Increased Susceptibility to Insulin Resistance Associated with Abdominal Obesity in Aging Rats**

Objective: Recent data have suggested that the insulin resistance observed with aging may be more related to adiposity than aging per se. We asked whether the insulin resistance observed in aged rats was comparable (both in magnitude and location) to that of fat‐fed rats. Research Methods and Procedures: We performed hyperinsulinemic (5 mU/min per kg) euglycemic clamps with tracer in conscious, 6‐hour fasted young (YL), fat‐fed young (YF), fat‐fed old (OF), and calorically restricted old (OL) rats. Results: Intraabdominal fat measurements showed that OF and YF rats were more obese than YL (p ≤ 0.001; YF > OF > YL). Caloric restriction not only prevented age‐related obesity but also reduced the ratio of intraabdominal fat to lean body mass (LBM) compared with YL (OL: 0.59 ± 0.05 vs. YL: 1.07 ± 0.04; p = 0.017). Despite similar incremental insulin, YF and OF rats required 40% less infused glucose to maintain euglycemia than YL and OL rats (p < 0.001). Insulin‐stimulated glucose uptake (Si_Rd: ΔRd/(ΔInsulin × Glucose_SS) was impaired in OF rats (OF: 14.03 ± 1.79 vs. YL: 23.08 ± 1.87 × 10³ dL/min × kg LBM per pM; p = 0.004) and improved in OL rats (29.41 ± 1.84 × 10³ dL/min × kg LBM per pM; p = 0.031) compared with YL. Despite greater obesity, YF rats did not exhibit lower Si_Rd compared with OF rats (p = 0.58). In contrast, the ability of insulin to suppress endogenous glucose production (EGP; Si_EGP: ΔEGP/(ΔInsulin × Glucose_SS) was not impaired in OF rats (OF vs. YL; p = 0.61) but was markedly impaired in YF rats by ～75% (1.72 ± 0.66 × 10³ dL/min × kg per pM; p = 0.013). Surprisingly, separate regression analysis for old and young animals revealed that old rats exhibited a significantly steeper regression between Si (Rd and EGP) and adiposity than young rats (p < 0.05). Thus, older rats showed a proportionately greater decrement in insulin sensitivity with an equivalent increase in adiposity. Discussion: These data suggest that, in rodents, youth affords significant protection against obesity‐induced insulin resistance.     

Racial Differences in Insulin Secretion and Sensitivity in Prepubertal Children: Role of Physical Fitness and Physical Activity

Objective: To investigate in prepubertal children whether physical fitness and/or physical activity are: 1) associated with insulin secretion and sensitivity and 2) account for racial differences in insulin secretion and sensitivity. Research Methods and Procedures: Subjects included 34 African American and 34 white nondiabetic children aged 5 to 11 years. Data were divided into two sets according to the availability of VO_2max and physical activity data. Body composition was measured by dual‐energy X‐ray absorptiometry. Subcutaneous abdominal adipose tissue and intra‐abdominal adipose tissue were examined by computed tomography. Insulin sensitivity (S_I) and acute insulin response (AIR) were determined by a frequently sampled intravenous glucose tolerance test. An all‐out, progressive treadmill exercise test was used for measuring VO_2max. Physical activity data were collected by questionnaire. Results: African American children had lower S_I and higher AIR than white children, after adjusting for total body fat mass. African Americans reported higher levels of physical activity (hours/wk) than whites, but had a lower VO_2max. In multiple linear regression analysis, hours/wk of activity and hours/wk of vigorous activity, but not moderate activity, were independently related to S_I and AIR after adjusting for race, total body fat mass or fat distribution, and total lean tissue mass. VO_2max was not related to AIR, and was inversely related to S_I, after adjusting for body composition. Race remained significantly associated with both S_I and AIR, even after adjusting for body composition, fat distribution, and hours/wk of activity or hours/wk of vigorous activity. Discussion: In summary, overall physical activity and, especially, vigorous activity were associated with insulin secretion and sensitivity. However, neither physical activity nor VO_2max explained the racial difference in insulin secretion (higher in African Americans) and sensitivity (lower in African Americans). Thus, racial (African American to white) differences in aspects of insulin action seem to be due to factors other than body composition, fat distribution, cardiovascular fitness, and amount of physical activity.     

Visceral Adipose Tissue and Markers of the Insulin Resistance Syndrome in Obese Black and White Teenagers

Objective: To determine the relationships between visceral and general adiposity, cardiovascular fitness, and markers of the insulin resistance syndrome in obese black and white teenagers. Research Methods and Procedures: Cross‐sectional survey of 81 obese 13‐ to 16‐year‐old youths. Visceral adipose tissue was measured with magnetic resonance imaging, and percentage body fat was measured with dual‐energy X‐ray absorptiometry. Cardiovascular fitness was assessed with a submaximal treadmill test. Fasting blood samples were analyzed for lipids/lipoproteins and insulin. Resting blood pressure was obtained using an automated cuff. Results: Visceral adipose tissue was significantly correlated with unfavorable levels of: triacylglycerol (r = 0.27, p < 0.05), total cholesterol (r = 0.27, p < 0.05), high‐density lipoprotein cholesterol (r = ?0.26, p < 0.05), the ratio of total cholesterol/high‐density lipoprotein cholesterol (r = 0.42, p < 0.01), low‐density lipoprotein cholesterol (r = 0.27, p < 0.05), apolipoprotein B (r = 0.38, p < 0.01), and systolic blood pressure (r = 0.30, p < 0.01). Multiple regression analyses revealed that visceral adipose tissue was more powerful than percentage body fat for explaining variance in lipoproteins (e.g., for the ratio of total cholesterol/high‐density lipoprotein cholesterol, r² = 0.13, p < 0.01, and for systolic blood pressure, r² = 0.07, p < 0.05). Ethnicity was the most powerful of the demographic predictors for blood lipids (r² = 0.15 for triacylglycerol with lower levels in blacks; r² = 0.10 for high‐density lipoprotein cholesterol with higher levels in blacks; r² = 0.06 for the ratio of total cholesterol/high‐density lipoprotein cholesterol with lower levels in blacks). Cardiovascular fitness was not retained as a significant predictor of markers of the insulin resistance syndrome. Discussion: Some of the deleterious relationships between visceral adiposity and markers for the insulin resistance syndrome seen in adults were already present in these obese young people.     

Insulin Action,Regional Fat,and Myocyte Lipid: Altered Relationships with Increased Adiposity

Objective: Abdominal fat and myocyte triglyceride levels relate negatively to insulin sensitivity, but their interrelationships are inadequately characterized in the overweight. Using recent methods for measuring intramyocyte triglyceride, these relationships were studied in men with a broad range of adiposity. Research Methods and Procedures: Myocyte triglyceride content (¹H‐magnetic resonance spectroscopy of soleus and tibialis anterior muscles and biochemical assessment of vastus lateralis biopsies), regional fat distribution (DXA and abdominal magnetic resonance imaging), serum lipids, insulin action (euglycemic hyperinsulinemic clamp), and substrate oxidation rates (indirect calorimetry) were measured in 39 nondiabetic men (35.1 ± 7.8 years) with a broad range of adiposity (BMI 28.6 ± 4.1 kg/m², range 20.1 to 37.6 kg/m²). Results: Relationships between insulin‐stimulated glucose disposal and regional body fat depots appeared more appropriately described by nonlinear than linear models. When the group was subdivided using median total body fat as the cut‐point, insulin‐stimulated glucose disposal correlated negatively to all regional body fat measures (all p ≤ 0.004), serum triglycerides and free fatty acids (p < 0.02), and both soleus intramyocellular lipid (p = 0.003) and vastus lateralis triglyceride (p = 0.04) in the normal/less overweight group. In contrast, only visceral abdominal fat showed significant negative correlation with insulin‐stimulated glucose disposal in more overweight men (r = ?0.576, p = 0.01), some of whom surprisingly had lower than expected myocyte lipid levels. These findings persisted when the group was subdivided using different cut‐points or measures of adiposity. Discussion: Interrelationships among body fat depots, myocyte triglyceride, serum lipids, and insulin action are generally absent with increased adiposity. However, visceral abdominal fat, which corresponds less closely to total adiposity, remains an important predictor of insulin resistance in men with both normal and increased adiposity.     

Influence of Total vs. Visceral Fat on Insulin Action and Secretion in African American and White Children

Objective: To examine whether total body fat (FAT) in general or visceral fat (VFAT) in particular is associated with greater metabolic risk in white and African American children. Research Methods and Procedures: A total of 68 white and 51 African American children had measures of insulin sensitivity (Si) and acute insulin response (AIR) by a frequently sampled intravenous glucose tolerance test, total body fat by DXA and abdominal fat distribution (visceral vs. subcutaneous) by computed tomography. The influence of FAT and VFAT on insulin parameters were examined by comparing subgroups of children with high or low FAT vs. high or low VFAT and by multiple regression analysis. Results: In whites, fasting insulin, Si, and AIR were significantly influenced by FAT, but not VFAT (e.g., for Si, 9.8 ± 0.8 in low FAT vs. 4.6 ± 0.7 × 10^?4/min/[μIU/mL] in high FAT, p < 0.05; 6.8 ± 0.7 in low VFAT vs. 7.5 ± 0.8 × 10^?4/min/[μIU/mL] in high VFAT, p > 0.1). In African Americans, fasting insulin and Si were also primarily influenced by FAT (e.g., for Si, 4.9 ± 0.4 in low FAT vs. 2.8 ± 0.5 × 10^?4/min/[μIU/mL] in high FAT, p < 0.05) but not by VFAT, and there were no significant effects of either fat compartment on AIR. In multiple regression analysis, Si was significantly influenced by FAT (negative effect), ethnicity (lower in African Americans), and gender (lower in females), whereas fasting insulin was significantly influenced by VFAT (positive effect), ethnicity (higher in African Americans), and fat free mass (positive effect). Discussion: Body fat in general is the predominant factor influencing Si, but VFAT may have additional effects on fasting insulin. The lack of major effects of VFAT on Si in children may be explained by lower levels of VFAT or because VFAT affects aspects of whole body insulin action that are not measured by the minimal model.     

Fitness Alters the Associations of BMI and Waist Circumference with Total and Abdominal Fat

Objective: We tested the following hypotheses in black and white men and women: 1) for a given BMI or waist circumference (WC), individuals with moderate cardiorespiratory fitness (CRF) have lower amounts of total fat mass and abdominal subcutaneous and visceral fat compared with individuals with low CRF; and 2) exercise training is associated with significant reductions in total adiposity and abdominal fat independent of changes in BMI or WC. Research Methods and Procedures: The sample included 366 sedentary male (111 blacks and 255 whites) and 462 sedentary female (203 blacks and 259 whites) participants in the HERITAGE Family Study. The relationships between BMI and WC with total fat mass (determined by underwater weighing) and abdominal subcutaneous and visceral fat (determined by computed tomography) were compared in subjects with low (lower 50%) and moderate (upper 50%) CRF. The effects of a 20‐week aerobic exercise training program on changes in these adiposity variables were examined in 86% of the subjects. Results: Individuals with moderate CRF had lower levels of total fat mass and abdominal subcutaneous and visceral fat than individuals with low CRF for a given BMI or WC value. The 20‐week aerobic exercise program was associated with significant reductions in total adiposity and abdominal fat, even after controlling for reductions in BMI and WC. With few exceptions, these observations were true for both men and women and blacks and whites. Discussion: These findings suggest that a reduction in total adiposity and abdominal fat may be a means by which CRF attenuates the health risk attributable to obesity as determined by BMI and WC.     

Racial Differences in Insulin Resistance and Mid‐Thigh Fat Deposition in Postmenopausal Women

Objective: To determine whether racial differences in insulin resistance between African American (AA) and white women exist in postmenopausal women and whether they are related to physical fitness and/or obesity. Research Methods and Procedures: We studied 35 obese AA (n = 9) and white (n = 26) women of comparable maximal oxygen consumption, obesity, and age. Total body fat was measured by DXA. Abdominal and mid‐thigh low‐density lean tissue (a marker of intramuscular fat) were determined with computed tomography. Glucose utilization (M) was measured during the last 30 minutes of a 3‐hour hyperinsulinemic‐euglycemic clamp. Insulin sensitivity was estimated from the relationship of M to the concentration of insulin during the last 30 minutes of the clamp. Results: The percentage of fat and total body fat mass were similar between AA and white women, whereas fat‐free mass was higher in African American women. Visceral adipose tissue was not different between groups, but subcutaneous abdominal fat was 17% higher in the AA than in the white women. AA women had an 18% greater mid‐thigh muscle area (p < 0.01) and a 34% greater mid‐thigh low‐density lean tissue area than the white women. Fasting glucose concentrations were not different, but fasting insulin concentrations were 29% higher in AA women. Glucose utilization was 60% lower in the AA women because of a lower non‐oxidative glucose disposal. Insulin sensitivity was 46% lower in the AA women. Discussion: AA postmenopausal women have more mid‐thigh intramuscular fat, lower glucose utilization, and are less insulin sensitive than white women despite comparable fitness and relative body fat levels.     

Cardiorespiratory fitness influences the blood pressure response to experimental weight gain

Objective: We tested the hypothesis that with similar weight gain the increase in blood pressure (BP) would be smaller in men with higher cardiorespiratory fitness (HCRF) than in men with lower cardiorespiratory fitness (LCRF). Research Methods and Procedures: Thirteen men (age = 23 ± 1, BMI = 24 ± 1) were overfed by ～1000 kcal/d over ～8 weeks to achieve a 5‐kg weight gain. Resting BP and 24‐hour ambulatory BP, body composition, and fat distribution were measured. Results: Cardiorespiratory fitness (CRF) was higher in the HCRF group compared with the LCRF group (49.9 ± 1.2 vs. 38.1 ± 1.4 mL/kg per minute, p < 0.001). At baseline, body weight was similar in the HCRF and LCRF groups, whereas the HCRF group displayed lower levels of total body fat (13.0 ± 1.7 vs. 16.9 ± 1.3 kg, p = 0.049) and abdominal visceral fat (49 ± 6 vs. 80 ± 14 cm², p = 0.032). Resting BP and 24‐hour ambulatory BP were similar in the two groups at baseline. After weight gain, body weight increased ～5 kg (p < 0.05) in both groups; the changes in body composition and regional fat distribution were similar. As hypothesized, the increases in resting systolic (1 ± 2 vs. 7 ± 2 mm Hg; p = 0.008) and diastolic (?1 ± 4 vs. 5 ± 1 mm Hg; p = 0.005) BP were smaller in the HCRF group. CRF was correlated with the increases in resting systolic (r = ?0.64; p = 0.009) and diastolic BP (r = ?0.80; p < 0.001). Furthermore, the relationship between CRF and BP remained significant after adjusting for the changes in the proportion of total abdominal fat gained as visceral fat. Discussion: These findings suggest that higher levels of CRF are associated with a smaller increase in BP with weight gain, independently of changes in abdominal visceral fat.     

Effect of Rosiglitazone on Insulin Sensitivity and Body Composition in Type 2 Diabetic Patients

Objective: To investigate the effects of rosiglitazone (RSG) on insulin sensitivity and regional adiposity (including intrahepatic fat) in patients with type 2 diabetes. Research Methods and Procedures: We examined the effect of RSG (8 mg/day, 2 divided doses) compared with placebo on insulin sensitivity and body composition in 33 type 2 diabetic patients. Measurements of insulin sensitivity (euglycemic hyperinsulinemic clamp), body fat (abdominal magnetic resonance imaging and DXA), and liver fat (magnetic resonance spectroscopy) were taken at baseline and repeated after 16 weeks of treatment. Results: There was a significant improvement in glycemic control (glycosylated hemoglobin −0.7 ± 0.7%, p ≤ 0.05) and an 86% increase in insulin sensitivity in the RSG group (glucose-disposal rate change from baseline: 17.5 ± 14.5 μmol glucose/min/kg free fat mass, p < 0.05), but no significant change in the placebo group compared with baseline. Total body weight and fat mass increased (p ≤ 0.05) with RSG (2.1 ± 2.0 kg and 1.4 ± 1.6 kg, respectively) with 95% of the increase in adiposity occurring in nonabdominal regions. In the abdominal region, RSG increased subcutaneous fat area by 8% (25.0 ± 28.7 cm², p = 0.02), did not alter intra-abdominal fat area, and reduced intrahepatic fat levels by 45% (−6.7 ± 9.7%, concentration relative to water). Discussion: Our data indicate that RSG greatly improves insulin sensitivity in patients with type 2 diabetes and is associated with an increase in adiposity in subcutaneous but not visceral body regions.     

Circulating Interleukin‐6 in Relation to Adiposity,Insulin Action,and Insulin Secretion

Objective: Plasma concentrations of interleukin‐6 (IL‐6), a proinflammatory cytokine produced and released in part by adipose tissue, are elevated in people with obesity and type 2 diabetes. Because recent studies suggest that markers of inflammation predict the development of type 2 diabetes, we examined whether circulating plasma IL‐6 concentrations were related to direct measures of insulin resistance and insulin secretory dysfunction in Pima Indians, a population with high rates of obesity and type 2 diabetes. Research Methods and Procedures: Fasting plasma IL‐6 concentrations (enzyme‐linked immunosorbent assay), body composition (DXA), insulin action (M; hyperinsulinemic euglycemic clamp), and acute insulin secretory responses to glucose (25 g intravenous glucose tolerance test) were measured in 58 Pima Indians without diabetes (24 women, 34 men). Results: Fasting plasma IL‐6 concentrations were positively correlated with percentage of body fat (r = 0.26, p = 0.049) and negatively correlated with M (r = ?0.28, p = 0.031), but were not related to acute insulin response (r = 0.13, p = 0.339). After adjusting for percentage of body fat, plasma IL‐6 was not related to M (partial r = ?0.23, p = 0.089). Discussion: Fasting plasma IL‐6 concentrations are positively related to adiposity and negatively related to insulin action in Pima Indians. The relationship between IL‐6 and insulin action seems to be mediated through adiposity.     

Visceral adiposity is associated with serum retinol binding protein-4 levels in healthy women

Objective: Retinol binding protein‐4 (RBP4) has been reported to impair insulin sensitivity throughout the body. We investigated the relationship between serum RBP4 levels and adiposity indices as well as metabolic risk variables. Research Methods and Procedure: We recruited a total of 102 healthy women 21 to 67 years old. We assessed body composition by computed tomography and divided the study population into four groups based on body weight and visceral fat area (non‐obese without visceral adiposity, non‐obese with visceral adiposity, obese without visceral adiposity, and obese with visceral adiposity). Serum RBP4 levels were measured by radioimmunoassay. Results: Despite similar levels of total body fat, non‐obese women had lower systolic blood pressure, total cholesterol, triglyceride (TG), low‐density lipoprotein (LDL)‐cholesterol levels, insulin resistance indices, and RBP4 levels than non‐obese women with visceral adiposity and had higher high‐density lipoprotein‐cholesterol levels. Similarly, obese women without visceral adiposity had lower blood pressure, total cholesterol, TG levels, insulin resistance indices, and RBP4 levels than obese women with visceral adiposity. In addition, despite having increased body fat, obese women without visceral adiposity had lower TGs, insulin resistance indices, and serum RBP4 levels than non‐obese women with visceral adiposity. By step‐wise multiple regression analysis, visceral fat areas and LDL‐cholesterol levels independently affected RBP4 levels. Discussion: We determined that serum RBP4 levels are independently associated with visceral fat and LDL‐cholesterol levels. These results suggest that, irrespective of body weight, visceral obesity is an independent predictor of serum RBP4 levels, and RBP4 may represent a link between visceral obesity and cardiovascular disease.     

Lower Serum Adiponectin Levels in African‐American Boys

Objective: To examine adiponectin, an adipocyte‐secreted hormone with anti‐inflammatory and insulin‐sensitizing effects, in relation to race or gender in younger subjects. Research Methods and Procedures: The relationship of adiponectin, quantitated by radioimmunoassay, to anthropometric and metabolic factors (fasting insulin, glucose, and leptin) and reproductive hormones was examined in 46 healthy African Americans (25 girls/21 boys) and 40 whites (20 girls/20 boys) ranging in age from 12 to 21 years. Results: There was no statistical difference in BMI or in BMI percentile among the four groups. Sums of skinfolds, but not skinfold percentile, were significantly lower in boys than girls (p = 0.001 and p = 0.896, respectively), whereas there was no difference between racial groups. Leptin was significantly greater in girls (p = 0.0002). There was no difference in fasting serum glucose, insulin, or homeostasis model assessment score among any of the groups. There was a significant negative univariate relationship between serum adiponectin and both BMI and BMI percentile for the entire group (p = 0.006 and p = 0.005). In a multivariate model, BMI percentile (p = 0.005) and the interaction between race and gender (p = 0.026) were significant predictors of serum adiponectin. In this model, African‐American boys had the lowest serum adiponectin level, 37% less than white boys, who had the highest adiponectin levels. Discussion: Serum adiponectin levels are reduced in young obese subjects (African Americans and whites) and are lower in African‐American boys than white boys. A lower adiponectin level in African‐American boys may predispose this group to a greater risk of diabetes and cardiovascular disease.     

Correlation between Serum Resistin Level and Adiposity in Obese Individuals

Objective: Resistin is associated with insulin resistance in mice and may play a similar role in humans. The aim of our study was to examine the relationship of serum resistin level to body composition, insulin resistance, and related obesity phenotypes in humans. Research Methods and Procedures: Sixty‐four young (age 32 ± 10 years), obese (BMI 32.9 ± 5.6), nondiabetic subjects taking no medication, and 15 lean (BMI 21.1 ± 1.3) volunteers were studied cross‐sectionally. Thirty‐five of the subjects were also reevaluated after 1.5 years on a weight reduction program entailing dieting and exercise; changes of serum resistin were compared with changes of BMI, body composition, fat distribution, and several indices of insulin sensitivity derived from plasma glucose and serum insulin levels measured during 75‐g oral glucose tolerance test. Results: In a cross‐sectional analysis, serum resistin was significantly higher in obese subjects than in lean volunteers (24.58 ± 12.93 ng/mL; n = 64 vs. 12.83 ± 8.30 ng/mL; n = 15; p < 0.01), and there was a correlation between resistin level and BMI, when the two groups were combined (ρ = 0.35, p < 0.01). Although cross‐sectional analysis in obese subjects revealed no correlation between serum resistin and parameters related to adiposity or insulin resistance, longitudinal analysis revealed change in serum resistin to be positively correlated with changes in BMI, body fat, fat mass, visceral fat area, and mean glucose and insulin (ρ = 0.39, 0.40, 0.44, 0.50, 0.40, and 0.50; p = 0.02, 0.03, 0.02, <0.01, 0.02, and <0.01, respectively). Discussion: Resistin appears to be related to human adiposity and to be a possible candidate factor in human insulin resistance.     

Obesity Attenuates the Contribution of African Admixture to the Insulin Secretory Profile in Peripubertal Children: A Longitudinal Analysis

The pubertal transition has been identified as a time of risk for development of type 2 diabetes, particularly among vulnerable groups, such as African Americans (AAs). Documented ethnic differences in insulin secretory dynamics may predispose overweight AA adolescents to risk for type 2 diabetes. The objectives of this longitudinal study were to quantify insulin secretion and clearance in a cohort of 90 AA and European American (EA) children over the pubertal transition and to explore the association of genetic factors and adiposity with repeated measures of insulin secretion and clearance during this critical period. Insulin sensitivity was determined by intravenous glucose tolerance test (IVGTT) and minimal modeling; insulin secretion and clearance by C‐peptide modeling; genetic ancestry by admixture analysis. Mixed‐model longitudinal analysis indicated that African genetic admixture (AfADM) was independently and positively associated with first‐phase insulin secretion within the entire group (P < 0.001), and among lean children (P < 0.01). When examined within pubertal stage, this relationship became significant at Tanner stage 3. Total body fat was a significant determinant of first‐phase insulin secretion overall and among obese children (P < 0.001). Total body fat, but not AfADM, was associated with insulin clearance (P < 0.001). In conclusion, genetic factors, as reflected in AfADM, may explain greater first‐phase insulin secretion among peripubertal AA vs. EA; however, the influence of genetic factors is superseded by adiposity. The pubertal transition may affect the development of the β‐cell response to glucose in a manner that differs with ethnic/genetic background.     

Association of Total and Central Adiposity Measures with Fasting Insulin in a Biracial Population of Young Adults with Normal Glucose Tolerance: the CARDIA Study

SIDNEY, STEPHEN, CORA E. LEWIS, JAMES O. HILL, CHARLES P. QUESENBERRY, JR, ELIZABETH R. STAMM, ANN SCHERZINGER, KIMBERLY TOLAN, AND BRUCE ETTINGER. Association of total and central adiposity measures with fasting insulin in a biracial population of young adults with normal glucose tolerance: the CARDIA study. Obes Res. Objective: To determine the association of computed tomography (CT)-measured visceral adipose tissue (AT) and other measures of adiposity with fasting insulin in a biracial (African American and Caucasian) study population of young adults. Research Methods and Procedures: The study population consisted of 251 young adults with normal glucose tolerance (NGT), ages 28–40 years, who were volunteers from the Birmingham, Alabama, and Oakland, California centers of the Coronary Artery Risk Development in Young Adults (CARDIA) study. Results: In regression models with total adiposity measures (body mass index or dual-energy X-ray absorptiometry-measured percent fat), visceral AT (measured as a cross-sectional area in cm²) was generally a stronger predictor of insulin than overall adiposity in all race/gender groups (partial correlation coefficients ranging from 0. 31 to 0. 47) except for black men, in whom the associations were nonsignificant. Partial correlation coefficients between waist circumference and insulin, controlling for percent fat, were nearly identical to those between visceral AT and insulin in women and in white men. Analyses performed on 2060 NGT CARDIA subjects who were not in this study of visceral AT showed significant correlations of waist circumference with insulin in all racelgender groups, including black men, and that black men in the visceral AT study group were significantly leaner than other black male CARDIA subjects. Discussion: We conclude that visceral AT was associated with fasting insulin in NGT participants in three of the four race/gender groups (black men excepted) and that waist circumference was a good surrogate for visceral AT in examining associations of central adiposity with fasting insulin.     

Skeletal muscle adiposity is associated with serum lipid and lipoprotein levels in Afro‐Caribbean men

Objective: When compared with other ethnic groups, African ancestry individuals have lower triglycerides and higher High‐density lipoprotein cholesterol (HDL‐C) levels, although the mechanisms for these differences remain unclear. A comprehensive array of factors potentially related to fasting serum lipid and lipoprotein levels in African ancestry men was evaluated. Design and Methods: Men (1,821) underwent dual‐energy X‐ray absorptiometry measures of total body fat and quantitative computed tomography assessments of calf skeletal muscle adiposity [subcutaneous and intermuscular adipose tissue (AT), and muscle density as a measure of intra‐muscular AT]. Results: Multivariable linear regression analysis identified age (?), total body fat (+), subcutaneous AT (?), fasting glucose (+), fasting insulin (+), diastolic blood pressure (+), and non‐African ancestry (+) as independent correlates of triglycerides (all P < 0.05). Total body fat (+), intra‐muscular AT (?), and diastolic blood pressure (+) were independent correlates of Low‐density lipoprotein cholesterol (LDL‐C) (all P < 0.001). Age (+), waist circumference (?), fasting insulin (?), physical activity (+), and alcohol intake (+) were independent correlates of HDL‐C (all P < 0.05). Conclusions: A novel relationship between skeletal muscle adiposity and serum lipid and lipoprotein levels in African ancestry men, independent of total and central adiposity was illuminated. In African ancestry populations, genetic factors are likely a significant determinant of triglycerides levels.     

Chronological approach of diet-induced alterations in muscle mitochondrial functions in rats

Objective: Mitochondrial dysfunction might predispose individuals to develop insulin resistance. Our objective was to determine whether mitochondrial dysfunction or insulin resistance was the primary event during high‐fat (HF) diet. Research Methods and Procedures: Rats were fed an HF diet for 0, 3, 6, 9, 14, 20, or 40 days and compared with control. Soleus and tibialis muscle mitochondrial activity were assessed using permeabilized fiber technique. Insulin [area under the curve for insulin (AUC_I)] and glucose [area under the curve for glucose (AUC_G)] responses to intraperitoneal glucose tolerance test as well as fasting plasma non‐esterified fatty acids (NEFAs), triglyceride, and glycerol concentrations were determined. Results: AUC_I and AUC_G were altered from Day 6 (p < 0.01 vs. Day 0). In soleus, oxidative phosphorylation (OXPHOS) activity was transiently enhanced by 26% after 14 days of HF diet (p < 0.05 vs. Day 0) conjointly with 62% increase in NEFA concentration (p < 0.05 vs. Day 0). This was associated with normalized AUC_G at Day 14 and with a decline of plasma NEFA concentration together with stabilization of intra‐abdominal adiposity at Day 20. Prolongation of HF diet again caused an increase in plasma NEFA concentration, intra‐abdominal adiposity, AUC_I, and AUC_G. At Day 40, significant decrease in OXPHOS activity was observed in soleus. Discussion: Mitochondria first adapt to overfeeding in oxidative muscle limiting excess fat deposition. This potentially contributes to maintain glucose homeostasis. Persistent overfeeding causes insulin resistance and results in a slow decline in oxidative muscle OXPHOS activity. This shows that the involvement of mitochondria in the predisposition to insulin resistance is mainly due to an inability to face prolonged excess fat delivery.     

Cardiorespiratory fitness, different measures of adiposity, and cancer mortality in men

Objective: The purpose was to examine the prospective relationship among cardiorespiratory fitness level (CRF), different measures of adiposity, and cancer mortality in men. Research Methods and Procedures: Participants were 38,410 apparently healthy men who completed a comprehensive baseline health examination between 1970 and 2001. Clinical measures included BMI, waist circumference (WC), percent body fat, and CRF quantified as duration of a maximal treadmill exercise test. Participants were divided into fifths of CRF, BMI, WC, and percent body fat. Hazard ratios were computed with Cox regression analysis. Results: During a mean follow‐up period of 17.2 ± 7.9 years, 1037 cancer deaths occurred. Adjusted hazard ratios across incremental BMI quintiles were 1.0, 1.23, 1.15, 1.39, and 1.72; those of WC were 1.0, 1.05, 1.03, 1.31, and 1.64; those of percent body fat were 1.0, 1.24, 1.17, 1.23, and 1.50; and those of CRF were 1.0, 0.70, 0.67, 0.70, and 0.49 (trend p < 0.01 for each). Further adjustment for CRF eliminated the significant trend in mortality risk across percent body fat groups and attenuated the trend in risk across BMI and WC groups. Adjustment of CRF for adiposity measures had little effect on mortality risk. When grouped into categories of fit and unfit (upper 80% and lower 20% of CRF distribution, respectively), mortality rates (per 10,000 man‐years) were significantly lower in fit compared with unfit men within each stratum of BMI, WC, and percent body fat. Discussion: Higher levels of CRF are associated with lower cancer mortality risk in men, independently of several adiposity measures.     

Insulin Sensitivity,Cardiorespiratory Fitness,and Physical Activity in Overweight Hispanic Youth

Objective: To determine whether cardiorespiratory fitness and/or physical activity (PA) were related to measures of insulin sensitivity and secretion independent of body composition in overweight Hispanic children. Research Methods and Procedures: Ninety‐five Hispanic children (n = 55 boys; n = 40 girls; 8 to 13 years old) participated in this investigation. The frequently sampled intravenous glucose tolerance test was used to determine the insulin sensitivity index (SI), the acute insulin response, and the disposition index. Cardiorespiratory fitness [maximal oxygen uptake (Vo_2max)] was evaluated using a treadmill protocol, and PA was determined by an interviewer‐administered questionnaire. Body composition was measured using DXA. Results: Unadjusted correlations indicated that Vo_2max (milliliters of O₂ per minute) was negatively related to SI (r = ?0.46, p < 0.05) and disposition index (r = ?0.31, p < 0.05) and positively associated with fasting insulin (r = 0.29, p < 0.05), but these relationships were no longer significant once gender, Tanner stage, fat mass, and soft lean tissue mass were included as covariates (all p > 0.05). Multivariate linear regression analysis showed that body fat mass explained 53% of the variance in SI and that Vo_2max (milliliters of O₂ per minute) was not independently related to SI. Cardiorespiratory fitness was positively related to both fat mass (r = 0.43, p < 0.001) and soft lean tissue mass (r = 0.89, p < 0.001). PA was not related to any measure of insulin sensitivity and secretion. Discussion: Cardiorespiratory fitness, as determined by Vo_2max (milliliters of O₂ per minute), was not independently related to insulin sensitivity or secretion, suggesting that Vo_2max influences insulin dynamics indirectly through fat mass.     

Relation of Leptin to Insulin Resistance Syndrome in Children

Objectives: To examine the relation of leptin to insulin resistance, as measured by euglycemic insulin clamp, and insulin resistance syndrome factors in thin and heavy children. Research Methods and Procedures: Anthropometrics, insulin, blood pressure, and leptin were measured in 342 11‐ to 14‐year‐old children (189 boys, 153 girls, 272 white, 70 black). Insulin sensitivity (M) was determined by milligrams glucose uptake per kilogram per minute and expressed as M/lean body mass (M_lbm). Children were divided by median BMI (boys = 20.5 kg/m²; girls = 21.4 kg/m²) into below‐median (thin) and above‐median (heavy) groups. Correlation coefficients between log‐leptin and components of insulin resistance syndrome were adjusted for Tanner stage, gender, and race. Results: BMI was related to leptin in boys (r = 0.70, p < 0.001) and girls (r = 0.75, p < 0.001). Leptin was higher in girls than boys (32.6 vs. 12.3 ng/mL, p = 0.0001). Leptin levels increased in girls and decreased in boys during puberty, paralleling the changes in body fat. Leptin was significantly correlated with insulin, M_lbm, triglycerides, and blood pressure in heavy children and only with insulin in thin children. After adjustment for body fat, the correlations remained significant for insulin and M_lbm in heavy children and with insulin in thin children. Discussion: Significant associations were found between leptin and insulin resistance in children, and these associations were attenuated by adjustment for adiposity. These findings at age 13 likely have long‐term consequences in the development of the obesity‐insulin resistance‐related cardiovascular risk profile.