Visceral adipose tissue measured by DXA correlates with measurement by CT and is associated with cardiometabolic risk factors in children.

BACKGROUND: Visceral adipose tissue (VAT) generally demonstrates a stronger relationship with cardiometabolic risk factors than total body fat or subcutaneous adipose tissue. OBJECTIVES: The purpose of this study was to compare VAT estimated in children by total volume dual-energy X-ray absorptiometry (DXA) with a gold standard measurement, single slice (L4-L5) computed tomography (CT). METHODS: A total of 329 (152 females, 177 males) children ages 6-18 years (mean age 12.3 ± 3.6) and with average body mass index percentile of 54.9% (3-99%) had their VAT estimated by both CT and DXA. Linear association between methods was measured using Pearson's correlation. Multiple linear regressions compared the associations between cardiometabolic risk factors and both CT-VAT and DXA-VAT, respectively. RESULTS: In children, DXA-VAT was correlated significantly with CT-VAT, with a stronger relationship in overweight and obese children. Multiple regression analysis showed that both estimates of VAT were significantly associated with lipids and insulin sensitivity, measured by euglycaemic-hyperinsulinaemic clamp. Additionally, DXA-VAT was associated with diastolic blood pressure, homeostasis model of insulin resistance and fasting insulin, but CT-VAT was not. CONCLUSION: In children, total volume DXA-VAT and single slice CT-VAT are significantly correlated and each demonstrates similar associations with cardiometabolic risk factors. This suggests that DXA is a useful and valid method for estimation of VAT in children.

The relative contributions of the abdominal visceral and subcutaneous fat depots to cardiometabolic risk in youth.

The aim of this study was to evaluate the association of abdominal visceral and subcutaneous fat, independent of total body fat, with cardiometabolic risk factors and insulin resistance among youth. Visceral and subcutaneous fat, percentage total body fat, insulin resistance (adjusted for lean body mass: Mlbm), blood pressure, glucose, insulin and lipids were obtained in 472 youth ages 6-18 years. Linear regression, adjusted for age, sex, race, Tanner stage and percentage total body fat, was used to evaluate associations of visceral and subcutaneous fat with cardiometabolic risk factors. Visceral fat was associated inversely with Mlbm (P = 0.003) and positively with fasting insulin (P = 0.002) and triglycerides (P = 0.002). Visceral fat levels above the mean were associated inversely with high-density lipoprotein (HDL) cholesterol (P = 0.002), and positively with systolic blood pressure (P < 0.0001) and non-HDL cholesterol (P < 0.0001). Subcutaneous fat was associated inversely with Mlbm (P = 0.003) and HDL cholesterol (P < 0.05), and positively with fasting glucose (P < 0.05), fasting insulin (P = 0.0003), systolic blood pressure (P = 0.005) and triglycerides (P = 0.003). Subcutaneous fat levels above the mean were associated with non-HDL cholesterol (P = 0.0002). These findings suggest that there may be a threshold level of visceral and subcutaneous fat (regardless of total body fat), that when exceeded in childhood, is more likely to be associated with many cardiometabolic risk factors. Triglycerides and insulin resistance appear to be associated with these fat depots at even lower thresholds of abdominal adiposity.

Relation of chemokines to BMI and insulin resistance at ages 18-21.

OBJECTIVE: In obesity, adipose tissue becomes a significant source of chemokines and inflammatory cytokines that are associated with chronic systemic low-grade inflammation and may lead to insulin resistance. Studies in children have mainly focused on inflammatory cytokines and there are limited data for chemokines in adolescents and young adults. We studied the relation of chemokines to cardiovascular (CV)-risk factors, insulin resistance and adipocytokines in 18-21-year-old individuals. SUBJECTS AND DESIGN: Cross-sectional data collected in a cohort originally enrolled at mean age 13, with data for the present study obtained from 252 examined at age 18.7±0.1 years. METHODS: Multiple linear regression models were used to analyze the associations among chemokines (monocyte chemotactic protein-1, macrophage inflammatory protein-1ß (MIP-1ß), visfatin and interleukin-8 (IL-8)) and between chemokines and body mass index (BMI), glucose, lipids, blood pressure (BP), insulin resistance (euglycemic hyperinsulinemic clamp) and adipocytokines (IL-6, TNF-α and adiponectin). RESULTS: Chemokine levels were significantly intercorrelated. Significant associations (P<0.05) with adjustment for age, race and sex included: MIP-1ß with waist circumference and IL-6, IL-8 with systolic BP and visfatin with IL-6. No other significant relations were found between the chemokines and the other variables. Further adjustment for BMI did not alter these conclusions. CONCLUSION: Considered in the context of prior studies in children and adults, these results suggest that in large part, the association between chemokines and CV risk or inflammatory factors does not appear to develop until adult life.

Development of associations among central adiposity, adiponectin and insulin sensitivity from adolescence to young adulthood.

OBJECTIVE: To examine associations of central adiposity, serum adiponectin and clamp-derived insulin sensitivity in a single longitudinal cohort from early adolescence to young adulthood. METHODS: The cohort was examined three times at mean ages 15 years (n = 308), 19 years (n = 218) and 22 years (n = 163). Insulin sensitivity was measured with the euglycaemic hyperinsulinaemic clamp. Circulating adiponectin was measured by enzyme-linked immunosorbent assay. Computed tomography scans were used at mean age 22 to compute subcutaneous and visceral abdominal fat volume. Partial Pearson correlations and linear regression were used to examine cross-sectional associations at each examination. RESULTS: The moderate negative correlation between waist circumference and adiponectin was significant and essentially unchanged from mean age 15 (-0.32, P < 0.0001) to mean age 22 (-0.29, P < 0.002), whereas the negative correlation between waist circumference and insulin sensitivity and the positive correlation between adiponectin and insulin sensitivity increased steadily in magnitude to mean age 22 (-0.29, P = 0.0002; and 0.32, P < 0.0001, respectively). In regression models including both visceral and subcutaneous fat, only visceral fat was significantly associated with insulin sensitivity, while only subcutaneous fat was nearly significantly associated with adiponectin. CONCLUSIONS: This study shows that the significant negative relationship between waist circumference and adiponectin predated the development of significant relationships between insulin sensitivity and both waist circumference and adiponectin. It also shows that adiponectin is more closely related to subcutaneous fat and insulin sensitivity is more closely related to visceral fat in young adults.

The relationship of retinal vessel diameter to changes in diabetic nephropathy structural variables in patients with type 1 diabetes.

AIMS/HYPOTHESIS: We examined whether retinal vessel diameter in persons with type 1 diabetes mellitus is associated with changes in subclinical anatomical and functional indicators of diabetic nephropathy. METHODS: Persons with type 1 diabetes mellitus had gradable fundus photographs and renal biopsy data at baseline and 5-year follow-up (n = 234). Retinal arteriolar and venular diameters were measured at baseline and follow-up. Central retinal arteriole equivalent (CRAE) and central retinal venule equivalent (CRVE) were computed. Baseline and 5-year follow-up renal structural variables were assessed by masked electron microscopic morphometric analyses from percutaneous renal biopsy specimens. Variables assessed included: mesangial fractional volume, glomerular basement membrane width, mesangial matrix fractional volume and glomerular basement membrane width composite glomerulopathy index. RESULTS: While controlling for other covariates, baseline CRAE was positively associated with change in the glomerulopathy index over the 5-year period. Change in CRAE was inversely related to a change in mesangial matrix fractional volume and abnormal mesangial matrix fractional volume, while change in CRVE was directly related to change in the volume fraction of cortex that was interstitium [Vv((Int/cortex))] over the 5-year period. Baseline CRAE or CRVE or changes in these diameters were not related to changes in other anatomical or functional renal endpoints. CONCLUSIONS/INTERPRETATION: Independently of other factors, baseline CRAE correlated with changes in glomerulopathy index, a composite measure of extracellular matrix accumulation in the mesangium and glomerular basement membrane. A narrowing of the CRAE was related to mesangial matrix accumulation. Changes in CRVE were related to changes in Vv((Int/cortex),) a measure of interstitial expansion in persons with type 1 diabetes mellitus.

Serum phospholipid and cholesteryl ester fatty acids and estimated desaturase activities are related to overweight and cardiovascular risk factors in adolescents.

AIM/HYPOTHESIS: The objective of this study was to describe the relation of serum fatty acids and desaturase activity (DA) to overweight, insulin sensitivity and cardiovascular disease (CVD) risk factors in adolescents. METHODS: The relations of % serum phospholipid (PL) and cholesteryl ester (CE) fatty acids and estimated DA with CVD risk factors were examined in 264 adolescents (average age 15 years). Fatty acids were determined by gas liquid chromotography. Surrogate measures of DA were expressed as ratios of serum fatty acids: Delta9 DA=16:0/16:1; Delta6 DA=20:3,n6/18:2,n6 (PL) or 18:3,n6/18:2,n6 (CE); and Delta5 DA=20:4,n6/20:3,n6. Spearman partial correlations of fatty acids (%) and DA ratios with CVD risk factors were reported, adjusting for age, sex, race, Tanner stage, energy intake and physical activity. RESULTS: Overweight adolescents compared to normal weight had more adverse levels of CVD risk factors, composition of PL and CE fatty acids in serum, and Delta6 DA and Delta5 DA ratios. Linoleic acid was inversely related to body mass index (BMI), waist circumference and triglycerides (P

Heritability and genetic correlations of insulin sensitivity measured by the euglycaemic clamp.

AIMS: Studies investigating genetic factors influencing insulin sensitivity/insulin resistance have measured this phenotype using a variety of methods. In this study, genetic correlations and heritability of insulin sensitivity measured using the euglycaemic hyperinsulinaemic clamp and related phenotypes were examined. METHODS: The study population included 818 non-diabetic individuals from 297 nuclear families. Genetic correlations and heritability estimates were calculated using variance components methods. RESULTS: Homeostasis model of insulin resistance (HOMA-IR) and fasting insulin were very highly phenotypically and genetically correlated (r = 0.99 and r = 0.99). HOMA-IR and insulin sensitivity measured with the euglycaemic clamp were only moderately genetically correlated (r = -0.53), suggesting that the two traits may be influenced, at least in part, by different genes. Heritabilities for fasting insulin (h2 = 0.36) and HOMA-IR (h2 = 0.38) were consistent with the published literature, but heritability for insulin sensitivity measured by the euglycaemic clamp was slightly lower than other published estimates (h(2) = 0.24). CONCLUSIONS: Because HOMA-IR (or fasting insulin) and insulin sensitivity measured with the euglycaemic clamp are not highly genetically correlated, they should not be used interchangeably in genetic studies. Given the very high correlations between fasting insulin and HOMA-IR, HOMA-IR does not offer any advantage over fasting insulin in analyses of insulin sensitivity in this population.

Comparison of body fatness measurements by BMI and skinfolds vs dual energy X-ray absorptiometry and their relation to cardiovascular risk factors in adolescents.

OBJECTIVE: To compare estimates of adiposity by dual emission X-ray absorptiometry (DXA), skinfolds and body mass index (BMI); and to evaluate the relation of these measures to cardiovascular risk in adolescents. DESIGN: In a cohort of adolescents participating in a longitudinal study of insulin resistance, Slaughter formulas were used to estimate adiposity from skinfolds and DXA was used to estimate adiposity as % body fat (%BF) and fat mass (FBM). BMI, blood pressure, lipids and insulin resistance were measured. SUBJECTS: Male and female, 11-17 y old (n=130). MEASUREMENTS: To compare DXA with two office-based methods of assessing fatness and cardiovascular risk. RESULTS: Slaughter estimates were highly correlated with DXA (%BF r=0.92, P=0.0001; FBM r=0.96, P=0.0001). Correlations were similar in heavy and thin children. BMI was also highly correlated with DXA (%BF r=0.85, P=0.0001; FBM r=0.95, P=0.0001), and these relations were stronger in heavy than thin children. BMI and the Slaughter formulas were similar to DXA in their relations to cardiovascular risk factors. CONCLUSIONS: Adiposity by BMI and Slaughter formulas are highly correlated with DXA and similarly related to cardiovascular risk factors. BMI is easy to obtain and is an acceptable method for initial office estimation of body fatness. BMI and skinfolds compare well with DXA in predicting adverse cardiovascular risk profile.

Insulin resistance (metabolic) syndrome in children.

The insulin resistance (metabolic) syndrome (IRS), also known as syndrome X, is characterized by a clustering of factors associated with cardiovascular risk (obesity, impaired glucose metabolism, hypertension, and dyslipidemia). As reported from the third National Health and Nutrition Examination survey, the IRS is present in approximately 24% of adults in the United States and is strongly associated with coronary heart disease, stroke, type 2 diabetes, and all-cause mortality. Of equal importance, it is now clear that the origins of the IRS extend back into childhood (the IRS is found in approximately 4-10% of children and adolescents) and that the high prevalence of adult IRS is strongly linked to the development of cardiovascular risk during childhood and tracking of the components of the IRS into adulthood. The goal of this review is to present a summary of the currently available information on the IRS in the pre-adult age group with reference to adult studies only when necessary for clarification. The review will specifically summarize insulin resistance in childhood; the important influence of obesity and, in particular, visceral fat, on insulin resistance and the IRS; differences between ethnic groups; relations to adipocytokines, inflammatory factors and oxidative stress; relations of hypertension and lipids to insulin resistance; familial factors; endocrine complications; and potential therapeutic effects from diet and physical activity. Despite the lesser amount of basic and clinical information on childhood IRS in comparison to information available from adult studies, there can now be little doubt that the adverse associations among risk factors comprising the IRS begin in childhood. The challenge is to identify etiologic relations and develop intervention strategies designed to reduce the increasing prevalence of type 2 diabetes and cardiovascular disease.

Association of physical activity with insulin sensitivity in children.

BACKGROUND: Physical activity (PA) has been shown to improve insulin resistance and other cardiovascular disease risk factors in normal and diabetic adults and in obese youth, but not in non-diabetic, normal-weight children. METHODS: Data from 357 non-diabetic children (10-16 y) were used to examine cross-sectional associations with PA. Insulin sensitivity was assessed with a euglycemic hyperinsulinemic clamp and expressed as M(ffm) (glucose utilization/kg of fat-free mass/min). RESULTS: Correlations were adjusted for age, sex, race and Tanner stage. PA was significantly correlated with fasting insulin and insulin sensitivity (r=-0.12, P=0.03 and r=0.13, P=0.001, respectively), more strongly in children with above-median systolic blood pressure (r=-0.17, P=0.03 and r=0.35, P=0.0001, respectively). Further adjustment for body mass index, body fat percentage, waist circumference or lipids did not alter these observations. CONCLUSIONS: Physical activity is correlated with lower fasting insulin and greater insulin sensitivity in childhood. These results are consistent with the hypothesis that increasing physical activity among youth may reduce the incidence of type 2 diabetes in children and adolescents.

Insulin resistance syndrome in childhood: associations of the euglycemic insulin clamp and fasting insulin with fatness and other risk factors.

OBJECTIVE: Our objective was to describe in children the relation of fatness and insulin resistance to the risk factors associated with the insulin resistance syndrome and to compare fasting insulin with the euglycemic insulin clamp as a measure of insulin resistance in children. STUDY DESIGN: This was a random selection of participants after blood pressure screening of 12,043 students in the fifth through eighth grades. Euglycemic insulin clamp studies with an insulin infusion rate of 1 mU/kg/min and a variable infusion of 20% glucose to maintain euglycemia, that is, plasma glucose at 5.6 mmol/L. Insulin sensitivity (M(lbm)) is defined as the amount of glucose required to maintain euglycemia (milligrams of glucose infused per kilogram lean body mass per minute). RESULTS: Body mass index was significantly correlated with fasting insulin and significantly inversely correlated with M(lbm). Fasting insulin was significantly correlated with systolic blood pressure in both sexes, all lipids, except high-density lipoprotein-cholesterol in males and triglycerides and high-density lipoprotein-cholesterol in females, but after adjustment was done for body mass index, it was significantly related only to triglycerides. M(lbm) was significantly correlated only with triglycerides and high-density lipoprotein-cholesterol, and this did not change after adjustment was done for body mass index. A clustering effect for the risk factors was seen in children in the lowest quartile of M(lbm) (highest degree of insulin resistance) compared with children in the highest quartile of M(lbm) (lowest degree of insulin resistance). CONCLUSIONS: As defined by M(lbm), there is an early association of insulin resistance, independent of body fat, with the risk factors. There is a significant relation between fasting insulin, as an estimate of insulin resistance, and the risk factors, but this is significantly influenced by body fatness. The clustering of risk factors according to level of M(lbm) suggests that adult cardiovascular disease is more likely to develop in children with the greatest degree of insulin resistance.

Prevalence of hypertension in junior high school-aged children: effect of new recommendations in the 1996 Updated Task Force Report.

The 1996 "Update on the 1987 Task Force Report on Blood Pressure in Children and Adolescents" adopted the fifth Korotkoff phase to define diastolic blood pressure and added height, in addition to age and gender, to develop new standards for blood pressure (BP) in children. The present study was performed to determine whether these changes altered the previously reported prevalence of hypertension in junior high school-aged children. Blood pressure screening was conducted in 19,452 fifth to eighth grade students. All students with a systolic blood pressure more than the 70th percentile had their BP measured a second time (rescreening). Using the 1996 criteria, systolic hypertension was found in 2.7% and diastolic hypertension in 2% after the screening. After the rescreening, systolic hypertension had fallen to 0.8% and diastolic hypertension to 0.4%. The prevalence of systolic hypertension was slightly higher and diastolic hypertension slightly lower than in 1987. These reports show that the overall prevalence of hypertension (1%) using the 1996 Updated Task Force criteria is similar to the prevalence using the original 1987 criteria. These results also confirm the importance of the Task Force recommendation that multiple BP measurements should be obtained before making a diagnosis of hypertension.

Adiposity in childhood predicts obesity and insulin resistance in young adulthood.

OBJECTIVE: To determine whether adiposity in children predicts adiposity, insulin resistance, and abnormal lipid levels in young adults. STUDY DESIGN: Children (n = 31) were recruited into an epidemiologic study at age 13.3 +/- 0.3 years and had blood pressure, weight, and height measured. They were reevaluated at age 21.8 +/- 0.3 years at which time the measurements were repeated, a euglycemic insulin clamp was performed, and fasting lipid levels were measured. All values are expressed as mean +/- SEM. Data were analyzed by analysis of variance and linear regression analysis. RESULTS: Body mass index (BMI) in childhood (22.6 +/- 0.6) was highly correlated with BMI in young adulthood (26.9 +/- 0.9). Childhood BMI was also inversely correlated with young adult glucose utilization (r = -0.5, P = .006) and positively correlated with total cholesterol (r = 0.37, P = .05), and low-density lipoprotein (LDL) cholesterol (r = 0.48, P = .01). CONCLUSIONS: These data confirm that adiposity in childhood is a strong predictor of young adult adiposity. In addition, these results demonstrate that cardiovascular risk in young adulthood is highly related to the degree of adiposity as early as age 13.

Echocardiographic diagnosis of heart disease in apparently healthy adolescents.

OBJECTIVE: Comprehensive data are currently unavailable on the prevalence of cardiac abnormalities in children after the newborn/infant period. The present report describes the prevalence of echocardiographically detected cardiac disease in a cohort of randomly selected healthy junior high school children. METHODS: The cohort for this report consists of 357 children (mean age: 13 years) randomly selected after blood pressure screening of 12 043 fifth through eighth grade students and having an echocardiographic examination as part of a study of insulin resistance in childhood. RESULTS: A physical examination performed by a board-certified pediatrician reported no cardiac abnormalities. However, echocardiography and Doppler studies identified 13 (3.6%) children (7 males and 6 females), with previously unknown cardiac abnormalities, as follows: abnormal mitral valve with mitral regurgitation (4), bicuspid aortic valve (2), atrial septal defect (2), coronary artery to pulmonary artery fistula (1), patent ductus arteriosus (1), pulmonary hypertension (1), cardiomyopathy (1), and pulmonary artery stenosis (1). Physical examination performed by a pediatric cardiologist detected abnormal cardiac findings in 7 (54%) of the children. Cardiac catheterization was required in 3 for additional diagnostic evaluation and in 2 for therapeutic intervention; 1 patient underwent open-heart surgery. Bacterial endocarditis prophylaxis was recommended in 8 (62%) of the 13 children. CONCLUSIONS: The results suggest that: 1) clinically significant cardiac disease in childhood is more prevalent than previously reported; and 2) improved screening methods should be considered to detect asymptomatic but significant cardiac abnormalities that may result in long-term complications. echocardiography, prevalence, incidence, heart disease, children.

Insulin resistance during puberty: results from clamp studies in 357 children.

Insulin resistance may be an important cause of a constellation of cardiovascular risk factors in adults, and onset of this syndrome may occur in childhood. However, children normally experience transient insulin resistance at puberty. There were 357 normal children (159 girls, 198 boys) age 10-14 years who underwent euglycemic clamp studies to assess the effects of Tanner stage (T), sex, ethnicity, and BMI on insulin resistance. Insulin resistance increased immediately at the onset of puberty (T2), but returned to near prepubertal levels by the end of puberty (T5). Its peak occurred at T3 in both sexes, and girls were more insulin resistant than boys at all T stages. White boys appeared to be more insulin resistant than black boys; no difference was seen between white and black girls. Insulin resistance was strongly related to BMI, triceps skinfold thickness, and waist circumference, and this relationship was independent of Tanner stage or sex. Differences in BMI and adiposity did not, however, entirely explain the insulin resistance of puberty. These results demonstrate that 1) significant differences in insulin resistance are present between boys and girls; 2) insulin resistance increases significantly at T2, T3, and T4, but decreases to near prepubertal levels at T5; and 3) while insulin resistance is related to BMI and anthropometric measures of fatness, these factors do not completely explain the insulin resistance that occurs during the Tanner stages of puberty.