Background

Uric acid is tightly linked to the metabolic syndrome (MetS) and among adults higher uric acid levels are associated with future risk for diabetes, cardiovascular disease, hypertension and renal disease.

Objective

Evaluate the sensitivity of MetS to identify adolescents with elevated uric acid levels on a race/ethnicity and gender-specific basis.

Methods

We evaluated 3,296 males and female adolescents 12-19y participating in the National Health and Nutrition Evaluation Survey ‘99-’06, comprised of 67.6% non-Hispanic whites, 15.1% non-Hispanic blacks, and 17.3% Hispanics. We used a definition of MetS modified for use in adolescents and evaluated the sensitivity of a diagnosis of MetS to identify individuals with uric acid elevations (approximately the 95th percentile of uric acid by gender among normal-weight adolescents).

Results

When used as a screening test to identify individuals with uric acid elevations MetS performed more poorly among females (18.0%) than among males (37.0%)(p<0.001). Among males, MetS exhibited a lower sensitivity among non-Hispanic blacks (17.8%) compared to Hispanics (45.9%)(p<0.01) and non-Hispanic whites (37.4%)(p<0.05). There were no race/ethnicity differences in detecting elevated uric acid levels among females (non-Hispanic-white 15.5%, non-Hispanic-black 19.4%, Hispanic 26.5%, p>0.05).

Conclusion

Current criteria to diagnose MetS exhibit racial/ethnic and gender differences in the ability to identify adolescents with elevated uric acid levels, performing poorly among non-Hispanic-black males and among females. Given emerging data regarding the ability of uric acid elevations for predicting future disease, these data may have implications regarding the use of MetS as a marker of risk among all gender and racial/ethnic groups.

Objective

To evaluate racial/ethnic and sex differences in the relationship between metabolic syndrome (MetS) diagnosis and fasting insulin among adolescents.

Study design

We analyzed data from the National Health and Nutrition Evaluation Survey 1999–2008 for 3,693 non-Hispanic-white, non-Hispanic-black and Hispanic adolescents (12–19y). We used linear regression to evaluate differences in fasting insulin between those with and without an adolescent adaptation of ATPIII-MetS in a sex- and race/ethnicity-specific basis.

Results

Females had higher insulin levels than males and non-Hispanic blacks and Hispanics had higher levels than non-Hispanic whites. Adolescents with MetS had higher insulin levels than those without MetS. The difference in insulin levels between those with and without MetS was greater among non-Hispanic blacks compared with non-Hispanic whites (p<0.05) but not Hispanics (p=0.10). The sensitivity of MetS for detecting elevated insulin levels was lower among non-Hispanic blacks and females compared with other ethnicities and males, respectively. Correlations between insulin and individual MetS components were similar among ethnicities.

Conclusion

MetS diagnosis performed more poorly in predicting elevated insulin levels among non-Hispanic blacks and among females. These data support the hypothesis that non-Hispanic blacks do not meet current criteria for MetS until they have reached a more advanced degree of insulin resistance.

Objective

To evaluate predictors for intervention dropout and successful reduction of metabolic syndrome risk factors among obese children enrolled in a short-term, clinic-based weight-loss intervention.

Design, Setting, Subjects

Retrospective database review of 1080 children 8 months-17 y.o. seen a a pediatric obesity clinic.

Interventions

Behavior modification counseling to induce change in dietary and exercise choices.

Main Outcome Measures

1). Pre-/post-intervention change in body mass index (BMI), waist circumference, blood pressure, glucose, insulin, and cholesterol (LDL, HDL, & total). 2) Predictors of successful decrease in BMI and clinic drop-out.

Analysis

Paired t-tests for pre-/post-intervention comparisons. Linear regression to assess predictors of success and predictors of drop-out, with adjustment for age, gender, race, insurance status, and service area.

Results

Among children evaluated, adolescent females were most likely to achieve successful decrease in BMI, insulin level, and LDL cholesterol post-intervention. Nearly 40% of children dropped out early in the intervention. Predictors of drop out included age <6y, public insurance status, follow-up scheduled during summer months, and residence in a tertiary service area.

Conclusions

Clinic-based weight loss interventions can lead to successful improvements in BMI and other metabolic parameters in pediatric populations and may be more likely among adolescent females than in younger children or males. Drop-out is common, particularly among younger children, children with public insurance and children scheduled for follow-up in the summer. Identification of these drop-out predictors in individual patients may help in targeting children likely to succeed in short-term, clinic-based, weight-loss interventions.

Inflammatory bowel diseases (IBD)—and in particular Crohn's disease—are immune-mediated processes that result in denuded intestinal mucosa and can produce decreased appetite, weight loss, and systemic inflammation. Current treatments include anti-inflammatory medications, immunomodulators, and feeding interventions. Ghrelin is an endogenous orexigenic hormone that directly stimulates growth hormone release, increases gut motility, and has cardiovascular and anti-inflammatory properties. Although ghrelin levels are elevated in active IBD, administration of ghrelin in most (but not all) animal models of colitis has produced improvements in disease activity and systemic inflammation. The mechanism for these effects is not known but may relate to decreased inflammation, increased motility, increased appetite, and increased colonic blood flow. Human trials have not been performed, however, and more research is clearly needed.

OBJECTIVE

Whereas it is known that the metabolic syndrome (MetS) has a paradoxically lower prevalence in non–Hispanic black adolescents than in non–Hispanic whites or Hispanics, the relative severity of MetS by race/ethnicity is unknown. Inflammation, indicated by high-sensitivity C-reactive protein (hsCRP), is a key factor linking MetS to cardiovascular disease and type 2 diabetes. Our goal was to determine whether elevations of hsCRP vary by race/ethnicity among adolescents with MetS.

RESEARCH DESIGN AND METHODS

We used the National Health and Nutrition Examination Survey (1999–2008) and evaluated adolescents (age 12–19 years) using a pediatric/adolescent adaptation of the ATP III definition of MetS. We used linear regression to evaluate the interaction between MetS status and ethnicity with respect to hsCRP concentration.

RESULTS

For male and female adolescents, MetS was associated with elevated hsCRP levels compared with adolescents without MetS. However, the elevation in hsCRP between adolescents with and without MetS was greater in non–Hispanic blacks compared with that in non–Hispanic whites (P = 0.04) but not that in Hispanics (P = 0.18). hsCRP concentrations correlated with individual MetS components similarly among all ethnicities. In an evaluation of adolescents diagnosed with MetS, non–Hispanic blacks had higher BMI and more hypertension than other ethnicities but there were no other racial/ethnic differences in the features of MetS.

CONCLUSIONS

Non–Hispanic black adolescents have a greater differential in hsCRP between those with and those without MetS than the differential in non–Hispanic whites but not that in Hispanics. Therefore, even though MetS has a low prevalence in non–Hispanic blacks, MetS is a particularly good indicator of inflammation in non–Hispanic black adolescents.

Objective

The metabolic syndrome (MetS) is a cluster of clinical indices that signals increased risk for cardiovascular disease and Type 2 diabetes. The diagnosis of MetS is typically based on cut-off points for various components, e.g. waist circumference and blood pressure. Because current MetS criteria result in racial/ethnic discrepancies, our goal was to use confirmatory factor analysis to delineate differential contributions to MetS by sub-group.

Research Design and Methods

Using 1999–2010 data from the National Health and Nutrition Examination Survey (NHANES), we performed a confirmatory factor analysis of a single MetS factor that allowed differential loadings across sex and race/ethnicity, resulting in a continuous MetS risk score that is sex and race/ethnicity-specific.

Results

Loadings to the MetS score differed by racial/ethnic and gender subgroup with respect to triglycerides and HDL-cholesterol. ROC-curve analysis revealed high area-under-the-curve concordance with MetS by traditional criteria (0.96), and with elevations in MetS-associated risk markers, including high-sensitivity C-reactive protein (0.71), uric acid (0.75) and fasting insulin (0.82). Using a cut off for this score derived from ROC-curve analysis, the MetS risk score exhibited increased sensitivity for predicting elevations in ≥2 of these risk markers as compared with traditional pediatric MetS criteria.

Conclusions

The equations from this sex- and race/ethnicity-specific analysis provide a clinically-accessible and interpretable continuous measure of MetS that can be used to identify children at higher risk for developing adult diseases related to MetS, who could then be targeted for intervention. These equations also provide a powerful new outcome for use in childhood obesity and MetS research.

In boys, inflammatory bowel disease often results in delayed puberty associated with decreased bone mineral density and decreased linear growth. Our goal was to investigate whether pubertal timing and levels of leptin differed between prepubertal male mice with colitis and food-restricted (FR) mice maintained at a similar weight. We induced colitis in 32-d-old male mice using dextran sodium sulfate (DSS), resulting in 10 d of worsening colitis. We followed up these mice for separation of the prepuce from the glans penis as a marker of pubertal progression. Compared with free-feeding control mice, DSS and FR mice had significantly lower weight on d 7–10 of treatment. DSS mice had later puberty than control and FR mice. DSS mice also had smaller testes, lower FSH levels, increased systemic cytokines, and increased colonic inflammation by histology. Leptin levels were similar between DSS and FR mice, whereas both had decreases in leptin compared with controls. We conclude that DSS colitis causes delayed puberty in sexually immature male mice beyond what is seen among FR mice of similar weight, food intake, and leptin levels. These experiments provide support for the hypothesis that pubertal delay in colitis is influenced by factors beyond poor weight gain alone.

Objective

The aim of this study was to compare currently proposed sets of pediatric metabolic syndrome criteria for the ability to predict elevations in “surrogate” factors that are associated with metabolic syndrome and with future cardiovascular disease and type 2 diabetes mellitus. These surrogate factors were fasting insulin, hemoglobin A1c (HbA1c), high-sensitivity C-reactive protein (hsCRP), and uric acid.

Methods

Waist circumference (WC), blood pressure, triglycerides, high-density lipoprotein cholesterol (HDL-C), fasting glucose, fasting insulin, HbA1c, hsCRP, and uric acid measurements were obtained from 2,624 adolescent (12–18 years old) participants of the 1999–2006 National Health and Nutrition Examination Surveys. We identified children with metabolic syndrome as defined by six commonly used sets of pediatric metabolic syndrome criteria. We then defined elevations in the surrogate factors as values in the top 5% for the cohort and calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for each set of metabolic syndrome criteria and for each surrogate factor.

Results

Current pediatric metabolic syndrome criteria exhibited variable sensitivity and specificity for surrogate predictions. Metabolic syndrome criteria had the highest sensitivity for predicting fasting insulin (40–70%), followed by uric acid (31–54%), hsCRP (13–31%), and HbA1c (7–21%). The criteria of de Ferranti (which includes children with WC >75 th percentile, compared to all other sets including children with WC >90 th percentile) exhibited the highest sensitivity for predicting each of the surrogates, with only modest decrease in specificity compared to the other sets of criteria. However, the de Ferranti criteria also exhibited the lowest PPV values. Conversely, the pediatric International Diabetes Federation criteria exhibited the lowest sensitivity and the highest specificity.

Conclusions

Pediatric metabolic syndrome criteria exhibit moderate sensitivity for detecting elevations in surrogate factors associated with metabolic syndrome and with risk for future disease. Inclusion of children with more modestly elevated WC improved sensitivity.

Cachexia is a syndrome of wasting and anorexia that worsens the prognosis of many chronic diseases including cancer, chronic kidney disease, chronic heart disease and chronic obstructive pulmonary disease. Properties of the orexigenic hormone ghrelin—including appetite-stimulation, weight-gain production and increased cardiac output—make it a logical treatment for cachexia. While endogenous ghrelin levels are increased in the setting of cachexia, treatment with ghrelin and other GHSR-1a agonists in animal models of cachexia and in humans with cachexia have demonstrated consistent effects of increased appetite and improved weight gain. These positive effects occur in multiple underlying diseases associated with cachexia and appear to be sustained over treatment duration of up to 12 weeks. The mechanism of action in producing these effects is likely related to stimulation of central appetite centers such as the central melanocortin system and to increased growth hormone release, though ghrelin’s effects may also relate to decreased systemic inflammation and other direct and indirect actions. Questions regarding the long-term safety of ghrelin treatment are still unanswered, as is the important question of whether successful treatment of cachexia will improve the prognosis of the underlying disease itself.

Cardiovascular disease (CVD) frequently has roots in childhood, including following childhood-onset hypertension. Incidence of CVD has increased in developing countries in East Africa during recent urbanization. Effects of these shifts on childhood hypertension are unclear. Our objectives were to (1) Determine the prevalence of hypertension among primary schoolchildren in Khartoum, Sudan; (2) Determine whether hypertension in this setting is associated with obesity. We performed a cross sectional study of 6-12y children from two schools randomly selected in Khartoum, Sudan. Height, weight, BMI, BP and family history of hypertension were assessed. Age-, height- and gender-specific BP curves were used to determine pre-hypertension (90–95%) and hypertension (>95%). Of 304 children, 45 (14.8%) were overweight; 32 (10.5%) were obese; 15 (4.9%) were pre-hypertensive and 15 (4.9%) were hypertensive. Obesity but not family history of hypertension was associated with current hypertension. In multiple logistic regression, adjusting for family history, children who were obese had a relative-risk of 14.7 (CI 2.45-88.2) for systolic hypertension compared to normal-weight children. We conclude that overweight and obesity are highly prevalent among primary schoolchildren in urban Sudan and are strongly associated with hypertension. That obesity-associated cardiovascular sequelae exist in the developing world at young ages may be a harbinger of future CVD in sub-Saharan Africa.

Pediatric obesity threatens the future health of a growing number of children worldwide. An added challenge in identifying the patients at greatest need for intervention due to their elevated risk for future disease is that pediatric obesity and the associated metabolic syndrome manifest differently among different ethnic groups. African–Americans and Hispanics are more likely to exhibit obesity and insulin resistance and are at a higher risk for developing Type 2 diabetes. Nevertheless, using current criteria, African–American adolescents are much less likely to be diagnosed with metabolic syndrome, largely owing to lower rates of dyslipidemia. Further development is needed in ethnicity-inclusive means of risk identification among adolescents to accurately target treatment toward children at highest risk for future disease and to motivate adolescent patients and their families towards lifestyle improvement. Effective targeting and intensive treatment efforts may help in avoiding future sequelae of obesity among all ethnicities.

Abstract

Objective

The aim of this study was to compare currently proposed sets of pediatric metabolic syndrome criteria for the ability to predict elevations in “surrogate” factors that are associated with metabolic syndrome and with future cardiovascular disease and type 2 diabetes mellitus. These surrogate factors were fasting insulin, hemoglobin A1c (HbA1c), high-sensitivity C-reactive protein (hsCRP), and uric acid.

Methods

Waist circumference (WC), blood pressure, triglycerides, high-density lipoprotein cholesterol (HDL-C), fasting glucose, fasting insulin, HbA1c, hsCRP, and uric acid measurements were obtained from 2,624 adolescent (12–18 years old) participants of the 1999–2006 National Health and Nutrition Examination Surveys. We identified children with metabolic syndrome as defined by six commonly used sets of pediatric metabolic syndrome criteria. We then defined elevations in the surrogate factors as values in the top 5% for the cohort and calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for each set of metabolic syndrome criteria and for each surrogate factor.

Results

Current pediatric metabolic syndrome criteria exhibited variable sensitivity and specificity for surrogate predictions. Metabolic syndrome criteria had the highest sensitivity for predicting fasting insulin (40–70%), followed by uric acid (31–54%), hsCRP (13–31%), and HbA1c (7–21%). The criteria of de Ferranti (which includes children with WC >75th percentile, compared to all other sets including children with WC >90th percentile) exhibited the highest sensitivity for predicting each of the surrogates, with only modest decrease in specificity compared to the other sets of criteria. However, the de Ferranti criteria also exhibited the lowest PPV values. Conversely, the pediatric International Diabetes Federation criteria exhibited the lowest sensitivity and the highest specificity.

Conclusions

Pediatric metabolic syndrome criteria exhibit moderate sensitivity for detecting elevations in surrogate factors associated with metabolic syndrome and with risk for future disease. Inclusion of children with more modestly elevated WC improved sensitivity.

Childhood obesity is a risk factor for the development of both type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). One marker that can be used to predict T2DM is the metabolic syndrome (MetS). MetS, a cluster of cardiovascular factors associated with insulin resistance, is defined by central obesity, impaired fasting glucose, hypertension, elevated triglycerides (TG), and low levels of high-density lipoprotein cholesterol. Some have advocated using a diagnosis of MetS to trigger increased intervention in children. However, ethnic differences in MetS may hamper identification of at-risk children. For example, non-Hispanic blacks are diagnosed with MetS less frequently than non-Hispanic whites, despite having higher rates of T2DM and CVD. These differences in MetS are predominantly due to a low frequency of hypertriglyceridemia in non-Hispanic blacks. Compared with non-Hispanic whites and Mexican Americans, non-Hispanic blacks have lower TG levels at baseline but exhibit worsening insulin resistance with increasing TG. Therefore “normal” TG levels appear to be falsely reassuring among insulin-resistant non-Hispanic blacks. Ethnic-specific tools may be needed to more accurately predict risk for T2DM and CVD in minorities.

Background

Inflammatory bowel disease that begins prior to puberty frequently causes a delay in puberty resulting in losses of growth, bone mineralization, and self-esteem. A major cause of this pubertal delay is likely due in part to the effect of decreased levels of leptin on the function of the hypothalamic–pituitary–gonadal axis, though systemic inflammation is also thought to play a role.

Methods

To investigate further whether low leptin levels alone were responsible for delayed puberty in colitis, we induced colitis in 23-day-old female mice using 3% dextran sodium sulfate (DSS), resulting in 10 days of worsening colitis. These mice were compared to controls that were free-feeding and food-restricted (FR) mice that were given only enough food to keep them the same weight as the DSS group. All groups were followed for the timing of vaginal opening until 33 days old, when they were euthanized and their serum collected.

Results

DSS-treated mice exhibited later timing of vaginal opening relative to both of the other groups, as well as increased colonic inflammation by cytology and increased serum levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α. The difference in the timing of vaginal opening between the DSS and FR groups occurred despite equivalent serum levels of leptin between the groups and despite an increase in corticosterone in the FR group relative to both of the other groups.

Conclusions

We conclude that DSS colitis causes delay in puberty in sexually immature mice beyond what would be expected from decreases in weight and leptin levels.

Inflammation-associated cachexia is associated with multiple chronic diseases and involves activation of appetite regulating centers in the arcuate nucleus of the hypothalamus (ARH). The nucleus of the solitary tract (NTS) in the brainstem has also been implicated as an important nucleus involved in appetite regulation. We set out to determine whether the NTS may be involved in inflammation-associated anorexia by injecting IL-1β into the 4th ventricle and assessing food intake and NTS neuronal activation. Injection of IL-1β produced a decrease in food intake at 3 and 12 h after injection which was ameliorated at the 12 h time point by a sub-threshold dose of agouti-related peptide (AgRP). Investigation into neuron types in the NTS revealed that IL-1β injection was associated with an increase in c-Fos activity in NTS neurons expressing tyrosine hydroxylase (TH). Additionally, injection of IL-1β into the 4th ventricle did not produce c-Fos activation of neurons expressing pro-opiomelanocortin (POMC) in the ARH, cells known to be involved in producing anorexia in response to systemic inflammation. Double-label in situ hybridization revealed that TH neurons did not express IL-1 receptor I (IL1-RI) transcript, demonstrating that c-Fos activation of TH neurons in this setting was not via direct stimulation of IL-1β on TH neurons themselves. We conclude that IL-1β injection into the 4th ventricle produces anorexia and is accompanied by an increase in activation in TH neurons in the NTS. This provides evidence that the brainstem may be an important mediator of anorexia in the setting of inflammation.