Shawn Sweeten

Obesity without Established Comorbidities of the Metabolic Syndrome Is Associated with a Proinflammatory and Prothrombotic State, Even before the Onset of Puberty in Children

BACKGROUND Metabolic syndrome (MS)-related comorbidities in obesity, such as hypertension, dyslipidemia, and glucose intolerance, are increasingly recognized in children, predisposing them to early cardiovascular disease. OBJECTIVE The objective of the study was to investigate whether markers of inflammation and prothrombosis are abnormal in obese children without established MS comorbidities across puberty, as compared with lean, age-matched controls. SUBJECTS AND METHODS Obese children (body mass index >95%) with normal fasting glucose, blood pressure, cholesterol and triglycerides were recruited; lean controls (body mass index 10-75%) had no first-degree relatives with MS. High-sensitivity C-reactive protein (hsCRP), IL-6, plasminogen activator inhibitor 1, and fibrinogen concentrations were measured. Body composition was assessed by waist circumference and dual-energy x-ray absorptiometry. RESULTS Of 623 children screened, 203 enrolled (106 males, 97 females), aged 7-18 yr, 115 obese, 88 lean (balanced for age and gender), 99 prepubertal, and 104 pubertal. Many screen failures were due to silent comorbidities. Obese subjects with insulin resistance but without MS comorbidities had about 10 times higher hsCRP concentrations than controls and higher fibrinogen, IL-6, and plasminogen activator inhibitor-1 (P < 0.01 all). Differences were significant, even in the prepubertal cohort. hsCRP and fibrinogen correlated with waist circumference (r = 0.73 and 0.40, respectively) and percent fat mass (r = 0.76 and 0.47) (P < 0.0001). CONCLUSION Childhood obesity per se is associated with a proinflammatory and prothrombotic state before other comorbidities of the MS are present and even before the onset of puberty. Whether biomarkers like hsCRP and fibrinogen are useful in assessing cardiovascular risk and whether these abnormalities are reversible with earlier therapeutic interventions in very young obese children requires further study.

Response of fractional synthesis rate (FSR) of fibrinogen, concentration of D-dimer and fibrinolytic balance to physical activity-based intervention in obese children

Summary.  Background: Physical activity‐induced reduction in obesity‐related hyperfibrinogenemia in children has been reported. The underlying mechanisms remain elusive. Further, the effect of such interventions on fibrinolysis in children is scarce. Objectives: To investigate in obese children, before and after a physical activity‐based intervention: (i) the mechanistic role of fractional synthesis rate (FSR) of fibrinogen in the reduction of hyperfibrinogenemia; and (ii) the changes in fibrinolytic factors. Methods: Subjects included 21 (age > 14 < 18 years; Tanner stage, IV–V) children (15 obese, BMI >95%tile for age and sex and six lean, BMI <85%tile). After baseline measurements of FSR of fibrinogen, and concentrations of fibrinogen, D‐dimer, PAI‐1 and t‐PA in all children, studies were repeated after a 3‐month randomized controlled physical activity‐based lifestyle intervention in obese children only. Results: FSR of fibrinogen was higher (P = 0.002) in the obese (vs. lean) group, which was reduced (P = 0.001) after intervention. This almost completely accounted for the reduction in obesity‐related hyperfibrinogenemia. High levels of D‐dimer decreased (P = 0.001) after intervention, whereas fibrinolysis was not enhanced. Conclusions: The direct reduction in the FSR of fibrinogen and the remarkable correlation between the magnitudes of reduction in fibrinogen FSR and concentration signify a mechanistic role for FSR in the regulation of physical activity‐induced reversal of hyperfibrinogenemia in obese children. The congruent reductions in the FSR of fibrinogen and the concentrations of fibrinogen and D‐dimer in response to intervention despite depressed fibrinolysis suggest an overall improvement in the hypercoagulable state in obese children with physical activity‐based lifestyle intervention.

Biomarkers for cardiovascular risk in children.

Purpose of review The magnitude of lifetime risk of cardiovascular disease (CVD) has radically increased along with the high prevalence of obesity in children. The spotlight is now on dysfunctional adiposity as a precursor for the development of premature CVD. As full-blown CVD is not present in childhood, there is a critical need for surrogate markers to best assess, predict, and treat the children who are vulnerable to developing CVD. Recent findings Accumulation of excess fat mass can be conceived as a derangement in the balance between energy intake and expenditure. This appears to provoke various structural and metabolic alterations leading to adipocyte dysfunction, with important cardiovascular health consequences. Subclinical inflammation, insulin resistance, oxidative stress, and endothelial dysfunction appear to play important roles early in the clinical course of obesity. Summary Associations between biomarkers and noninvasive measures of early atherosclerosis in children continue to emerge and several biomarkers appear to be promising. At present, there are no explicit data to recommend any of these biomarkers as a routine clinical marker of CVD in children. More work is needed to validate these biomarkers and to improve understanding of their role in CVD risk prediction in the pediatric population.

Poorly controlled type 1 diabetes is associated with altered glutathione homeostasis in adolescents: apparent resistance to N-acetylcysteine supplementation

Blood glutathione concentrations represent a measure of protection against oxidative damage. In earlier studies, we observed that, in adolescents with poorly controlled type 1 diabetes mellitus (T1DM), blood glutathione is significantly depleted because of increased rates of glutathione utilization. To determine whether increased availability of cysteine – one of the three constitutive amino acids of glutathione – would attenuate the alterations in glutathione metabolism, ten 16 ± 1 yr‐old adolescents with poorly controlled T1DM [hemoglobin A1c (HbA1c): 9.9 ± 1.3%] received 5‐h infusions of l‐[3,3‐2H2] cysteine and d‐[6,6‐2H2]glucose on two occasions, 3 wk apart, after a 10‐d oral supplementation with (i) N‐acetylcysteine (NAC, 30–45 mg/kg/d) or (ii) l‐alanine, in randomized order, and with a 3‐wk ‘washout’ interim period. Blood glucose was maintained in the same hyperglycemic range on both infusion study days, using intravenous insulin. Glutathione fractional synthesis rate (FSR) was determined from 2H2‐cysteine incorporation into blood glutathione. NAC supplementation failed to raise erythrocyte cysteine concentrations (23 ± 6 vs. 17 ± 1 μmol/L, p = 0.853) and did not alter erythrocyte glutathione concentrations (838 ± 106 vs. 793 ± 111 μmol/L, p = 0.220) or glutathione FSR (96 ± 20 vs. 89 ± 19%/d, p = 0.974). We conclude that in adolescents with poorly controlled T1DM, dietary cysteine supplementation alone cannot correct glutathione status. In the presence of relative insulinopenia, either higher amino acid doses or aggressive insulin therapy may be needed to achieve this goal. This would require further study.

Biologic Mechanisms of Environmental Tobacco Smoke in Children with Poorly Controlled Asthma: Results from a Multicenter Clinical Trial

BACKGROUND Environmental tobacco smoke (ETS) negatively affects children with asthma. The prevalence of ETS exposure among children with poor asthma control may be changing. Importantly, the mechanisms by which ETS worsens asthma control are poorly understood. OBJECTIVE We describe how ETS affects gastroesophageal reflux (GER), respiratory infections, and leukotriene production among children with poor asthma control. METHODS We analyzed data from 306 children between 6 and 17 years of age with poorly controlled asthma enrolled in a 6-month clinical trial. We evaluated prevalence and determinants of ETS exposure by interview, questionnaire, and urinary cotinine and the association of ETS exposure on leukotriene production, respiratory infections, GER, lung function, and asthma control. We used multivariable linear, logistic, and Poisson regressions to assess outcomes. RESULTS ETS prevalence estimates ranged from 6% to 30%. Children with domestic indoor exposure had worse asthma control (c-Asthma Control Test, 17.8 vs 21.5; P = .04), worse FEV1 % predicted (84.1 vs 90.7; P = .02), and a trend for increased mean urinary leukotriene E4. ETS from any setting was associated with increased symptomatic respiratory infections (adjusted incidence rate ratio: 1.30; P = .02). However, children exposed to ETS did not have symptoms or pH probe results, suggestive of heightened GER. CONCLUSIONS Domestic smoking exposure was associated with both higher rates of symptomatic respiratory infection and poorer asthma control despite generally intensive controller therapy. ETS exposure is common among asthmatic children with poor control and may worsen asthma control by promoting respiratory infections. Further investigation is required to elucidate ETS mechanisms in poor asthma control.

Acute changes in blood glucose do not alter blood glutathione synthesis in adolescents with poorly controlled type 1 diabetes mellitus

Depletion of blood glutathione (GSH), a key antioxidant, is associated with type 1 diabetes mellitus (T1D) and contributes to the pathophysiology of diabetes complications. The aim of the current study was to determine whether acute normalization of blood glucose would restore GSH kinetics in adolescents with poorly controlled T1D. Ten 16.9 ± 1.5-year-old (SE) adolescents who had had T1D for 8.5 ± 1.9 years and were free of complications but were in poor control (hemoglobin A(1c), 9.2% ± 0.5%) received two 5-hour intravenous infusions of L-[3,3-(2)H(2)]cysteine in the postabsorptive state on 2 separate days after blood glucose had been maintained overnight at 246 ± 24 mg/dL (hyperglycemia) or 118 ± 23 mg/dL (euglycemia) using intravenous insulin infusion. Blood GSH fractional synthesis rates were determined by mass spectrometry from (2)H(2)-cysteine incorporation into GSH. Neither blood GSH (551 ± 169 vs 541 ± 232 μmol/L, P = .629) nor GSH fractional synthesis rate (84% ± 30% vs 82% ± 33% d(-1), P = .965) was altered by the short-term change in glycemic control. This finding suggests that, in adolescents with poorly controlled T1D, either (a) blood glucose per se does not regulate GSH metabolism or (b) GSH may only respond to sustained, more chronic changes in blood glucose level.