using a USA-derived %BF chart incidences were 17%, 2% (boys) and 21%, 8% (girls) and using a UK-derived %BF chart 51%, 24% (boys) and 53%, 36% (girls). Sensitivity of BMI varied according to the %BF reference chart. CONCLUSIONS: In contrast to the BMI-based charts, there were considerable variations in depicted incidences of obesity between the %BF-based charts. These discordances were considered to result from previously reported variation within and between BIA and DXA %BF assessments underlying the charts. The present study highlights the need for valid, reliable, unchanging BIA and DXA procedures.