Plasma Markers of Cholesterol Homeostasis and Apolipoprotein B‐100 Kinetics in the Metabolic Syndrome

Objective: The metabolic syndrome is characterized by defective hepatic apolipoprotein B‐100 (apoB) metabolism. Hepato‐intestinal cholesterol metabolism may contribute to this abnormality. Research Methods and Procedures: We examined the association of cholesterol absorption and synthesis with the kinetics of apoB in 35 obese subjects with the metabolic syndrome. Plasma ratios of campesterol and lathosterol to cholesterol were used to estimate cholesterol absorption and synthesis, respectively. Very‐low‐density lipoprotein (VLDL), intermediate‐density lipoprotein (IDL), and low‐density lipoprotein apoB kinetics were studied using stable isotopy and mass spectrometry. Kinetic parameters were derived using multicompartmental modeling. Results: Compared with controls, the obese subjects had significantly lower plasma ratios of campesterol, but higher plasma ratios of lathosterol (p < 0.05 in both). This was associated with elevated VLDL‐apoB secretion rate (p < 0.05) and delayed fractional catabolism of IDL and low‐density lipoprotein‐apoB (p < 0.01). In the obese group, plasma ratios of campesterol correlated inversely with VLDL‐apoB secretion (r = ?0.359, p < 0.05), VLDL‐apoB (r = ?0.513, p < 0.01) and IDL‐apoB (r = ?0.511, p < 0.01) pool size, and plasma lathosterol ratio (r = ?0.366, p < 0.05). Subjects with low cholesterol absorption had significantly higher VLDL‐apoB secretion, VLDL‐apoB and IDL‐apoB pool size, and plasma lathosterol ratio (p < 0.05 in both) than those with high cholesterol absorption. Discussion: Subjects with the metabolic syndrome have oversecretion of VLDL‐apoB and decreased catabolism of apoB‐containing particles and low absorption and high synthesis rates of cholesterol. These changes in cholesterol homeostasis may contribute to the kinetic defects in apoB metabolism in the metabolic syndrome.     

Effects of Obesity and Body Fat Distribution on Lipids and Lipoproteins in Nondiabetic American Indians: The Strong Heart Study

Objectives: To examine the relationship between obesity and lipoprotein profiles and compare the effects of total obesity and central adiposity on lipids/lipoproteins in American Indians. Research Methods and Procedures: Participants were 773 nondiabetic American Indian women and 739 men aged 45 to 74 years participating in the Strong Heart Study. Total obesity was estimated using body mass index (BMI). Central obesity was measured as waist circumference. Lipoprotein measures included triglycerides, high‐density lipoprotei in (HDL) cholesterol, low‐density lipoprotein (LDL) cholesterol, apolipoprotein AI (apoAI), and apolipoprotein B (apoB). Partial and canonical correlation analyses were used to examine the associations between obesity and lipids/lipoproteins. Results: Women were more obese than men in Arizona (median BMI 32.1 vs. 29.2 kg/m²) and South Dakota and North Dakota (28.3 vs. 28.0 kg/m²), but there was no sex difference in waist circumference. Men had higher apoB and lower apoAI levels than did women. In women, when adjusted for center, gender, and age, BMI was significantly related to HDL cholesterol (r = ?0.24, p < 0.001). There was a significant but weak relation with apoAI (r = ?0.14 p < 0.001). Waist circumference was positively related to triglycerides (r = 0.14 p < 0.001) and negatively related to HDL cholesterol (r = ?0.23, p < 0.001) and apoAI (r = ?0.13, p < 0.001). In men, BMI was positively correlated with triglycerides (r = 0.30, p < 0.001) and negatively correlated with HDL cholesterol (r = ?0.35, p < 0.001) and apoAI (r = ?0.23, p < 0.001). Triglycerides increased with waist circumference (r = 0.30, p < 0.001) and HDL cholesterol decreased with waist circumference (r = ?0.36 p < 0.001). In both women and men there was an inverted U‐shaped relationship between obesity and waist with LDL cholesterol and apoB. In canonical correlation analysis, waist circumference received a greater weight (0.86) than did BMI (0.17) in women. However, the canonical weights were similar for waist (0.46) and BMI (0.56) in men. Only HDL cholesterol (?1.02) carried greater weight in women, whereas in men, triglycerides (0.50), and HDL cholesterol (?0.64) carried a large amount of weight. All the correlation coefficients between BMI, waist circumference, and the first canonical variable of lipids/lipoproteins or between the individual lipid/lipoprotein variables and the first canonical variable of obesity were smaller in women than in men. Triglycerides and HDL cholesterol showed clinically meaningful changes with BMI and waist circumference in men. All lipid/lipoprotein changes in women in relation to BMI and waist circumference were minimal. Discussion: The main lipoprotein abnormality related to obesity in American Indians was decreased HDL cholesterol, especially in men. Central adiposity was more associated with abnormal lipid/lipoprotein profiles than general obesity in women; both were equally important in men.     

Predictors of Long‐term Weight Maintenance

Objective: The purpose of this study was to evaluate available variables of a long‐term weight maintenance study to investigate possible factors predisposing to weight regain after a period of weight loss. Research Methods and Procedures: The Maastricht Weight Maintenance Study is an ongoing longitudinal study of healthy men and women (29 men and 62 women; 18 to 65 years of age; BMI = 30.2 ± 3.1 kg/m²). A variety of parameters were measured before and after a very‐low‐energy diet and after a follow‐up of at least 2 years. Results: Mean weight loss was 7.9 ± 3.6 kg, and percent weight regain was 113.8 ± 98.1%. Percent BMI regain was negatively associated with an increase in dietary restraint (r = ?0.47, p < 0.05). Percent weight regain was negatively correlated with baseline resting metabolic rate (r = ?0.38, p = 0.01) and baseline fat mass (r = ?0.24, p = 0.05) and positively correlated with the magnitude of change in body weight (BW) expressed as maximum amplitude of BW (r = 0.21, p < 0.05). In addition, amplitude of BW was positively correlated with the frequency of dieting (r = 0.57, p < 0.01). Discussion: The best predictors for weight maintenance after weight loss were an increase in dietary restraint during weight loss, a high baseline resting metabolic rate, a relatively high baseline fat mass favoring a fat‐free mass–sparing effect during weight loss, a rather stable BW, and a low frequency of dieting. Therefore, BW maintenance after BW loss seems to be a multifactorial issue, including mechanisms that regulate an individuals’ energy expenditure, body composition, and eating behavior in such a way that energy homeostasis is maintained.     

High‐density Lipoprotein Apolipoprotein A‐I Kinetics in Obesity

Objective: Low plasma concentrations of high‐density lipoprotein (HDL)‐cholesterol and apolipoprotein A‐I (apoA‐I) are independent predictors of coronary artery disease and are often associated with obesity and the metabolic syndrome. However, the underlying kinetic determinants of HDL metabolism are not well understood. Research Methods and Procedures: We pooled data from 13 stable isotope studies to investigate the kinetic determinants of apoA‐I concentrations in lean and overweight—obese individuals. We also examined the associations of HDL kinetics with age, sex, BMI, fasting plasma glucose, fasting insulin, Homeostasis Model Assessment score, and concentrations of apoA‐I, triglycerides, HDL‐cholesterol and low‐density lipoprotein‐cholesterol. Results: Compared with lean individuals, overweight—obese individuals had significantly higher HDL apoA‐I fractional catabolic rate (0.21 ± 0.01 vs. 0.33 ± 0.01 pools/d; p < 0.001) and production rate (PR; 11.3 ± 4.4 vs. 15.8 ± 2.77 mg/kg per day; p = 0.001). In the lean group, HDL apoA‐I PR was significantly associated with apoA‐I concentration (r = 0.455, p = 0.004), whereas in the overweight—obese group, both HDL apoA‐I fractional catabolic rate (r = ?0.396, p = 0.050) and HDL apoA‐I PR (r = 0.399, p = 0.048) were significantly associated with apoA‐I concentration. After adjustment for fasting insulin or Homeostasis Model Assessment score, HDL apoA‐I PR was an independent predictor of apoA‐I concentration. Discussion: In overweight—obese subjects, hypercatabolism of apoA‐I is paralleled by an increased production of apoA‐I, with HDL apoA‐I PR being the stronger determinant of apoA‐I concentration. This could have therapeutic implications for the management of dyslipidemia in individuals with low plasma HDL‐cholesterol.     

Leptin Levels Are Associated with Fat Oxidation and Dietary‐Induced Weight Loss in Obesity

Objective: To examine the relationship between fasting plasma leptin and 24‐hour energy expenditure (EE), substrate oxidation, and spontaneous physical activity (SPA) in obese subjects before and after a major weight reduction compared with normal weight controls. To test fasting plasma leptin, substrate oxidations, and SPA as predictive markers of success during a standardized weight loss intervention. Research Methods and Procedures: Twenty‐one nondiabetic obese (body mass index: 33.9 to 43.8 kg/m²) and 13 lean (body mass index: 20.4 to 24.7 kg/m²) men matched for age and height were included in the study. All obese subjects were reexamined after a mean weight loss of 19.2 kg (95% confidence interval: 15.1–23.4 kg) achieved by 16 weeks of dietary intervention followed by 8 weeks of weight stability. Twenty‐four‐hour EE and substrate oxidations were measured by whole‐body indirect calorimetry. SPA was assessed by microwave radar. Results: In lean subjects, leptin adjusted for fat mass (FM) was correlated to 24‐hour EE before (r = ?0.56, p < 0.05) but not after adjustment for fat free mass. In obese subjects, leptin correlated inversely with 24‐hour and resting nonprotein respiratory quotient (r = ?0.47, p < 0.05 and r = ?0.50, p < 0.05) both before and after adjustments for energy balance. Baseline plasma leptin concentration, adjusted for differences in FM, was inversely related to the size of weight loss after 8 weeks (r = ?0.41, p = 0.07), 16 weeks (r = ?0.51, p < 0.05), and 24 weeks (r = ?0.50, p < 0.05). Discussion: The present study suggests that leptin may have a stimulating effect on fat oxidation in obese subjects. A low leptin level for a given FM was associated with a greater weight loss, suggesting that obese subjects with greater leptin sensitivities are more successful in reducing weight.     

Plasma Adiponectin Levels in High Risk African‐Americans with Normal Glucose Tolerance,Impaired Glucose Tolerance,and Type 2 Diabetes**

Objective: We studied plasma adiponectin, insulin sensitivity, and insulin secretion before and after oral glucose challenge in normal glucose tolerant, impaired glucose tolerant, and type 2 diabetic first degree relatives of African‐American patients with type 2 diabetes. Research Methods and Procedures: We studied 19 subjects with normal glucose tolerance (NGT), 8 with impaired glucose tolerance (IGT), and 14 with type 2 diabetes. Serum glucose, insulin, C‐peptide, and plasma adiponectin levels were measured before and 2 hours after oral glucose tolerance test. Homeostasis model assessment‐insulin resistance index (HOMA‐IR) and HOMA‐β cell function were calculated in each subject using HOMA. We empirically defined insulin sensitivity as HOMA‐IR < 2.68 and insulin resistance as HOMA‐IR > 2.68. Results: Subjects with IGT and type 2 diabetes were more insulin resistant (as assessed by HOMA‐IR) when compared with NGT subjects. Mean plasma fasting adiponectin levels were significantly lower in the type 2 diabetes group when compared with NGT and IGT groups. Plasma adiponectin levels were 2‐fold greater (11.09 ± 4.98 vs. 6.42 ± 3.3811 μg/mL) in insulin‐sensitive (HOMA‐IR, 1.74 ± 0.65) than in insulin‐resistant (HOMA‐IR, 5.12 ± 2.14) NGT subjects. Mean plasma adiponectin levels were significantly lower in the glucose tolerant, insulin‐resistant subjects than in the insulin sensitive NGT subjects and were comparable with those of the patients with newly diagnosed type 2 diabetes. We found significant inverse relationships of adiponectin with HOMA‐IR (r = ?0.502, p = 0.046) and with HOMA‐β cell function (r = ?0.498, p = 0.042) but not with the percentage body fat (r = ?0.368, p = 0.063), serum glucose, BMI, age, and glycosylated hemoglobin A1C (%A1C). Discussion: In summary, we found that plasma adiponectin levels were significantly lower in insulin‐resistant, non‐diabetic first degree relatives of African‐American patients with type 2 diabetes and in those with newly diagnosed type 2 diabetes. We conclude that a decreased plasma adiponectin and insulin resistance coexist in a genetically prone subset of first degree African‐American relatives before development of IGT and type 2 diabetes.     

Assessing Body Composition among 3‐ to 8‐Year‐Old Children: Anthropometry,BIA, and DXA

Objective: To examine the inter‐relationships of body composition variables derived from simple anthropometry [BMI and skinfolds (SFs)], bioelectrical impedance analysis (BIA), and dual energy x‐ray (DXA) in young children. Research Methods and Procedures: Seventy‐five children (41 girls, 34 boys) 3 to 8 years of age were assessed for body composition by the following methods: BMI, SF thickness, BIA, and DXA. DXA served as the criterion measure. Predicted percentage body fat (%BF), fat‐free mass (FFM; kilograms), and fat mass (FM; kilograms) were derived from SF equations [Slaughter (SL)1 and SL2, Deurenberg (D) and Dezenberg] and BIA. Indices of truncal fatness were also determined from anthropometry. Results: Repeated measures ANOVA showed significant differences among the methods for %BF, FFM, and FM. All methods, except the D equation (p = 0.08), significantly underestimated measured %BF (p < 0.05). In general, correlations between the BMI and estimated %BF were moderate (r = 0.61 to 0.75). Estimated %BF from the SL2 also showed a high correlation with DXA %BF (r = 0.82). In contrast, estimated %BF derived from SFs showed a low correlation with estimated %BF derived from BIA (r = 0.38); likewise, the correlation between DXA %BF and BIA %BF was low (r = 0.30). Correlations among indicators of truncal fatness ranged from 0.43 to 0.98. Discussion: The results suggest that BIA has limited utility in estimating body composition, whereas BMI and SFs seem to be more useful in estimating body composition during the adiposity rebound. However, all methods significantly underestimated body fatness as determined by DXA, and, overall, the various methods and prediction equations are not interchangeable.     

Enhanced Erythrocyte Adhesiveness/Aggregation in Obesity Corresponds to Low‐Grade Inflammation

Objective: Previous studies have suggested that obesity enhances the inflammatory response, producing macromolecules involved in the induction and/or maintenance of increased erythrocyte aggregation. The objectives of this study were to evaluate the correlation between inflammation markers, erythrocyte adhesiveness/aggregation, and the degree of obesity and to assess phosphatidylserine expression on erythrocyte surface membrane of obese vs. nonobese individuals. Research Methods and Procedures: Erythrocyte adhesiveness/aggregation in the peripheral venous blood was evaluated by using a new biomarker, phosphatidylserine expression was assessed by means of flow cytometry, and markers of inflammation were measured in 65 subjects: 30 obese [body mass index (BMI) = 41 ± 7.7 kg/m²] and 35 nonobese (BMI = 24 ± 2.7 kg/m²) individuals. Pearson correlations and Student's t test were performed. Results: A highly significant difference was noted in the degree of erythrocyte adhesiveness/aggregation and markers of inflammation between the study groups. BMI correlated with erythrocyte adhesiveness/aggregation (r = 0.42, p = 0.001), erythrocyte sedimentation rate (r = 0.42, p = 0.001), high‐sensitive C‐reactive protein (r = 0.55, p < 10^?4), fibrinogen (r = 0.37, p = 0.004), and white blood cell count (r = 0.45, p < 10^?4). The degree of erythrocyte adhesiveness/aggregation correlated with erythrocyte sedimentation rate (r = 0.5, p < 10^?4), high‐sensitive C‐reactive protein (r = 0.56, p < 10^?4), fibrinogen (r = 0.54, p < 10^?4), and white blood cell count (r = 0.32, p = 0.01). Discussion: Our results suggest that obesity‐related erythrocyte adhesiveness/aggregation is probably mediated through increased concentrations of adhesive macromolecules in the circulation and not necessarily through hyperlipidemia or phosphatidylserine exposure on erythrocyte's membrane.     

Association of the TNF‐α−308 G/A Promoter Polymorphism with Insulin Resistance in Obesity

Objective: Obesity is a major risk factor for the development of type 2 diabetes. Tumor necrosis factor (TNF)‐α is a candidate gene for the development of both obesity and insulin resistance. We investigated whether a common polymorphism in the promoter region (?308 G/A) of the TNF‐α gene was associated with increased risk for the development of insulin resistance and cardiovascular disease in an obese Australian population. Research Methods and Procedures: Obese, non‐diabetic subjects (146 women and 34 men) were genotyped with polymerase chain reaction‐restriction fragment length polymorphism techniques, and anthropometric and biochemical measurements were analyzed. A homeostasis model assessment (HOMA) score was used to gauge the level of insulin resistance. Results: The frequencies of the G allele and the A allele were 0.759 and 0.241, respectively. Subjects homozygous for the A allele had higher fasting insulin levels (226 vs. 131 pM; p < 0.001), higher HOMA scores (10.2 vs. 5.3; p < 0.001), higher systolic blood pressure (143 vs. 129 mm Hg; p = 0.02), and lower high‐density lipoprotein (HDL) cholesterol (1.13 vs. 1.25 mM; p = 0.04) than did subjects homozygous for the G allele. Whereas an association between insulin resistance and body mass index or waist circumference was seen in all subjects, a highly significant negative correlation of HDL cholesterol to HOMA scores (r = ?0.710; p < 0.001) occurred in subjects with the A allele only. Discussion: The ?308 G/A TNF‐α gene variant conveys an increased risk for the development of insulin resistance in obese subjects. The presence of low HDL cholesterol levels further increases the risks associated with insulin resistance in carriers of the A allele.     

Leptin Responses to Weight Loss in Postmenopausal Women: Relationship to Sex‐Hormone Binding Globulin and Visceral Obesity

Objective: Leptin concentrations increase with obesity and tend to decrease with weight loss. However, there is large variation in the response of serum leptin levels to decreases in body weight. This study examines which endocrine and body composition factors are related to changes in leptin concentrations following weight loss in obese, postmenopausal women. Research Methods and Procedures: Body composition (DXA), visceral obesity (computed tomography), leptin, cortisol, insulin, and sex hormone‐binding globulin (SHBG) concentrations were measured in 54 obese (body mass index [BMI] = 32.0 ± 4.5 kg/m²; mean ± SD), women (60 ± 6 years) before and after a 6‐month hypocaloric diet (250 to 350 kcal/day deficit). Results: Body weight decreased by 5.8 ± 3.4 kg (7.1%) and leptin levels decreased by 6.6 ± 11.9 ng/mL (14.5%) after the 6‐month treatment. Insulin levels decreased 10% (p < 0.05), but mean SHBG and cortisol levels did not change significantly. Relative changes in leptin with weight loss correlated positively with relative changes in body weight (r = 0.50, p < 0.0001), fat mass (r = 0.38, p < 0.01), subcutaneous fat area (r = 0.52, p < 0.0001), and with baseline values of SHBG (r = 0.38, p < 0.01) and baseline intra‐abdominal fat area (r = ?0.27, p < 0.06). Stepwise multiple regression analysis showed that baseline SHBG levels (r² = 0.24, p < 0.01), relative changes in body weight (cumulative r² = 0.40, p < 0.05), and baseline intra‐abdominal fat area (cumulative r² = 0.48, p < 0.05) were the only independent predictors of the relative change in leptin, accounting for 48% of the variance. Discussion: These results suggest that obese, postmenopausal women with a lower initial SHBG and more visceral obesity have a greater decrease in leptin with weight loss, independent of the amount of weight lost.     

Relationship of Neck Circumference to Cardiovascular Risk Factors

Objective: To determine a relationship between neck circumference (NC) and risk factors for coronary heart disease by evaluating the components of the metabolic syndrome. Research Methods and Procedures: The study group included 561 subjects (231 men and 330 women) who had no known major medical conditions and were not receiving any medication therapy. The subjects were those who attended a family health clinic for any reason between 1998 and December 2001. Main indicators studied included NC, waist circumference, waist‐to‐hip ratio, body mass index, blood pressure, and lipoprotein, glucose, and uric acid levels. Results: Pearson's correlation coefficients indicated a significant association between NC and body mass index (men, r = 0.71; women, r = 0.81; each, p < 0.0001), waist circumference (men, r = 0.75; women, r = 0.79; each, p < 0.0001), waist‐to‐hip ratio (men, r = 0.56; women, r = 0.63; each, p < 0.0001), total cholesterol (men, r = 0.50; women, r = 0.66; each, p < 0.0001), low‐density lipoprotein‐cholesterol (men, r = 0.42; women, r = 0.60; each, p < 0.0001), triglycerides (men, r = 0.48; women, r = 0.49; each, p < 0.0001), glucose (men, r = 0.21, p < 0.001; women, r = 0.44; p < 0.0001), uric acid (men, r = 0.50, p < 0.0001; women, r = 0.60, p < 0.001), and systolic (men, r = 0.53; women, r = 0.69; each, p < 0.0001), and diastolic (men, r = 0.55; women, r = 0.65; each, p < 0.0001) blood pressure. Discussion: Higher NC is correlated positively with the factors of the metabolic syndrome; therefore, it is likely to increase the risk of coronary heart disease.     

Lipid Profile in the Severely Obese: Changes with Weight Loss after Lap‐Band Surgery

Objective: To characterize dyslipidemia before and after weight loss in the severely obese. Research Methods and Procedures: Five hundred fifteen subjects who had Lap‐Band surgery were followed with yearly conventional lipid profiles for up to 4 years. Preoperative data were collected from the most recent 381 subjects, and predictors of dyslipidemia were sought. One hundred seventy‐one subjects completed a 1‐year review, providing data to assess predictors of change in lipids. Results: Favorable changes in fasting triglycerides (TG), high‐density lipoprotein‐cholesterol (HDL‐C), and total cholesterol (TC):HDL‐C ratio occurred within 1 year. All improvements were maintained up to 4 years. Male gender, central obesity, elevated fasting glucose, and insulin resistance were associated with less favorable lipid levels. Fasting plasma glucose best predicted TG (r = 0.46, p < 0.001), whereas insulin sensitivity using the homeostatic model assessment (HOMA %S) correlated best with the HDL‐C (r =0.34, p < 0.001). Higher preoperative fasting glucose best predicted the decrease in TG; improved HOMA %S with weight loss correlated best with HDL‐C. The extent of weight loss had limited influence on lipid changes. However, low preoperative HOMA %S was associated with lower weight loss. Greater weight loss was associated with more favorable lipid measures after controlling for preoperative HOMA %S. Discussion: Dyslipidemia of obesity is related to weight distribution, insulin sensitivity, and impaired glucose tolerance. Improvement with weight loss is related to the decrease in fasting glucose, improvement in insulin sensitivity, and the extent of weight lost. Improvement in dyslipidemia is sustained with long‐term weight loss.     

Estimation of Free‐Living Energy Expenditure Using a Novel Activity Monitor Designed to Minimize Obtrusiveness

The aim of this study was to investigate the ability of a novel activity monitor designed to be minimally obtrusive in predicting free‐living energy expenditure. Subjects were 18 men and 12 women (age: 41 ± 11 years, BMI: 24.4 ± 3 kg/m²). The habitual physical activity was monitored for 14 days using a DirectLife triaxial accelerometer for movement registration (Tracmor_D) (Philips New Wellness Solutions, Lifestyle Incubator, the Netherlands). Tracmor_D output was expressed as activity counts per day (Cnts/d). Simultaneously, total energy expenditure (TEE) was measured in free living conditions using doubly labeled water (DLW). Activity energy expenditure (AEE) and the physical activity level (PAL) were determined from TEE and sleeping metabolic rate (SMR). A multiple‐linear regression model predicted 76% of the variance in TEE, using as independent variables SMR (partial‐r² = 0.55, P < 0.001), and Cnts/d (partial r² = 0.21, P < 0.001). The s.e. of TEE estimates was 0.9 MJ/day or 7.4% of the average TEE. A model based on body mass (partial‐r² = 0.31, P < 0.001) and Cnts/d (partial‐r² = 0.23, P < 0.001) predicted 54% of the variance in TEE. Cnts/d were significantly and positively associated with AEE (r = 0.54, P < 0.01), PAL (r = 0.68, P < 0.001), and AEE corrected by body mass (r = 0.71, P < 0.001). This study showed that the Tracmor_D is a highly accurate instrument for predicting free‐living energy expenditure. The miniaturized design did not harm the ability of the instrument in measuring physical activity and in determining outcome parameters of physical activity such as TEE, AEE, and PAL.     

Effect of apolipoprotein E genotype on apolipoprotein B-100 metabolism in normolipidemic and hyperlipidemic subjects

The effect of apolipoprotein (apo) E genotype on apoB-100 metabolism was examined in three normolipidemic apoE2/E2, five type III hyperlipidemic apoE2/E2, and five hyperlipidemic apoE3/E2 subjects using simultaneous administration of ¹³¹I-VLDL and ¹²⁵I-LDL, and multi-compartmental modeling. Compared with normolipidemic apoE2/E2 subjects, type III hyperlipidemic E2/E2 subjects had increased plasma and VLDL cholesterol, plasma and VLDL triglycerides, and VLDL and intermediate density lipoprotein (IDL) apoB concentrations (P < 0.05). These abnormalities were chiefly a consequence of decreased VLDL and IDL apoB fractional catabolic rate (FCR). Compared with hyperlipidemic E3/E2 subjects, type III hyperlipidemic E2/E2 subjects had increased IDL apoB concentration and decreased conversion of IDL to LDL particles (P < 0.05). In a pooled analysis, VLDL cholesterol was positively associated with VLDL and IDL apoB concentrations and the proportion of VLDL apoB in the slowly turning over VLDL pool, and was negatively associated with VLDL apoB FCR after adjusting for subject group. VLDL triglyceride was positively associated with VLDL apoB concentration and VLDL and IDL apoB production rates after adjusting for subject group. A defective apoE contributes to altered lipoprotein metabolism but is not sufficient to cause overt hyperlipidemia. Additional genetic mutations and environmental factors, including insulin resistance and obesity, may contribute to the development of type III hyperlipidemia.     

Short‐Term Effects of Gastric Bypass Surgery on Circulating Ghrelin Levels

Objective: To prospectively evaluate the short‐term effects of Roux‐en‐Y gastric bypass (RYGBP) on ghrelin secretion and its relevance on food intake and body weight changes. Research Methods and Procedures: Ghrelin response to a standardized test meal was evaluated in eight obese patients (BMI, 43.5 to 59.1 kg/m²) before and 6 weeks after RYGBP. Ghrelin response was compared with that of an age‐matched group of six normal weight individuals (BMI, 19.6 to 24.9 kg/m²). Results: Fasting serum ghrelin levels were lower in obese subjects compared with controls (p < 0.05). Meal ingestion significantly suppressed ghrelin concentration in controls (p < 0.05) and obese subjects (p < 0.05), albeit to a lesser degree in the latter group (p < 0.05). Despite a 10.3 ± 1.5% weight loss, fasting serum ghrelin levels were paradoxically further decreased in obese subjects 6 weeks after RYGBP (p < 0.05). Moreover, at this time‐point, food intake did not elicit a significant ghrelin suppression. The changes in ghrelin secretion after RYGBP correlated with changes in insulin sensitivity (p < 0.05) and caloric intake (p < 0.05). Discussion: This study showed that the adaptive response of ghrelin to body weight loss was already impaired 6 weeks after RYGBP. Our study provides circumstantial evidence for the potential role of ghrelin in the negative energy balance in RYGBP‐operated patients.     

High‐Sensitivity C‐Reactive Protein in Japanese Patients with Type 2 Diabetes

Objective: To assess the relationship between high‐sensitivity (HS) C‐reactive protein (CRP) and metabolic syndrome (MetS) or atherosclerosis and to assess effects of strict metabolic control on the degree of inflammation and MetS in patients with type 2 diabetes. Research Methods and Procedures: Four hundred thirteen patients with diabetes were enrolled in the cross‐sectional study. Of these 413 patients, 161 patients were further admitted for 2.4 ± 0.4 weeks (mean ± SD) to investigate the change in HS‐CRP or other parameters under strict metabolic control. Results: Log‐transformed HS‐CRP value (log HS‐CRP) was strongly correlated with BMI (r = 0.448, p < 0.01). Log HS‐CRP was also correlated with the presence of MetS or each component of MetS. Furthermore, a positive significant trend in HS‐CRP levels was shown with an increasing number of MetS components (p < 0.05). Log HS‐CRP showed a significant positive correlation with carotid artery intima‐media thickness (IMT) (r = 0.152, p < 0.01). In multiple step‐wise regression analysis, BMI, hemoglobin A_1c, right IMT, duration of diabetes, and triglyceride were selected as explanatory variables for log HS‐CRP (R² = 0.412). Under strict metabolic control, HS‐CRP was significantly (p < 0.01) lower, together with lower levels of other markers for MetS. The change in HS‐CRP was significantly correlated with the change in BMI (r = 0.161, p = 0.04). Discussion: In subjects with type 2 diabetes, HS‐CRP levels are related to MetS and subclinical atherosclerosis. Strict weight management and metabolic control were associated with a reduction in HS‐CRP levels, and changes in HS‐CRP were related to changes in weight, supporting the hypothesis that lifestyle modification reduces inflammation and the risk of CHD.     

Fasting Plasma Insulin Modulates Lipid Levels and Particle Sizes in 2‐ to 3‐Year‐Old Children

Objective: Obesity and hyperinsulinemia are associated with dyslipidemia in adults and older children, but little is known about these relationships in very young children. We examined the relation of fasting insulin to lipid levels and lipid particle size in young healthy children. Research Methods and Procedures: Analyses were performed on data from 491 healthy 2‐ and 3‐year old Hispanic children enrolled in a dietary study conducted in New York City, 1992–1995. Obesity measures included BMI, ponderal index, skinfold thickness, and waist circumference. Low‐density lipoprotein (LDL)‐ and high‐density lipoprotein (HDL)‐cholesterol particle size were measured by nuclear magnetic resonance. Results: Fasting insulin level was positively correlated with triglyceride levels (r = 0.24 for boys and r = 0.23 for girls; p < 0.001 for both) and inversely correlated with HDL‐cholesterol level in boys (r = ?0.20; p < 0.01). Higher fasting insulin level was also correlated with smaller mean HDL particle size in both boys (r = ?0.21; p < 0.001) and girls (r = ?0.14; p < 0.05) and smaller mean LDL particle size in boys (r = ?0.13; p < 0.05). The associations of fasting insulin level with triglyceride and HDL‐cholesterol levels and HDL and LDL particle size remained significant after multivariate regression adjustment for age, sex, and BMI or ponderal index. Discussion: Fasting insulin level is associated with relative dyslipidemia in healthy 2‐ and 3‐year‐old Hispanic children.     

Four‐Compartment Cellular Level Body Composition Model: Comparison of Two Approaches**

Objective: The aim of this study was to develop and compare two DXA‐based four‐compartment [body weight = body cell mass (BCM) + extracellular fluid (ECF) + extracellular solids (ECS) + fat] cellular level models. Research Methods and Procedures: Total body potassium (TBK) model: BCM from TBK by whole‐body counting—ECF_TBK = LST ? [BCM_TBK + 0.73 × osseous mineral (Mo)]. Bromide model: ECF from sodium bromide dilution—BCM_BROMIDE = LST ? (ECF_BROMIDE + 0.73 × Mo); Mo and LST measurements came from DXA. The two approaches were evaluated in 99 healthy men and 118 women. Results: BCM estimates were highly correlated (r = 0.97, p < 0.001), as were ECF estimates (r = 0.87, p < 0.001); a small statistically significant mean difference was present (mean ± SD; BCM_TBK model, 30.4 ± 8.9 kg; BCM_BROMIDE, 31.4 ± 9.3 kg; Δ = 1.0 ± 2.8 kg; p < 0.001; ECF_TBK, 18.5 ± 4.2 kg; ECF_BROMIDE, 17.5 ± 3.6 kg; Δ = 1.0 ± 2.8 kg; p < 0.001). A high correlation (r = 0.97, p < 0.001) and good agreement (38.9 ± 9.5 vs. 38.9 ± 9.5 kg; Δ = 0.0 ± 2.4 kg; p = 0.39) were present between TBW, derived as the sum of intracellular water from TBK and ECW from bromide, and measured TBW by ²H₂O dilution. Discussion: Two developed four‐compartment cellular level DXA models, one of which is appropriate for use in most clinical and research settings, provide comparable results and are applicable for BCM and ECF estimation of subject groups with hydration disturbances.     

Longitudinal Analyses among Overweight,Insulin Resistance,and Cardiovascular Risk Factors in Children

Objective: It has been questioned whether insulin resistance or obesity is the central abnormality contributing to the cardiovascular risk factors dyslipidemia and hypertension in obesity. Research Methods and Procedures: We studied weight status [SD score (SDS)‐BMI], lipids (triglycerides, low‐density lipoprotein‐ and high‐density lipoprotein‐cholesterol), blood pressure, and insulin resistance index [as homeostasis model assessment (HOMA) model] over a 1‐year period in 229 obese white children (median age 12 years). Results: Any degree of decrease in HOMA was associated with significant decreases in triglycerides (p < 0.001), systolic blood pressure (p < 0.001), and diastolic blood pressure (p < 0.001), whereas the children with different changes in HOMA did not differ significantly in their weight changes. Only the children in the highest quartile of weight reduction (decrease in SDS‐BMI > 0.5) demonstrated a significant decrease in systolic blood pressure (p < 0.001), diastolic blood pressure (p < 0.001), and triglycerides (p = 0.012), and an increase in high‐density lipoprotein‐cholesterol (p = 0.023), whereas with a lower degree of weight loss, there were no significant changes in cardiovascular risk factors. In contrast with a lower degree of weight loss, a reduction of >0.5 SDS‐BMI was associated with a significant decrease in HOMA (p < 0.001). Discussion: Because blood pressure and triglycerides decreased with any degree of decrease in HOMA, independently of changes in weight status, these findings support the hypothesis that insulin resistance is the central abnormality contributing to these cardiovascular risk factors. Therefore, improving insulin resistance seems more important than reducing overweight to prevent or treat hypertension and dyslipidemia in obese children.