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Objective: 2 Childhood-onset type 1 diabetes is associated with neurocognitive deficits, but there is limited evidence to date regarding associated neuroanatomical brain changes and their relationship to illness variables such as age at disease onset. This report examines age-related changes in volume and T2 relaxation time (a fundamental parameter of magnetic resonance imaging that reflects tissue health) across the whole brain.Research Design and Methods: Type 1 diabetes, N = 79 (mean age 20.32 ± 4.24 years), and healthy control participants, N = 50 (mean age 20.53 ± 3.60 years). There were no substantial group differences on socioeconomic status, sex ratio, or intelligence quotient.Results: Regression analyses revealed a negative correlation between age and brain changes, with decreasing gray matter volume and T2 relaxation time with age in multiple brain regions in the type 1 diabetes group. In comparison, the age-related decline in the control group was small. Examination of the interaction of group and age confirmed a group difference (type 1 diabetes vs. control) in the relationship between age and brain volume/T2 relaxation time.Conclusions: We demonstrated an interaction between age and group in predicting brain volumes and T2 relaxation time such that there was a decline in these outcomes in type 1 diabetic participants that was much less evident in control subjects. Findings suggest the neurodevelopmental pathways of youth with type 1 diabetes have diverged from those of their healthy peers by late adolescence and early adulthood but the explanation for this phenomenon remains to be clarified. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The objectives of the study were to (i) determine the incidence of type 1 diabetes mellitus (T1DM) in children aged <15 yr in Victoria, Australia, from 1999 to 2002 and (ii) to analyze trends in incidence over this period. METHODS: Prospective population-based incidence study. The primary source of case ascertainment was from the Australasian Paediatric Endocrine Group (APEG) Victorian diabetes register. The secondary source was the National Diabetes Register (NDR), which ascertains cases from the National Diabetes Service Scheme (NDSS), a Commonwealth government initiative, where patients register to receive diabetes supplies at a subsidized price. MAIN OUTCOME MEASURES: Age-standardized incidence, trends in incidence by age, sex and year, and variation in incidence by region, season, and socioeconomic status. RESULTS: Case ascertainment was 99.1% complete using the capture-recapture method. The mean annual age-standardized incidence was 19.3 per 100 000 person years from 1999 to 2002. On average, incidence increased by 9.3% per year, with a greater relative increase in the 0-4 yr age-group (p = 0.037). No gender bias in incidence was found, but the increase in females was statistically significant (13.6% per year, 95% confidence interval 3.7-24.3). Variation in geographical distribution and seasonal onset of incidence was not statistically significant. CONCLUSIONS: The marked increase in the incidence of T1DM in Victoria is greater than that recently described in other Australia states and developed nations. The etiology of this rise is unclear, while the increased caseload has major implications for diabetes health care providers for current and future resource allocation. [ABSTRACT FROM AUTHOR]

The case of five pediatric patients who presented to the Royal Children's Hospital, Melbourne with newly diagnosed diabetes mellitus between January 2001 and September 2003 is reported. Each case was complicated by hyperosmolarity and hypernatremia and required intensive therapy. Fluid intake prior to admission in each case was documented and consisted of between 5 and 12 L of carbonated carbohydrate beverages and 'isotonic' sports drinks. At presentation, biochemical results of the four cases (four males and one female), mean age 13.6 yr (range 11.7-15.1 yr) included glucose (mean 1460 mg/dL; range 864-2106), adjusted sodium (mean 176.3 mmol/L; range 165-183), serum osmolarity (mean 399 mmol/kg; range 364-424), anion gap (mean 48 mEq/L; range 42-84), and pH (mean 7.15; range 7.01-7.27). All five cases had evidence of ketonuria on presentation. Treatment in all five cases consisted of replacement of fluids over a prolonged period of 72 h and careful monitoring of electrolyte response. Three of five cases required hemofiltration in the first 48 h postadmission. All five cases made a complete recovery without neurological sequelae. Carbonated carbohydrate fluid intake may precipitate a more severe presentation of type 1 diabetes mellitus (T1DM). Fluid composition and intake should be carefully estimated at admission to help identify and manage similar cases. [ABSTRACT FROM AUTHOR]

AIMS: To describe psychiatric status and relationship to metabolic control in adolescents with Type 1 diabetes studied prospectively from diagnosis. METHODS: Adolescents (n = 41) completed a self-report measure of psychiatric status 10 years after disease onset. Metabolic control information was recorded prospectively from diagnosis. The rate and type of psychiatric disorder were determined and the relationship between mental health status and metabolic control history examined. RESULTS: Thirty-seven per cent of the adolescents met criteria for a DSM-IV psychiatric disorder, two to three times higher than community levels of psychiatric morbidity. Females were significantly more likely to receive a diagnoses (chi2 = 4.98, P < 0.05). Two thirds of participants had experienced at least one serious hypoglycaemic episode and one third had a history of chronic poor metabolic control. DSM-IV diagnoses were present in half of those with a history of chronic poor control, one third of the hypoglycaemia group and one quarter of well controlled participants. Adolescents with a current Mood (t = -2.83, P < 0. 01), Anxiety (t = -3.77, P = 0.001) or Behaviour (t = 2.56, P < 0.05) disorder and those with a history of poorly controlled diabetes (F (2,29) = 5.4, P = 0.01) had higher externalizing behaviour problem scores at diagnosis than those without current disorder. CONCLUSIONS: Adolescents with Type 1 diabetes are at high risk for psychiatric disorder. Poorly controlled diabetes over the first 10 years of illness was associated with pre-existing behaviour problems at diagnosis and there was a trend for an association with current psychiatric status. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor binding protein 2 (IGFBP-2) may represent a critical link between body composition and insulin sensitivity. We investigated the relationship between circulating IGFBP-2 levels, body composition, insulin sensitivity, energy intake and physical activity in children with obesity. Children were recruited via the Weight Management Service at the Royal Children's Hospital, Melbourne, as part of the Childhood Overweight BioRepository of Australia (COBRA). Comprehensive anthropometric, biochemical and environmental data were collected and compared to serum IGFBP-2 levels (measured by enzyme-linked immunosorbent assay). Multiple regression modelling was used to assess the influence of circulating IGFBP-2 levels on anthropometric and biochemical measures. One hundred and ninety-four children were included in this study (46% male). Circulating IGFBP-2 negatively correlated with age, anthropometric measures, blood pressure and insulin concentration. Positive associations were observed between insulin sensitivity index-homeostasis model assessment (ISI-HOMA) and serum IGFBP-2. In multiple regression modelling, IGFBP-2 significantly contributes to variance in systolic blood pressure (-19%, P < 0.05), circulating triglycerides (-16%, P < 0.05) and ISI-HOMA (18%, P < 0.05). No associations were observed between dietary energy intake or physical activity and IGFBP-2 levels. Circulating IGFBP-2 levels in children with obesity correlate inversely with body mass and markers of metabolic dysfunction, and positively with insulin sensitivity. These findings suggest that reduced levels of IGFBP-2 may play an important role in the pathogenesis of obesity complications in early life., (© 2018 World Obesity Federation.)

Objective: Antiepileptic drugs (AEDs) are associated with reduced bone density, balance impairment, and increased fracture risk in adults. However, pediatric data are limited. Therefore, we aimed to examine bone, muscle, and balance outcomes in young patients taking AEDs., Methods: We undertook a case-control study utilizing an AED exposure-discordant matched-pair approach. Subjects were aged 5-18 years with at least 12 months of AED exposure. Pairs were twins, nontwin siblings and first cousins, sex- and age-matched (to within 2 years), allowing for greater power than with unrelated control subjects. Dual energy x-ray absorptiometry (DXA), peripheral quantitative computed tomography (pQCT), and muscle force/balance were tested, with questionnaires were administered for bone health and epilepsy details., Results: Twenty-three pairs were recruited, (median age 12.9 years [subjects] and 13.5 years [controls])-7 twin, 14 sibling, and 2 cousin pairs. Those taking AEDs had an increased prevalence of fractures (15 fractures in 8 subjects, compared with 4 fractures in 3 controls, p < 0.01). Trabecular volumetric bone mineral density (vBMD) measured by pQCT at the 4% site (tibia) was reduced by 14% (p = 0.03) in subjects. Subjects exerted a decreased maximum force compared to body weight (F max total/g) at the tibia. There were no differences seen in either bone mineral parameters measured by DXA or balance measures., Significance: Young people taking AEDs reported more fractures and had reductions in tibial vBMD and lower limb muscle force compared to their matched controls. These findings suggest that further exploration of bone health issues of young patients on AED therapy is required. Longitudinal studies are required to confirm these changes in the muscle-bone unit and to further explore the clinical outcomes., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Growth failure is frequently encountered in children with chronic inflammatory conditions like juvenile idiopathic arthritis, inflammatory bowel disease, and cystic fibrosis. Delayed puberty and attenuated pubertal growth spurt are often seen during adolescence. The underlying inflammatory state mediated by proinflammatory cytokines, prolonged use of glucocorticoid, and suboptimal nutrition contribute to growth failure and pubertal abnormalities. These factors can impair growth by their effects on the GH-IGF axis and also directly at the level of the growth plate via alterations in chondrogenesis and local growth factor signaling. Recent studies on the impact of cytokines and glucocorticoid on the growth plate further advanced our understanding of growth failure in chronic disease and provided a biological rationale of growth promotion. Targeting cytokines using biological therapy may lead to improvement of growth in some of these children, but approximately one-third continue to grow slowly. There is increasing evidence that the use of relatively high-dose recombinant human GH may lead to partial catch-up growth in chronic inflammatory conditions, although long-term follow-up data are currently limited. In this review, we comprehensively review the growth abnormalities in children with juvenile idiopathic arthritis, inflammatory bowel disease, and cystic fibrosis, systemic abnormalities of the GH-IGF axis, and growth plate perturbations. We also systematically reviewed all the current published studies of recombinant human GH in these conditions and discussed the role of recombinant human IGF-1.

Massive insulin overdose may be associated with unpredictable and prolonged hypoglycemia. Concerns surrounding the potential provocation of insulin release from beta cells have previously prevented the use of intravenous glucagon as an adjunct to infusion of dextrose in this situation. We describe the case of a 15-yr-old boy with type 1 diabetes mellitus (T1DM) who presented with profound hypoglycemia following an overdose of an unknown quantity of premixed insulin. Owing to an increasing dextrose requirement and a dependence on hourly intramuscular glucagon injections, a continuous intravenous infusion of glucagon was commenced which successfully avoided the requirement for central venous access or concentrated dextrose infusion. Nausea was managed with anti-emetics. Intramuscular and subcutaneous glucagon is effective in the management of refractory and severe hypoglycemia in youth with both T1DM and hyperinsulinism. Concerns regarding the precipitation of rebound hypoglycemia with the use of intravenous glucagon do not relate to those with T1DM. This treatment option may be a useful adjunct in the management of insulin overdose in youth with T1DM and may avoid the requirement for invasive central venous access placement., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: We analyzed mRNA expression of X-linked inhibitor of apoptosis protein (XIAP) in patients with Turner syndrome (TS) and examined its association with phenotypic features., Subjects and Methods: XIAP mRNA expression levels were investigated in 98 patients with TS in total RNA extracted from blood leucocytes by real time quantitative polymerase chain reaction., Results: Levels of XIAP mRNA were significantly lower in patients with bicuspid aortic valves (BAV; n=13) than those without (log XIAP -1.17±0.3 vs. -0.94±0.2, p=0.002). Significantly higher expression of XIAP mRNA was seen in patients with a mosaic karyotype and renal malformations (log XIAP -0.79±0.3 vs. -1.0±0.3, p=0.03). No correlations were seen between XIAP and other manifestations., Conclusion: Abnormal expression of XIAP may be an important underlying mechanism in the development of BAV and renal malformations in TS. However, abnormal XIAP mRNA expression, as determined from peripheral mononuclear cells, does not appear to explain all the somatic and visceral stigmata of TS.

The activity of the Insulin-like Growth Factors (IGFs) ligands elicited via their receptors and transduced by various intracellular signal pathways is modulated by the IGF Binding Proteins (IGFBPs). Among all the IGFBPs, IGFBP-2 has been implicated in the regulation of IGF activity in most tissue and organs. Besides binding to IGFs in the circulation these IGF-regulatory activities of IGFBP-2 involve interactions with components of the extracellular matrix, cell surface proteoglycans and integrin receptors. In addition to these local peri-cellular activities, IGFBP-2 exerts other key functions within the nucleus, where IGFBP-2 directly or indirectly promotes transcriptional activation of specific genes. All of these IGFBP-2 activities, intrinsic or dependent on IGFs, contribute to its functional roles in growth/development, metabolism and malignancy as evidenced by studies in IGFBP-2 animal models and also by many in vitro studies. Finally, preclinical studies have demonstrated that IGFBP-2 administration can be beneficial in improving metabolic responses (inhibition of adipogenesis and enhanced insulin sensitivity), while blockade of IGFBP-2 appears to be an effective approach to inhibiting tumour growth and metastasis.

The ubiquitous nature of the IGF system, expressed early in embryonic development throughout postnatal and adult life, indicates a key role for this system in human biology. Studies of transgenic mice over-expressing components of the IGF system or mice with disruptions of the same genes have clearly shown that the IGF system plays an important role in vivo. The activity of the IGF ligands, elicited via their receptors and transduced by various intracellular signal pathways, is modulated by the IGFBPs. Among all the IGFBPs, IGFBP-2 has been implicated in the regulation of IGF activity in the nervous system, peripheral tissue and organs. Besides binding to IGFs in the circulation, these IGF-regulatory activities of IGFBP-2 involve interactions with components of the extracellular matrix and cell surface proteoglycans and integrin receptors. In addition to these "local" peri-cellular activities of IGFBP-2, it became evident that IGFBP-2 exerts other key functions within the cell. In the cytoplasm IGFBP-2, most likely in the absence of the IGFs, interacts with regulatory proteins including transcription factors and cytoplasm-nuclear transporters. Within the nucleus IGFBP-2, directly or indirectly, promotes transcriptional activation of specific genes. These intrinsic activities of IGFBP-2 are mediated via specific functional domains. All of these IGFBP-2 activities, intrinsic or dependent on IGFs, contribute to its functional roles in growth/development, metabolism and malignancy as evidenced by studies in IGFBP-2 animal models and also by many in vitro studies. Finally, preclinical studies have demonstrated that IGFBP-2 administration can be beneficial in improving metabolic responses (inhibition of adipogenesis and enhanced insulin sensitivity), while blockade of IGFBP-2 appears to be an effective approach to inhibiting tumor growth and metastasis., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background/objective: IGF-binding protein (IGFBP)-2 is the principal IGFBP produced by white adipocytes during adipogenesis, and circulating levels are reduced in obesity. Overexpression of IGFBP-2 in transgenic mice prevents obesity, but depot-specific effects of IGFBP-2 on adipo/lipogenesis are unknown. The present study aimed to investigate whether IGFBP-2 affects adipo/lipogenesis in a depot-specific manner and explore potential mechanisms., Methods: Following adipocyte characterisation, IGFBP-2 levels were measured from human subcutaneous and visceral preadipocytes, and IGFBP-2 dose-responses were then undertaken with exogenous IGFBP-2 in an in vitro IGF-I-free system to examine adipo/lipogenesis. Following this, both types of adipocytes were transfected with human siRNA IGFBP-2 to assess auto-/para-/intra-crine effects, with and without additional add-back IGFBP-2. To elucidate the potential mechanisms, visceral preadipocytes were treated with either wild-type or Heparin Binding Domain (HBD)-mutant IGFBP-2 (which is unable to bind to cell-surface components), and experiments were also undertaken using Echistatin (an integrin receptor blocker). Outcomes included gene expression profiles, protein levels and phosphorylation and lipid staining., Results: Human visceral adipocytes produced significantly more IGFBP-2 than subcutaneous adipocytes. Subsequent dose-responses to IGFBP-2 demonstrated significant reductions in adipo/lipogenesis in visceral, but not subcutaneous, adipocytes in response to increasing IGFBP-2. Silencing IGFBP-2 resulted in exaggerated adipo/lipogenesis in visceral, but not subcutaneous, adipocytes, an effect completely inhibited by add-back IGFBP-2. These effects occurred in the absence of changes in IGF-I levels. HBD-mutant IGFBP-2 had reduced effects compared with wild-type IGFBP-2. Wild-type IGFBP-2 increased phosphorylation of focal adhesion kinase (FAK) and decreased phosphatase and tensin homolog (PTEN) levels, suggestive of integrin-mediated signalling. Blockade of this signalling, using Echistatin, completely negated the effects of IGFBP-2 on visceral adipo/lipogenesis., Conclusion: IGFBP-2 inhibits both adipogenesis and lipogenesis in visceral, but not subcutaneous, adipocytes. This depot-specific impairment appears to be independent of IGF-I and involves cell-surface association of IGFBP-2 and activation of integrin signalling pathways.

Objective: This study examined illness-related change in intelligence quotient (IQ) in a cohort of youth with type 1 diabetes studied prospectively from disease onset in childhood to follow-up 12 years later in late adolescence/early adulthood., Research Design and Methods: Participants included type 1 diabetes patients (n = 95; mean age at follow-up 21.3 years) and healthy control participants (HCs; n = 67; mean age at follow-up 21.0 years) from a cohort followed prospectively. Measures included Wechsler Preschool and Primary Scale of Intelligence-Revised, Wechsler Intelligence Scale for Children-Revised, and Wechsler Abbreviated Scale of Intelligence and prospective collection of data on metabolic control history., Results: Young people with type 1 diabetes showed greater decline in verbal IQ (VIQ) and full-scale IQ (FSIQ), but not performance IQ (PIQ), than HCs. Within the diabetes group, a younger age at diabetes onset was associated with a decline in PIQ and FSIQ (P ≤ 0.001). A history of hypoglycemic seizures was associated with a decline in VIQ (P = 0.002). Long-term metabolic control was not associated with changes in IQ. Interaction terms were not significant, suggesting no moderating effect of one diabetes-related variable over another., Conclusions: The presence of diabetes may negatively influence some aspects of IQ over time. Specific illness risk factors, such as an earlier age of disease onset and a history of hypoglycemic seizures, appear to put the young person at greater risk. Academic progress of children identified as at risk should be monitored and educational supports provided if necessary., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Aims: Waist circumference (WC) measurement is a useful tool in the assessment of overweight/obese individuals, but standard measures may miss an apron of 'overhanging' fat (termed 'panniculus'). The objective of this study was to assess whether, in clinically overweight/obese youth, 'pannicular' WC better correlates with fat mass than a standard WC measurement., Methods: Standard and pannicular WC, alongside body composition (BC) measures, were collected from 181 consultations on 127 overweight and obese children/adolescents (52% male; mean (standard deviation) age 12.5 (3.4) years). Correlation coefficients describe associations between WC and measures of BC, and between ΔWC and ΔBC, while linear regression models assessed which of the WC measures explained more of the variability in BC and ΔBC over time., Results: Standard and pannicular WC were highly correlated (r = 0.95). Correlation coefficients with measures of BC were generally greater for pannicular than standard WC, with greatest correlations seen for whole body (r = 0.94 vs. 0.85, respectively) and truncal (r = 0.86 vs. 0.77) fat mass. Furthermore, pannicular and Δpannicular WC explained more variability in truncal fat and Δtruncal fat than the standard measure of WC., Conclusions: These data show that pannicular, rather than standard, WC measurements better correlate with absolute measures of fat mass, and their change over time, in clinically overweight/obese youth., (© 2014 The Authors. Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians).)

Leptin is produced from white adipose tissue and acts primarily to regulate energy balance. Obesity is associated with leptin resistance and increased circulating levels of leptin. Leptin has recently been shown to influence levels of IGF binding protein-2 (IGFBP-2), a protein that is reduced in obesity and type 2 diabetes. Overexpression of IGFBP-2 protects against obesity and type 2 diabetes. As such, IGFBP-2 signaling may represent a novel pathway by which leptin regulates insulin sensitivity. We sought to investigate how leptin regulates skeletal muscle IGFBP-2 levels and to assess the impact of this on insulin signaling and glucose uptake. In vitro experiments were undertaken in cultured human skeletal myotubes, whereas in vivo experiments assessed the effect of intracerebroventricular leptin on peripheral skeletal muscle IGFBP-2 expression and insulin sensitivity in sheep. Leptin directly increased IGFBP-2 mRNA and protein in human skeletal muscle through both signal transducer and activator of transcription-3 and phosphatidylinositol 3-kinase signaling, in parallel with enhanced insulin signaling. Silencing IGFBP-2 lowered leptin- and insulin-stimulated protein kinase B phosphorylation and glucose uptake. In in vivo experiments, intracerebroventricular leptin significantly increased hind-limb skeletal muscle IGFBP-2, an effect completely blocked by concurrent peripheral infusion of a β-adrenergic blocking agent. Sheep receiving central leptin showed improvements in glucose tolerance and circulating insulin levels after an iv glucose load. In summary, leptin regulates skeletal muscle IGFBP-2 by both direct peripheral and central (via the sympathetic nervous system) mechanisms, and these likely impact on peripheral insulin sensitivity and glucose metabolism.

IGFBP-2 is highly expressed in both the serum and tumor tissues of most cancers, and is considered one of the most significant genes in the signature of major cancers. IGFBP-2 mainly modulates IGF actions in the pericellular space; however, there is considerable evidence to suggest that IGFBP-2 may also act independently of the IGFs. These IGF-independent actions of IGFBP-2 are exerted either via interactions at the cell surface or intracellularly, via interaction with cytoplasmic or nuclear-binding partners. The precise mechanism underlying the intracellular/intranuclear localization of IGFBP-2 remains unclear. In this study, we investigated IGFBP-2 nuclear localization in several common cancer cells with the aim of dissecting the mechanism of its nuclear trafficking. IGFBP-2 is detected in the nuclei of common cancer cells, including breast, prostate and several neuroblastoma cell lines, using cell fractionation and confocal microscopy. Via nuclear import assays, we show that nuclear entry of IGFBP-2 is mediated by the classical nuclear import mechanisms, primarily through importin-α, as demonstrated by the use of blocking, competition and co-immunoprecipitation assays. Bioinformatics analysis of the IGFBP-2 protein sequence with PSORT II identified a classical nuclear localization signal (cNLS) sequence at 179PKKLRPP185, within the IGFBP-2 linker domain, mutagenesis of which abolishes IGFBP-2 nuclear import. Accordingly, the NLSmutIGFBP-2 fails to activate the VEGF promoter, which would otherwise occur in the presence of wild-type IGFBP-2. As a consequence, no activation of angiogenic processes were observed in NLSmutIGFBP-2 expressing SHEP cells when implanted onto our in vivo quail chorio-allantoic membrane model. Taken together, these data show for the first time that IGFBP-2 possesses a functional NLS sequence and that IGFBP-2 actively translocates into the nucleus by a classical nuclear import mechanism, involving formation of IGFBP-2 complexes with importin-α. Nuclear IGFBP-2 is required for the activation of VEGF expression and consequent angiogenesis.

There is increasing evidence for glucose fluctuation playing a role in the damaging effects of diabetes on various organs, including the brain. We aimed to study the effects of glycaemic variation (GV) upon mitochondrial activity using an in vitro human neuronal model. The metabolic disturbance of GV in neuronal cells, was mimicked via exposure of neuroblastoma cells SH-SY5Y to constant glucose or fluctuating (i.e. 6 h cycles) for 24 and 48 h. Mitochondrial dehydrogenase activity was determined via MTT assay. Cell mitochondrial activity (MTT) was moderately decreased in constant high glucose, but markedly decreased following 24 and 48 h of cyclical glucose fluctuations. Glucose transport determined via 2-deoxy-D-[1-(14)C] glucose uptake was regulated in an exaggerated manner in response to glucose variance, accompanied by modest changes in GLUT 1 mRNA abundance. Osmotic components of these glucose effects were investigated in the presence of the osmotic-mimics mannitol and L: -glucose. Both treatments showed that fluctuating osmolality did not result in a significant change in mitochondrial activity and had no effects on (14)Cglucose uptake, suggesting that adverse effects on mitochondrial function were specifically related to metabolically active glucose fluctuations. Apoptosis gene expression showed that both intrinsic and extrinsic apoptotic pathways were modulated by glucose variance, with two major response clusters corresponding to (i) glucose stress-modulated genes, (ii) glucose mediated osmotic stress-modulated genes. Gene clustering analysis by STRING showed that most of the glucose stress-modulated genes were components of the intrinsic/mitochondrial apoptotic pathway including Bcl-2, Caspases and apoptosis executors. On the other hand the glucose mediated osmotic stress-modulated genes were mostly within the extrinsic apoptotic pathway, including TNF receptor and their ligands and adaptors/activators/initiators of apoptosis. Fluctuating glucose levels have a greater adverse effect on neuronal cell energy regulation mechanisms than either sustained high or low glucose levels.

Purpose of Review: Human growth ensues from a complex interplay of physiological factors, in the wider setting of varying genetic traits and environmental influences. Intensive research in these divergent areas, and particularly in the field of genetics, continues to clarify the molecular basis of disorders which result in overgrowth, and it is therefore timely to provide a review of these findings., Recent Findings: This article provides an overview of the factors which regulate growth, followed by a discussion of the more commonly encountered overgrowth syndromes and their genetic basis as it is understood at the current time. There is also an added focus on recently discovered genetic associations in some conditions, such as Weaver, Perlman and Proteus syndromes., Summary: New discoveries continue to be made regarding the genetic basis for many overgrowth syndromes and the development of a much needed molecular classification system for overgrowth may become possible as the interlinking functions of these genes on growth are unravelled. As there exists a wide spectrum of syndromes, disorders resulting in overgrowth can represent a diagnostic and therapeutic challenge, from those causing prenatal overgrowth with a poor prognosis to less severe genetic aberrations which are identified in later childhood or adult life.

The pathophysiology of cerebral oedema (CE) in diabetic ketoacidosis (DKA) remains enigmatic. We investigated the role of the idiogenic osmol taurine and aquaporin channels in an in vitro model, the SH-SY5Y neuroblastoma cell line, by sequentially mimicking DKA-like hyperglycemia/hypertonicity and hypotonic fluid therapy. Exposure to DKA-like hyperosmolarity led to shrinkage, while hypotonic fluid exposure led to cell swelling and impaired viability. Low sodium compensated in part for elevated glucose, pointing to a critical role for overall osmolality. Taurine, was synthesized and retained intracellularly during DKA-like hypertonicity, and released during hypotonicity, in part mitigating neuronal swelling. Metabolic labeling showed that the rate of taurine release was inadequate to fully prevent neuronal swelling during hypotonic fluid therapy following DKA-like hypertonicity. Under these conditions, Aquaporin4 & 9 channels were respectively down and up-regulated. Our study provides further novel insights into molecular mechanisms contributing to CE in DKA and its therapy.

The aim of this study was to investigate effects of dietary supplementation with fat or sugar on body composition (BC) and insulin sensitivity (IS) in maturing pigs. Fifty newborn pigs randomized to a control diet or 18% saturated fat (SF), 18% monounsaturated fat (MUF), 18% mixed fat (MF), or 50% sucrose (SUC), from 1 to 16 weeks of age. Outcomes included weight gain, BC (dual energy X-ray absorptiometry, DXA), IS (fasting insulin and hyperinsulinaemic-euglycaemic clamps), fasting Non-Esterified Fatty Acid (NEFA) concentrations, and mRNA expression of genes involved in lipogenesis and IS in skeletal muscle (SM), subcutaneous (SAT), and visceral adipose tissue (VAT). In vitro studies examined direct effects of fatty acids on insulin-like growth factor-binding protein 2 (IGFBP2) mRNA in C2C12 myotubes. While SUC-fed pigs gained most weight (due to larger quantities consumed; P < 0.01), those fed fat-enriched diets exhibited more weight gain per unit energy intake (P < 0.001). Total (P = 0.03) and visceral (P = 0.04) adiposity were greatest in MUF-fed pigs. Whole-body IS was decreased in those fed fat (P = 0.04), with fasting insulin increased in MUF-fed pigs (P = 0.03). SM IGFBP2 mRNA was increased in MUF-fed pigs (P = 0.009) and, in all animals, SM IGFBP2 mRNA correlated with total (P = 0.007) and visceral (P = 0.001) fat, fasting insulin (r = 0.321; P = 0.03) and change in NEFA concentrations (r = 0.285; P = 0.047). Furthermore, exposure of in vitro cultured myotubes to MUF, but not SF, reduced IGFBP2 mRNA suggesting a converse direct effect. In conclusion, diets high in fat, but not sugar, promote visceral adiposity and insulin resistance in maturing pigs, with evidence that fatty acids have direct and indirect effects on IGFBP2 mRNA expression in muscle.

IGF binding protein (IGFBP)-2 is one of the most significant genes in the signature of major aggressive cancers. Previously, we have shown that IGFBP-2 enhances proliferation and invasion of neuroblastoma cells, suggesting that IGFBP-2 activates a protumorigenic gene expression program in these cells. Gene expression profiling in human neuroblastoma SK-N-SHEP (SHEP)-BP-2 cells indicated that IGFBP-2 overexpression activated a gene expression program consistent with enhancement of tumorigenesis. Regulation was significant for genes involved in proliferation/survival, migration/adhesion, and angiogenesis, including the up-regulation of vascular endothelial growth factor (VEGF) mRNA (>2-fold). Specific transcriptional activation of the VEGF gene by IGFBP-2 overexpression was demonstrated via cotransfection of a VEGF promoter Luciferase construct in SHEP-BP-2. Cotransfection of VEGF promoter Luciferase construct with IGFBP-2 protein in wild-type SHEP cells indicated that transactivation of VEGF promoter only occurs in the presence of intracellular IGFBP-2. Cell fractionation and immunofluorescence in SHEP-BP-2 cells demonstrated nuclear localization of IGFBP-2. These findings suggest that transcriptional activation of VEGF promoter is likely to be mediated by nuclear IGFBP-2. The levels of secreted VEGF (up to 400 pg/10(6) cells) suggested that VEGF might elicit angiogenic activity. Hence, SHEP-BP-2 cells and control clones cultured in collagen sponge were xenografted onto chick embryo chorioallantoic membrane. Neomicrovascularization was observed by 72 h, solely in the SHEP-BP-2 cell xenografts. In conclusion, our data indicate that IGFBP-2 is an activator of aggressive behavior in cancer cells, involving nuclear entry and activation of a protumorigenic gene expression program, including transcriptional regulation of the VEGF gene and consequent proangiogenic activity of NB cell xenografts in vivo.

While oestrogen is recognized to play a key role in regulating growth, particularly in relation to epiphyseal fusion, the mechanisms that mediate its effects are still unclear. We utilized an in vitro model of chondrogenesis, the RCJ3.1C5.18 cell line, to explore the effect of oestrogen on this process. We demonstrated the presence of oestrogen receptors (ER) α and β in these cells, with increased abundance of both receptor sub-types evident as the cells differentiated. ERα localized to the nucleus, suggesting it was signalling by genomic pathways, while ERβ was seen predominantly in the cytoplasm, suggesting it may be utilizing non-genomic signalling. While exogenous oestrogen had no effect on proliferation or differentiation, we found some evidence for the endogenous production of oestrogen (intracrinology), as suggested by the expression of aromatase in these cells. Selective ERα blockade with methyl piperidinopyrazole (MPP) led to a significant reduction in both proliferation and differentiation, while ERβ blockade with R,R tetrahydrochrysene (THC) led to an increase in these parameters. This is in keeping with results from mouse knockout models suggesting that unopposed ERβ signalling leads to an inhibition of skeletal growth. Our results are further evidence for the importance of differential ER signalling in regulating chondrogenesis. Future studies examining in vivo effects of these agents are required to extrapolate these findings to a mammalian model.

The growth hormone/insulin-like growth factor-I (IGF-I) axis is at the centre of normal human childhood growth. Six well characterised binding proteins (IGFBP-1 to IGFBP-6) act as general carriers of IGF-I, but they also modulate IGF-I bioavailability and activity in a tissue-specific, and developmentally appropriate, manner. Recent findings also point to several binding proteins possessing specific 'lGF-independent' actions and, in particular, there is now substantial evidence linking IGFBP-2 with nutritional status and insulin sensitivity. IGFBP-2 concentrations are reduced in obesity, and further reductions are seen in those with Type 2 diabetes. As IGFBP-2 is the major IGFBP expressed in infancy, and is also the predominant IGFBP produced from adipocytes, it is ideally positioned to act as a keystone between nutrition, growth and metabolism. Childhood obesity is associated with an increased risk of long-term morbidity and mortality, but the factors that determine which obese children will develop these long-term complications are not fully understood. IGFBP-2 may be integrally involved in the molecular processes that govern the development of obesity and subsequent weight-related disease. Within this manuscript, we explore the associations between IGFBP-2 and obesity with a particular emphasis on how an increased understanding of the role of IGFBP-2 in metabolism may lead to improvements in the prevention and treatment of childhood obesity.

Childhood overweight and obesity is highly prevalent within society. In the majority of individuals, weight gain is the result of exposure to an 'obesogenic' environment, superimposed on a background of genetic susceptibility brought about by evolutionary adaptation. These individuals tend to be tall in childhood with a normal final adult height, as opposed to those who have an underlying monogenic cause where short stature is more common (although not universal). Identifying genetic causes of weight gain, or tall stature and overgrowth, within this setting can be extremely problematic and yet it is imperative that clinicians remain alert, as identification of a genetic diagnosis has major implications for the individual, family and potential offspring. Alongside this, the recognition of new genetic mutations in this area is furthering our knowledge on the important mechanisms that regulate childhood growth and body composition. This review describes the genetic syndromes associated with obesity and overgrowth., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Type 2 diabetes mellitus (T2DM) is emerging as a significant clinical problem within the pediatric population., Objective: The objective of this study was to identify patients with T2DM in a large tertiary hospital diabetes service and examine aspects relating to clinical course and management., Methods: An initial audit of our diabetes service (over 6 yr) was followed by a 2-yr period of prospective case ascertainment to identify patients with T2DM. Comprehensive data collection was then undertaken in these individuals., Results: Within our service (n = 1574), 33 young people with T2DM were identified. Significant levels of co-morbidity were evident - dyslipidaemia (56%), microalbuminuria (45%), hypertension (30%) and abnormal retinal findings (25%). Hypertension was more likely in those with greater initial and follow-up body mass index (BMI) [mean (SD) BMI: 36.3 (5.0) vs. 28.0 (6.3) kg/m(2) , p = 0.001, and 36.8 (5.3) vs. 28.5 (7.8) kg/m(2) , p = 0.007, respectively] and BMI standard deviation score (SDS) [mean (SD) BMI SDS: 2.34 (0.30) vs. 1.72 (0.66), p = 0.001, and 2.26 (0.31) vs. 1.38 (0.87), p < 0.001, respectively], whereas abnormal retinal findings were seen in those with higher HbA1c values at last appointment [geometric mean (range) 10.9 (8.4-13.6) vs. 7.4 (5.6-12.5)%, p = 0.01) and those with greater increases in HbA1c over time (+4.1 (3.1) vs. +0.2 (1.9)%, p = 0.009). Of the 33,9 (27%) were lost to follow-up., Conclusions: At present, T2DM in youth remains a low burden on our services. Patients with this diagnosis, however, have significant problems that present a major challenge to the development of effective management strategies., (© 2010 John Wiley & Sons A/S.)

Aromatase inhibitors have been increasingly used in boys with growth retardation to prolong the duration of growth and increase final height. Multiple important roles of oestrogen in males point to potential adverse effects of this strategy. Although the deleterious effects of aromatase deficiency in early childhood and adulthood are well documented, there is limited information about the potential long-term adverse effects of peripubertal aromatase inhibition. To address this issue, we evaluated short-term and long-term effects of peripubertal aromatase inhibition in an animal model. Peripubertal male Wistar rats were treated with aromatase inhibitor letrozole or placebo and followed until adulthood. Letrozole treatment caused sustained reduction in bone strength and alteration in skeletal geometry, lowering of IGF1 levels, inhibition of growth resulting in significantly lower weight and length of treated animals and development of focal prostatic hyperplasia. Our observation of adverse long-term effects after peripubertal male rats were exposed to aromatase inhibitors highlights the need for further characterisation of long-term adverse effects of aromatase inhibitors in peripubertal boys before further widespread use is accepted. Furthermore, this suggests the need to develop more selective oestrogen inhibition strategies in order to inhibit oestrogen action on the growth plate, while beneficial effects in other tissues are preserved.

Objective: Type 1 diabetes in youth and community controls were compared on functional outcomes. Relationships were examined between psychosocial variables at diagnosis and functional outcome 12 years later., Research Design and Methods: Participants were subjects with type 1 diabetes (n = 110, mean age 20.7 years, SD 4.3) and control subjects (n = 76, mean age 20.8 years, SD 4.0). The measures used included the Youth Self-Report and Young Adult Self-Report and a semi-structured interview of functional outcomes. Type 1 diabetes participants also provided information about current diabetes care and metabolic control from diagnosis., Results: Type 1 diabetes participants and control subjects reported similar levels of current well-being but for the youth with type 1 diabetes, the mental health referral rates over the previous 12 years were higher by 19% and school completion rates were lower by 17%. Over one-third of clinical participants were not currently receiving specialist care and this group had higher mental health service usage in the past (61 vs. 33%) and lower current psychosocial well- being. Within the type 1 diabetes group, behavior problems, high activity, and low family cohesion at diagnosis predicted lower current well-being, but were not associated with metabolic control history. Poorer metabolic control was associated with higher mental health service usage., Conclusions: Type 1 diabetes participants report similar levels of current psychosocial well-being compared with control subjects, but higher levels of psychiatric morbidity since diagnosis and lower school completion rates. Psychiatric morbidity was associated with poor metabolic control and failure to transition to tertiary adult diabetes care.

Background: Lowered neuropsychological performance is evident in youth with type 1 diabetes, although evidence for associations with specific illness variables is inconsistent. This study examined the neuropsychological profiles of a cohort of youth with type 1 diabetes studied prospectively from diagnosis 12 yr previously., Methods: A total of 106 youth with type 1 diabetes and 75 healthy controls participated. There were no significant group differences on Full-scale IQ assessed on study entry 12 yr previously, current socioeconomic status, gender distribution, or age. Neuropsychological tests assessed eight cognitive domains: verbal abilities, perceptual reasoning, new learning, working memory, non-verbal processing speed, mental efficiency, divided attention, and sustained attention. Episodes of serious hypoglycemia and HbA(1c) levels were recorded from diagnosis., Results: Youth with type 1 diabetes performed more poorly than controls on working memory (p < .05). Early onset diabetes was related to poorer sustained (p < .001) and divided attention (p = .001), new learning, and mental efficiency (both p < .05). Hypoglycemia was found to adversely effect verbal abilities, working memory, and non-verbal processing speed (all p < .05). Poorer working memory was associated with hyperglycemia (p < .05). Youth with any combination of two or three illness risk factors (i.e., early onset diabetes, hypo-, hyperglycemia), performed more poorly than controls and youth with no or one risk on verbal abilities, working memory, and mental efficiency., Conclusions: This study documents poorer neuropsychological performance and its association with illness risk factors in youth with type 1 diabetes. Findings suggest that early disease onset and hypoglycemia impact on the developing central nervous system, with hyperglycemia playing a lesser role.

Background: During recovery from an ischemic brain injury, a cerebral growth hormone (GH) axis is activated. Whilst GH has been demonstrated to be neuroprotective both in vitro and in vivo, a role for GH in neuro-restorative processes after brain injury has yet to be studied., Objective: To explore a role for GH in injury-induced neurogenesis by examining GH receptor (GH-R) immunoreactivity within the subventricular zone (SVZ) of juvenile rats after brain injury and by testing the proliferative capacity of GH on embryonic mouse neural stem cells., Design: Twenty-one day old rats were subjected to unilateral hypoxic-ischemia of the brain and sacrificed 1-15days later. Coronal brain sections from these animals and age-matched naïve controls were immunostained for GH-R and cell markers of neurogenesis. The level of GH-R immunoreactivity in the ipsilateral and contralateral SVZ of each animal was semi-quantified both by independent blinded scoring by two examiners and blinded image analysis. To examine the effect of GH on proliferation of embryonic mouse neural stem cells, cells were treated with increasing concentrations of rat pituitary GH for 48h in the presence of 5'-bromo-2'-deoxyuridine., Results: The level of GH-R immunoreactivity in the ipsilateral SVZ was significantly increased 5days after injury vs. the contralateral SVZ, coinciding both spatially and temporally with injury-induced neurogenesis. The population of GH-R immunopositive cells in the ipsilateral SVZ at this time was found to include proliferating cells (Ki67 immunopositive), neural progenitor cells (nestin immunopositive) and post-proliferative migratory neuroblasts (doublecortin immunopositive). Stimulation of embryonic mouse NSCs with physiological concentrations of rat pituitary GH elicited a dose-dependent proliferative response., Conclusion: These results indicate a novel role for GH and its receptor in injury-induced neurogenesis, and suggest that GH treatment may potentiate endogenous neuro-restorative processes after brain injury.

Obesity is rife within the community, and associated conditions such as type 2 diabetes and cardiovascular disease threaten the future health of our children. While type 2 diabetes has been the focus of much media attention, type 1 diabetes mellitus remains the commonest form of newly diagnosed diabetes in childhood. This case study acts to remind practitioners that all young people (even those with established obesity) who present with symptoms, and/or biochemical derangements compatible with diabetes, should be managed acutely in order to avoid a delayed diagnosis of type 1 diabetes.

We have recently demonstrated that fibroblast growth factor (FGF)-2 promotes neuroblastoma cell differentiation and overrides their mitogenic response to IGF-I. However, the mechanisms involved are unknown. SK-N-MC cells were cultured with FGF-2 (50 ng/ml) and/or IGF-I (100 ng/ml) up to 48 h. Fluorescence-activated cell sorting analysis indicated that FGF-2 promotes G1/G0 cell cycle phase arrest. Gene expression by RT2-PCR and cellular localization showed up-regulation of p21. We then investigated whether FGF-2-induced differentiation of SK-N-MC cells (by GAP43 and NeuroD-6 expression) involves epithelium-mesenchyme transition interconversion. Real-time PCR (RT2-PCR) showed modulation of genes involved in maintenance of the epithelial phenotype and cell-matrix interactions (E-cadherin, Snail-1, MMPs). Zymography confirmed FGF-2 up-regulated MMP2 and induced MMP9, known to contribute to neuronal differentiation and neurite extension. Id1-3 expression was determined by RT2-PCR. FGF-2 induced Id2, while down-regulating Id1 and Id3. FGF-2 induced nuclear accumulation of ID2 protein, while ID1 and ID3 remained cytoplasmic. RNA interference demonstrated that Id3 regulates differentiation and cell cycle (increased Neuro-D6 and p21 mRNA), while d Id2 modulates epithelium-mesenchyme transition-like events (increased E-cadherin mRNA). In conclusion, we have shown for the first time that FGF-2 induces differentiation of neuroblastoma cells via activation of a complex gene expression program enabling modulation of cell cycle, transcription factors, and suppression of the cancer phenotype. The use of RNA interference indicated that Id-3 is a key regulator of these events, thus pointing to a novel therapeutic target for this devastating childhood cancer.

The hypoxia inducible factor-1alpha (HIF1alpha) is a key regulator of oxygen homeostasis, modulating cell survival, and growth in cells exposed to hypoxia. In this study, neuroblastoma (NB) cells SH-SY5Y and SK-N-MC were employed to determine the mechanisms regulating adaptation to hypoxia. NB cells were cultured in a serum-free medium in the presence or absence of CoCl(2) (100 muM, hypoxia mimic) for up to 48 h. SH-SY5Y and SK-N-MC cell numbers were not affected by CoCl(2) treatment, while mitochondrial activity was reduced by approximately 50% in SH-SY5Y cells and by approximately 70% in SK-N-MC cells. Intracellular accumulation of HIF1alpha protein was detected as early as 30 min of post-hypoxia, followed by the increase of mRNA for vascular endothelial growth factor (VEGF) and nuclear accumulation of the ID1-2 transcription factors by 4 h. In hypoxic SH-SY5Y NB cells, real-time PCR analysis showed that the genes involved in maintenance of cell-cell and cell-matrix interactions (i.e. adenomatosis polyposis coli, E-cadherin, catenin, EphB2, fibronectin-1, HTATIP2, tissue inhibitor of metalloprotease-4) were down-regulated by up to 90%, while genes involved in enhancement of metastatic behavior (integrin a7b1, hepatocyte growth factor receptor, transforming growth factor-beta1, VEGF, kisspeptin, interleukin-1beta) were dramatically up-regulated above 200%. These changes were all consistent with the induction of epithelial-mesenchymal transition. We have thus demonstrated that NB cell adaptation to hypoxia, in addition to the modulation of HIF1alpha and VEGF expression and nuclear translocation of ID1 and ID2 transcription factors, involve in the activation of a gene expression program consistent with the pro-metastatic events. These processes are probably responsible for the NB cell transition from an adherent phenotype to a highly migratory, invasive and aggressive NB cell type.

Objective: In this study, we used neurocognitive assessment and neuroimaging to examine brain function in youth with type 1 diabetes studied prospectively from diagnosis., Research Design and Methods: We studied type 1 diabetic (n = 106) and control subjects (n = 75) with no significant group difference on IQ at baseline 12 years previously by using the Wechsler Abbreviated Scale of General Intelligence, magnetic resonance spectroscopy and imaging, and metabolic control data from diagnosis., Results: Type 1 diabetic subjects had lower verbal and full scale IQs than control subjects (both P < 0.05). Type 1 diabetic subjects had lower N-acetylaspartate in frontal lobes and basal ganglia and higher myoinositol and choline in frontal and temporal lobes and basal ganglia than control subjects (all P < 0.05). Type 1 diabetic subjects, relative to control subjects, had decreased gray matter in bilateral thalami and right parahippocampal gyrus and insular cortex. White matter was decreased in bilateral parahippocampi, left temporal lobe, and middle frontal area (all P < 0.0005 uncorrected). T2 in type 1 diabetic subjects was increased in left superior temporal gyrus and decreased in bilateral lentiform nuclei, caudate nuclei and thalami, and right insular area (all P < 0.0005 uncorrected). Early-onset disease predicted lower performance IQ, and hypoglycemia was associated with lower verbal IQ and volume reduction in thalamus; poor metabolic control predicted elevated myoinositol and decreased T2 in thalamus; and older age predicted volume loss and T2 change in basal ganglia., Conclusions: This study documents brain effects 12 years after diagnosis in a type 1 diabetic sample whose IQ at diagnosis matched that of control subjects. Findings suggest several neuropathological processes including gliosis, demyelination, and altered osmolarity.

Estrogen plays a key role in the regulation of growth in both genders, via its stimulation of the pubertal growth spurt and mediation of epiphyseal fusion. Mouse knockout models suggest a differential effect of oestrogen receptor (ER) alpha and beta on the growth plate, with ER beta possibly being more important in regulating epiphyseal fusion. Epiphyseal fusion may also depend on growth plate senescence, which is regulated by oestrogen. While molecular mechanisms for oestrogen's actions remain unclear, local production of oestrogen may be important for growth. Aromatase inhibitors appear to be effective in improving final height outcome in short stature, however long term safety data is lacking particularly in regards to reproductive function. Future studies are required to further understand the mechanisms by which ER alpha and ER beta affect growth plate function, while longer term studies of aromatase inhibitor usage, preferably utilising animal models, are required to verify the safety of these compounds.