Novel mutations and genes that impact on growth in short stature of undefined aetiology: the EPIGROW study. Supplemental data

Supplemental data from the European EPIGROW Study

Maternal Factors in Pregnancy and Ethnicity Influence Childhood Adiposity, Cardiac Structure, and Function

ImportanceThe links between maternal and offspring adiposity and metabolic status are well established. There is much less evidence for the impact of these relationships combined with ethnic background on cardiac structure and function in childhood.ObjectiveTo test the hypothesis that ethnicity, maternal adiposity and glycemic status, and child adiposity affect cardiac structure and function.DesignA prospective cohort study.SettingA single-center mother-child cohort study. The cohort is a subset of the international multi-center Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study.ParticipantsThis study included 101 healthy pre-pubertal British-born children [56 White Europeans (WEs) and 45 South Asians (SAs)] with a median age of 9.1 years, range 6.0–12.2 years, at the time of the investigation.Main Outcomes and MeasuresAnthropometric and echocardiographic measurements were made on the cohort. Maternal pregnancy and birth data were available. Relationships between maternal parameters (BMI and glucose status), child adiposity, and echo measures were assessed.ResultsDespite no ethnic difference in BMI SDS at a median age of 9.1 years, SA children exhibited higher levels of body fat than WE children (whole body, right arm, and truncal fat all p < 0.001). SA children also exhibited greater changes in weight and height SDS but not BMI SDS from birth than WE children. As expected, maternal BMI correlated with child BMI (r = 0.28; p = 0.006), and body fat measures (e.g., whole body fat r = 0.25; p = 0.03). Maternal fasting glucose levels were associated with child body fat measures (r = 0.22–0.28; p = 0.02–0.05). Left ventricular (LV) indices were not different between SA and WE children, but E/A and E′/A′ (measures of diastolic function) were lower in SA when compared with WE children. LV indices correlated positively to BMI SDS and body fat markers only in SA children. Maternal fasting and 2-h glucose were negatively correlated with E′/A′ in SA children (r = −0.53, p = 0.015, and r = −0.49, p = 0.023, respectively) but not in WE children.Conclusion and RelevanceSA and WE children exhibit differences in adiposity and diastolic function at a median age of 9.1 years. Novel relationships between maternal glycemia, child adiposity, and cardiac structure and function, present only in SA children, were identified

Metabolites involved in glycolysis and amino acid metabolism are altered in short children born small for gestational age

BACKGROUND: Later life metabolic dysfunction is a well-recognised consequence of being born Small for Gestational Age (SGA). This study has applied metabolomics to identify whether there are changes in these pathways in pre-pubertal short SGA children and aimed to compare the intracellular and extracellular metabolome in fibroblasts derived from healthy children and SGA children with post-natal growth impairment. METHODS: Skin fibroblast cell lines were established from eight SGA children (age 1.8 -10.3 years) with failure of catch-up growth and from three healthy control children. Confluent cells were incubated in serum free media and the spent growth medium (metabolic footprint) and intracellular metabolome (metabolic fingerprint) were analysed by gas-chromatography mass spectrometry. RESULTS: 19 metabolites were significantly altered between SGA and control cell lines. The greatest fold difference (FD) was seen for alanine (fingerprint FD, SGA: control) 0.3, p=0.01 and footprint FD=0.19, p=0.01), aspartic acid (fingerprint FD=5.21, p=0.01) and cystine (footprint FD=1.66, p=0.02). Network analysis of the differentially expressed metabolites predicted inhibition of insulin and activation of ERK/AKT/PI3K signalling in SGA cells. CONCLUSIONS: This study indicates that changes in cellular metabolism associated with both growth failure and insulin insensitivity are present in pre-pubertal short children born SGA

A Pilot Interventional Study to Evaluate the Impact of Cholecalciferol Treatment on HbA1c in Type 1 Diabetes (T1D)

Background Higher 25(OH)D3 levels are associated with lower HbA1c, but there are limited UK interventional trials assessing the effect of cholecalciferol on HbA1c. Aims (1) To assess the baseline 25(OH)D3 status in a Manchester cohort of children with type 1 diabetes (T1D). (2) To determine the effect of cholecalciferol administration on HbA1c. Methods Children with T1D attending routine clinic appointments over three months in late winter/early spring had blood samples taken with consent. Participants with a 25(OH)D3 level &lt;50 nmol/L were treated with a one-off cholecalciferol dose of 100,000 (2–10 years) or 160,000 (&gt;10 years) units. HbA1c levels before and after treatment were recorded. Results Vitamin D levels were obtained from 51 children. 35 were Caucasian, 11 South Asian and 5 from other ethnic groups. 42 were vitamin D deficient, but 2 were excluded from the analysis. All South Asian children were vitamin D deficient, with mean 25(OH)D3 of 28 nmol/L. In Caucasians, there was a negative relationship between baseline 25(OH)D3 level and HbA1c (r = −0.484, P &lt; 0.01). In treated participants, there was no significant difference in mean HbA1c at 3 months (t = 1.010, P = 0.328) or at 1 year (t = −1.173, P = 0.248) before and after treatment. One-way ANCOVA, controlling for age, gender, ethnicity, BMI and diabetes duration showed no difference in Δ HbA1c level. Conclusion We report important findings at baseline, but in children treated with a stat dose of cholecalciferol, there was no effect on HbA1c. Further studies with larger sample sizes and using maintenance therapy are required. </jats:sec