Vascular Function and Distribution of Adiponectin Isomers during Puberty in Children and Adolescents with Obesity.

INTRODUCTION: Youth with obesity have abnormal vascular function that relates to the anti-atherogenic adipose-derived hormone, adiponectin. The distribution of adiponectin isomers changes during normal puberty, but there are no data in relation to vascular function. We aimed to evaluate vascular function, adiponectin, and its isomers longitudinally in peri-pubertal youth with obesity and controls. METHODS: The study is a cohort longitudinal study involving 30 children and adolescents with obesity (body mass index [BMI] z-score 2.31 ± 0.24; age 12.8 ± 3 years, 17 male participants) and 28 age-/sex-matched healthy controls (12.8 ± 3 years, 14 male participants). Vascular function (flow-mediated dilatation [FMD], glyceryl trinitrate-mediated dilatation [GTN]), total adiponectin and isomers, and laboratory and clinical variables were assessed at 0, 18, and 36 months. RESULTS: FMD and GTN were stable during puberty in both groups, remaining consistently lower in obese children (p = 0.02, p < 0.001). The change in total (p = 0.02) and high-molecular weight (HMW) (p = 0.02) adiponectin differed between the groups: falling in controls by the end of puberty but not falling further during puberty in obesity. In obesity, impaired GTN was associated longitudinally with lower total (B = 7.85, p = 0.006) and HMW (B = 3.72, p = 0.03) adiponectin. In controls, more favourable GTN was longitudinally associated with a lower BMI z-score (B = -3.04, p = 0.027) and lower waist circumference (B = -0.35, p = 0.009). CONCLUSIONS: Vascular dysfunction and lower levels of adiponectin are associated in children and adolescents with obesity during puberty and do not deteriorate further. Healthy children's better vascular function, within the normal range, is associated with a lower BMI z-score and waist circumference.

High dose folic acid is a potential treatment for pulmonary hypertension, including when associated with COVID-19 pneumonia.

BACKGROUND: Pulmonary hypertension is a significant complication for some patients with COVID-19 pneumonia, especially those requiring intensive care. Tachyphylaxis to the current therapy, inhaled nitric oxide (iNO), is also common. In vitro, folic acid directly increases nitric oxide (NO) production and extends its duration of action; effects which could be of benefit in reversing pulmonary hypertension and severe hypoxaemia. Our work has shown that, in the systemic circulation, folic acid in high dose rapidly improves nitric oxide mediated vasodilation, by activating endothelial nitric oxide synthase (eNOS). HYPOTHESIS: A similar effect of high dose folic acid on pulmonary endothelial function would be expected from the same mechanism and would lead to improvement in pulmonary perfusion. We therefore hypothesise that folic acid, 5 mg or greater, is a useful therapeutic option for pulmonary hypertension and/or refractory severe hypoxaemia, in patients with severe COVID-19 associated pneumonia in whom NO therapy is considered, with a very low risk of adverse effects.

Adherence to metformin is reduced during school holidays and weekends in children with type 1 diabetes participating in a randomised controlled trial.

BACKGROUND: Non-adherence to treatment in childhood chronic illness has serious consequences for health and healthcare costs. Accurate detailed objective data on adherence are minimal in this age group. OBJECTIVE: To evaluate medication adherence using electronic monitoring systems in children with type 1 diabetes (T1D). DESIGN: A cohort study of 90 T1D children (aged 13.6±2.5 years, 41 males) from two paediatric diabetes clinics, participated in a 12-month double-blind, randomised, placebo-controlled trial (1:1 allocation). This cohort provided 28 336 days of study observations; 7138 school holiday and 8875 weekend/public holiday days. METHOD: Adherence to intervention (metformin (n=45) or placebo (n=45)) was measured objectively by Medication Event Monitoring Systems (MEMS) including proportion of medication doses taken and daily adherence patterns and by tablet count at 3, 6 and 12 months. The trial was completed in June 2015. RESULTS: There was an average (SD) of 363.3 (42) days of MEMS observations available for each study participant (94.1 (12.6) school holiday days and 117.1 (13.4) weekend/public holiday days). Adherence reduced during school holidays (adjusted OR (aOR) 0.81; 95% CI 0.72 to 0.91; p<0.001) and during weekends/public holidays (aOR 0.74; 95% CI 0.69 to 0.80; p<0.001). Adverse effects to the intervention did not affect overall adherence (aOR 0.77; 95% CI 0.3 to 2.01; p=0.6). Age, gender, body mass index, diabetes duration, insulin dose, HbA1c (Haemoglobin A1c) or socioeconomic status did not predict adherence. CONCLUSION: Medication adherence was reduced during school holidays and on weekends in children with T1D. Clinical characteristics including socioeconomic status and the presence of adverse effects did not predict adherence. TRIAL REGISTRATION NUMBER: ACTRN12611000148976.

Children With Type 1 Diabetes Have Delayed Flow-Mediated Dilation.

OBJECTIVES: Children with type 1 diabetes have accelerated atherosclerosis with early endothelial dysfunction as measured by reduced flow-mediated dilation (FMD) at 60 seconds postischemic stress (early FMD). Delayed dilation may also occur in the presence of cardiovascular risk factors and may be a more sensitive marker. No data exist that evaluate FMD beyond 60 seconds (delayed FMD) in children with type 1 diabetes. We aimed to compare early and delayed FMD in children with type 1 diabetes and in healthy children. METHODS: We studied 66 children 13.5±2.8 years of age; 29 were males. Of the 66 children, 38 had type 1 diabetes, and 28 were healthy age- and gender-matched controls. Evaluation of brachial artery FMD was performed at 60 seconds (FMD60s) and 120 seconds (FMD120s) postischemic stress. Early FMD was defined as peak FMD60s and delayed FMD as peak FMD120s. RESULTS: Children with type 1 diabetes had diabetes durations of 5.4±4.6 years and median glycated hemoglobin levels of 8.8 (6.6 to 14)% (73 [49 to 130] mmol/mol). Of the children, 8 with type 1 diabetes and 1 healthy child had delayed FMD; a relationship was seen between the prevalence of early FMD and delayed FMD in children with type 1 diabetes and healthy children, respectively (p=0.019). Children with type 1 diabetes and delayed FMD had lower FMD60s than children without delayed FMD (2.50±3.61 vs. 6.14±3.83 percentage units; p=0.02). Children with type 1 diabetes had lower FMD60s than healthy children (5.38±4.0 percentage units; p=0.03) but not FMD120s (7.56±3.5 percentage units; p=0.47). CONCLUSIONS: Delayed FMD patterns occur in children with type 1 diabetes and detect children who have more severe vascular abnormalities. The standard FMD60s remains the better marker to identify children at increased risk for cardiovascular disease.

Laparoscopic Adjustable Gastric Banding in Australian Adolescents: Should It Be Done?

OBJECTIVE: There are very few studies on laparoscopic adjustable gastric banding (LAGB) in obese adolescents with follow up for more than 36 months, let alone good prospective data beyond 24 months in Australian adolescents. We aimed to evaluate medium term (>36 months) safety and efficacy of LAGB in adolescents with severe obesity. METHODS: This is a prospective cohort study (March 2009-December 2015) in one tertiary referral hospital including obese adolescents (14-18 years) with a body mass index (BMI) >40 (or ≥35 with comorbidities) who consented to have LAGB. Exclusion criteria were syndromal causes of obesity, depression and oesophageal motility disorders. Main outcome measures include change in weight and BMI at 6, 12, 24, 36 and 48 months post LAGB; postoperative complications; and admissions. RESULTS: Twenty-one adolescents (median [interquartile range (IQR)] 17.4 [16.5-17.7] years, 9 males, mean ± SD BMI 47.3 ± 8.4 kg/m2) had a median follow up of 45.5 [32-50] months post LAGB. Follow up data were available for 16 adolescents. Weight and BMI improved significantly at all follow up times (all p < 0.01). The median maximum BMI loss was 10 [7.1-14.7] kg/m2. There were four minor early complications. Seven bands were removed due to weight loss failure/regain (two had also obstructive symptoms). CONCLUSIONS: We have shown in the longest prospective LAGB postoperative follow up study of Australian adolescents that LAGB improves BMI in the majority of adolescents without significant comorbidities. LAGB is still a reasonable option to be considered as a temporary procedure to manage severe obesity during adolescence.

Folate fortification and supplementation do not provide vascular health benefits in type 1 diabetes.

OBJECTIVE: To evaluate the lowest effective dose-response of folic acid on endothelial function in children with type 1 diabetes. STUDY DESIGN: A randomized, double-blind, crossover, placebo-controlled trial was conducted in 20 children with type 1 diabetes (age range 10-18 years) after mandatory folate fortification in Australia. Each child received orally 4 interventions (1 per month)-3 folic acid doses (0.5, 2, and 5 mg) and 1 placebo dose--in random order. The primary outcome was 2-hour postintervention change in endothelial function measured with flow-mediated dilatation (FMD). Thirty-five children with type 1 diabetes from our folic acid interventional trial before folate fortification were used for comparison. RESULTS: All children completed the study. There were no differences in baseline FMD or folate status between the visits. Folic acid supplementation increased serum folate (P = .0001) and red cell folate (P < .0001), but none of the doses improved FMD (P = .96). Baseline serum folate and red cell folate levels and FMD and glyceryl trinitrate-mediated dilatation were significantly higher in these children compared with children from our trial before mandatory folate fortification (P = .0001, .0001, .014, and .04, respectively). CONCLUSIONS: Folate status and vascular function have improved in children with type 1 diabetes since the introduction of mandatory folate fortification, but the beneficial endothelial effects of additional folic acid are no longer present.

Adiponectin relates to smooth muscle function and folate in obese children.

OBJECTIVE: Adiponectin, an adipocyte-specific protein, stimulates nitric oxide production and may mediate associations between visceral obesity and vascular dysfunction. Adiponectin is lower in obese children but its relationship with vascular function has not been clarified in childhood. We aimed to evaluate the association between adiponectin and vascular function in obese and healthy children. METHODS: Forty-nine obese and thirty-three non-obese children (aged 13.4+/-2.8 years, 37 males) participated in a cross-sectional study. We measured adiponectin, vascular endothelial and smooth muscle function (Flow mediated dilatation [FMD] and glyceryl trinitrate induced dilatation [GTN]), serum folate, red cell folate (RCF), homocysteine, lipids, glucose and insulin. Because adiponectin related to RCF we examined the effect of folate supplementation on adiponectin levels in obese children in a previously conducted randomized folate intervention trial. This included two assessments prior to intervention and two post intervention. RESULTS: Adiponectin, FMD and GTN were lower in obese compared with non-obese children (p = 0.002, p = 0.03 and p < 0.001, respectively). In obesity, adiponectin related to GTN (beta = 0.46, p < 0.001), RCF (beta = 0.4, p = 0.001) and LDL cholesterol (beta = 0.33, p = 0.004). Adiponectin associations were affected by gender and adiponectin related to female gender (B = 0.22, p = 0.03). During the intervention trial, folic acid did not improve adiponectin levels (p = 0.8) in spite of increasing serum folate and RCF (p < 0.001, p < 0.001, respectively) and decreasing homocysteine levels (p = 0.008). CONCLUSIONS: Obese children have lower adiponectin, which relates to decreased smooth muscle function and lower folate status. Despite adiponectin relating to folate status, folic acid supplementation does not improve adiponectin in obese children.

Vascular endothelial and smooth muscle function relates to body mass index and glucose in obese and nonobese children.

CONTEXT: Endothelial and smooth muscle dysfunction are critical precursors of atherosclerosis. These can be detected in children at risk of cardiovascular disease. OBJECTIVE: The objective of this study is to evaluate endothelial and smooth muscle function and their determinants using flow-mediated dilatation (FMD) and glyceryl trinitrate-mediated dilatation (GTN) in obese, nonobese, and type 1 diabetes mellitus (T1DM) children. DESIGN: This is a cross-sectional study. SUBJECTS: The study subjects were 270 children [140 males, mean age 13.7 (2.8) yr] including 58 obese, 53 nonobese, and 159 T1DM children. MEASUREMENTS: Vascular function (FMD and GTN), body mass index (BMI) z-score, blood pressure, glucose, glycosylated hemoglobin, lipids, folate, homocysteine, and high sensitive C-reactive protein were measured. RESULTS: FMD and GTN were significantly lower in obese and T1DM compared with nonobese subjects (P < 0.001, P < 0.001). FMD and GTN were similarly reduced in obese and T1DM subjects (P = 0.22, P = 0.28). In all nondiabetic subjects (n = 111), both FMD and GTN were significantly and independently related to BMI z-score (r = -0.28, P = 0.003, beta = -0.36, P < 0.001) and weight z-score (beta = -0.31, P = 0.002; r = -0.52, P < 0.001). FMD related independently to total cholesterol (beta = -0.22, P = 0.02). GTN related independently to vessel diameter (beta = -0.49, P < 0.001). GTN related to glucose within the normal range (r = -0.34, P = 0.001). CONCLUSIONS: Children with obesity and T1DM have a similar degree of vascular dysfunction. BMI and weight adjusted for age and sex relate to endothelial and smooth muscle function in nonobese and obese children. Glucose relates to smooth muscle function in nonobese nondiabetic children. This suggests a continuum effect of BMI and glucose within the normal range on vascular function in childhood.

Folic acid improves endothelial function in children and adolescents with type 1 diabetes.

OBJECTIVE: To evaluate the effect of folate supplementation on endothelial function in children and adolescents with type 1 diabetes. STUDY DESIGN: Thirty-six subjects with type 1 diabetes age 13.6+/-2.6 years completed a randomized, double-blind, placebo-controlled crossover trial. Each subject received 8 weeks of oral folic acid (5 mg/d) and 8 weeks of placebo, with an 8-week washout period. Before and after each intervention, we assessed endothelial function by using brachial artery responses to flow (flow-mediated dilatation [FMD]) and glyceryl trinitrate, von Willebrand factor, glucose, hemoglobin A1c, total plasma homocyst(e)ine (tHcy), vitamin B(12), serum folate, and red cell folate (RCF). RESULTS: Folic acid increased FMD by 2.58 (3.1-5.7) % (95% confidence interval, 1.28-3.88), whereas placebo did not change FMD (-0.42%; 95% confidence interval, -1.67 to 0.83; P<.001). Folic acid increased serum folate by 14 nmol/L (6.2 ng/mL, P<.001) and RCF by 467.2 nmol/L (206 ng/mL, P<.001). Change in FMD was related to change in serum folate (r=0.46, P=.005) and RCF (r=0.39, P=.02). Glyceryl trinitrate responses, von Willebrand factor, tHcy, and hemoglobin A1c were not affected by the intervention. CONCLUSIONS: Short-term high-dose folic acid improves endothelial function in children and adolescents with type 1 diabetes and normal folate status independently of tHcy.