Subcutaneous central fat is associated with cardiovascular risk factors in men independently of total fatness and fitness

The purpose of this study was to analyze the single and independent associations of whole body composition and fat distribution with cardiovascular disease (CVD) risk factors and fitness in middle-aged men. Sixty-two healthy Caucasian men (37.6 +/- 2.9 yr, 81.8 +/- 11.3 kg, 171.5 +/- 4.9 cm) participated in the study. Dual-energy x-ray absorptiometry (DXA) was used to assess total and regional body composition. The triceps, biceps, midthigh, calf, subscapular, chest, abdominal and suprailiac skinfolds, and the waist, hip and midthigh circumferences, and sagittal diameter were estimated. Cardiovascular fitness was estimated with a submaximal test. Bivariate and partial correlation analysis were used to study the association of total body percent fat (%fat), DXA trunk fat and trunk skinfolds (sum of subscapular, chest, abdominal, and suprailiac) and fitness with insulin, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), TC/HDL-C, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), apolipoprotein AI (apo AI), apolipoprotein B (apo B), lipoprotein(a) [Lp(a)], and diastolic and systolic blood pressure. All anthropometric and DXA body composition variables were significantly correlated with TC/HDL-C (from .26 to .50, P < .05). Similar relationships were found for insulin, HDL-C, and systolic blood pressure (r from .26 to .47, P < .05). Cardiovascular fitness was significantly (P < .05) associated with insulin (r = -.36), HDL-C (r = .27), TC/HDL (r = -.27), and with systolic blood pressure (r = -.37). After controlling for trunk skinfolds, none of the anthropometric and DXA body composition variables were correlated with any of the CVD risk factors. Similarly, when controlling for trunk skinfolds, cardiovascular fitness was not related to any of the metabolic variables. After adjusting for %fat, DXA trunk fat, and cardiovascular fitness, trunk skinfolds remained significantly (P < .05) related to insulin (r = .35), HDL-C (r = -.40), TC/HDL-C (r = .43), and apo AI (r = -.39). In conclusion, this study suggests that subcutaneous truncal fat, as estimated by skinfolds, is an independent predictor of CVD risk factors, and that the association between cardiovascular fitness and these risk factors may be mediated by the levels of abdominal subcutaneous fat in Caucasian middle-aged men.     

Relationship between lipoprotein levels and in vivo insulin action in normal young white men

In epidemiologic studies, hyperinsulinemia has been found to be an independent risk factor for coronary heart disease (CHD). However, the mechanisms responsible for its role in atherogenesis remain unclear. We studied the relationship of in vivo insulin action and plasma lipids and lipoproteins in 44 normotriglyceridemic white men (aged 18 to 34 years). The euglycemic, hyperinsulinemic glucose clamp technique was used to quantitate insulin-mediated glucose disposal (M/I value) at a plasma insulin concentration of approximately 100 microU/mL. The M/I value correlated negatively with plasma triglycerides (r = -0.553, P less than .0001), as well as with fasting plasma insulin levels (r = -0.483, P less than .001), independent of age, body mass index, and fasting plasma glucose levels. A negative correlation of the M/I value was also observed with very low density lipoprotein (VLDL)-cholesterol (r = -0.347, P less than .05), VLDL-triglycerides (r = -0.474, P less than 0.005), and total cholesterol/high density lipoprotein (HDL)-cholesterol ratio (r = -0.431, P less than .01). The relationship between the M/I value and the total cholesterol/HDL-cholesterol ratio was independent of VLDL-cholesterol and VLDL-triglycerides, however, not independent of plasma triglycerides. No relationship was observed between insulin-mediated glucose uptake and total cholesterol, low density lipoprotein (LDL)-cholesterol, and HDL-cholesterol values. Individual differences in plasma triglycerides, fasting insulin concentration, and the total cholesterol/HDL-cholesterol ratio accounted for about half the variance observed in the M/I value.(ABSTRACT TRUNCATED AT 250 WORDS)     

The insulin resistance syndrome and the binding capacity of cortisol binding globulin (CBG) in men and women

BACKGROUND: Both insulin resistance and cortisol binding globulin (CBG) capacity have been found to correlate with plasma free fatty acid (FFA) concentration. OBJECTIVE: To examine the changes in CBG binding with varying degrees of insulin resistance and plasma FFA levels. SUBJECTS AND METHODS: Anthropometric parameters, serum cortisol levels, plasma CBG, CBG binding and insulin sensitivity (using the frequently sampled intravenous glucose tolerance test with minimal model analysis) were measured in a group of 38 healthy subjects (19 men, mean age 36.2 +/- 1.9; body mass index (BMI) 28.8 +/- 1.2, range 22.2-35.7), and 19 women, age 34.9 +/- 1.4; BMI 28.1 +/- 0.8, range 19-37.9)]. RESULTS: Plasma CBG levels did not differ between men and women. In men, CBG binding was associated with several parameters of the insulin resistance syndrome, including area under the curve for glucose during an oral glucose tolerance test (MBG, r = 0.45, P = 0.04), fasting insulin (r = 0.66, P = 0. 002), plasma triglycerides (r = 0.75, P < 0.0001), VLDL-triglycerides (r = 0.59, P = 0.007), fasting FFA (r = 0.72, P = 0.002), uric acid (r = 0.57 (P = 0.01) and insulin sensitivity (SI, r = - 0.58, P = 0.008). Free cortisol (estimated as the ratio of cortisol to CBG) was not associated with waist-to-hip ratio (WHR) or parameters of insulin sensitivity. In contrast to men, CBG binding was not associated with MBG, fasting insulin, plasma triglycerides, VLDL-triglycerides, FFA, uric acid or SI (all P = NS) in women. Serum free cortisol, however, correlated positively with WHR (r = 0. 62, P = 0.02) and negatively with SI (r = - 0.68, P = 0.01) in obese women. A multiple linear regression to predict CBG binding was constructed, with plasma CBG concentration and insulin sensitivity as independent variables. In this model, only SI entered the equation at a statistically significant level (P = 0.0012) contributing to 52% of the variance in CBG binding in men. When plasma FFA levels were added to the model, both SI (P = 0.04) and FFA levels (P = 0.039) contributed to 66% of the variance of CBG binding in men. In women, both plasma CBG concentration (P = 0.0005) and insulin sensitivity (P = 0.047) entered the equation at a statistically significant level, contributing to 60% of the variance in CBG binding. When plasma FFA levels were added to the model, only plasma CBG concentration (P = 0.043) was found to significantly contribute to 38% of the variance in CBG binding. The latter finding suggests that FFA levels constituted a confounding variable in the association between SI and CBG binding in women. CONCLUSIONS: Both plasma free fatty acid and insulin sensitivity influence cortisol binding globulin binding capacity in men. Whether cortisol binding globulin binding is a factor implicated in the pathophysiology of insulin resistance or represents an adaptative tool in this situation awaits further studies.     

Gender differences of regional abdominal fat distribution and their relationships with insulin sensitivity in healthy and glucose-intolerant Thais

To determine gender differences of regional abdominal fat distribution and their relationships with insulin sensitivity in healthy and glucose-intolerant Thais, 44 subjects, 22 men and 22 body mass index-matched women, with normal and abnormal glucose tolerance, which included subjects with impaired glucose tolerance and diabetes, were studied. Total body fat and total abdominal fat (TAF) at L1-L4 were measured by dual-energy x-ray absorptiometry. Regional abdominal fat, which consists of sc abdominal fat and visceral abdominal fat, was determined by single-slice computerized tomography of the abdomen at L4-L5 disc space level. Insulin sensitivity was determined by euglycemic hyperinsulinemic clamp and expressed as glucose infusion rate (GIR). With comparable body mass index, visceral abdominal fat was most strongly correlated with GIR after adjustment with percent total body fat in both healthy (r = -0.8155; P = 0.007) and glucose-intolerant women (r = -0.7597; P = 0.011), whereas TAF was most strongly correlated with GIR in both healthy (r = -0.8114; P = 0.008) and glucose-intolerant men (r = -0.6194; P = 0.101). By linear regression analysis, visceral abdominal fat accounted for 35.0% (beta = -3.53 x 10(-2); P = 0.001) of GIR variance in women, whereas TAF accounted for 39.3% (beta = -1.28 x 10(-4); P < 0.0001) of GIR variance in men. We conclude that there are gender differences in the relationships of regional abdominal fat and insulin sensitivity in slightly obese healthy and glucose-intolerant Thais, the difference of which may possibly be in part due to the difference of abdominal fat patterning between genders.     

Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women

There is increasing evidence that systemic inflammation and insulin resistance constitute interrelated events that contribute to atherosclerosis. We studied the effect of the association between circulating interleukin 6 (IL-6) levels, one of the major mediators of inflammation, and C-reactive protein on insulin resistance and blood pressure in 228 healthy volunteers. The plasma IL-6 concentration was significantly and similarly associated with systolic (SBP) and diastolic (DBP) blood pressure, fasting insulin, and the fasting insulin resistance index (FIRI) in all subjects. When smokers were excluded from the analysis, plasma IL-6 levels correlated with percent fat mass (r = 0.19; P = 0.02), absolute fat mass (r = 0.17; P = 0.03), SBP, DBP, fasting insulin levels, and FIRI. The latter associations persisted after controlling for body mass index (r = 0.15 and r = 0.19; P = 0.02 and P: = 0.0004 for SBP and DBP, respectively; r = 0.24 and r = 0.19, P = 0.004 and P = 0.03, for fasting insulin and FIRI, respectively). Gender and smoking status significantly influenced the results. Although IL-6 levels were significantly associated with fasting insulin and FIRI in men, these significant correlations were not observed in women. Conversely, although IL-6 levels were significantly associated with SBP and DBP in women, these coefficients were not statistically significant in men. All of these associations were lost among smokers and remained significant in nonsmokers. As IL-6 is the major mediator of the acute phase response by hepatocytes and induces the synthesis of C-reactive protein (CRP), we also controlled for the latter. Serum CRP levels correlated significantly with IL-6 in all the subjects, but mainly in nonsmokers and men. Of note was that this significant relationship was lost among smokers. CRP was associated with fasting insulin (r = 0.28; P < 0.0001) and FIRI (r = 0.25; P < 0.0001), but not with SBP or DBP (P = NS), in all subjects. Unlike IL-6, the associations between CRP and these parameters were similar in men and women and in smokers and nonsmokers. For insulin and FIRI they were stronger in women and in nonsmokers. CPR significantly correlated with the WHR only in men (r = 0.22; P = 0.01). Using multiple linear regression in a stepwise manner to predict circulating IL-6 levels, smoking status (P = 0.0059) and FIRI (P = 0.03), but not fat mass or SBP, independently contributed to 11% of its variance in men. When CRP was introduced into the model, the latter (P < 0.0001) and smoking status (P = 0.02), but not FIRI, fat mass, or SBP, contributed to 33% of the variance in IL-6 levels. In women, only SBP (P = 0.04) contributed to 5% of its variance. When CRP was introduced into the model, again only SBP (P = 0.01) contributed to 10% of the variance in IL-6 levels. In 25 of these subjects, insulin sensitivity was determined using the frequently sampled iv glucose tolerance test with minimal model analysis, and circulating IL-6 levels were strongly associated with the insulin sensitivity index (r = -0.65; P < 0.0001). Again, this relationship was even stronger in men (r = -0.75; P < 0.001) and was not significant in women (r = -0.26; P = NS). In all of these subjects, only insulin sensitivity (P = 0.0037), not fat mass, contributed to 21% of the variance of IL-6 levels in a multiple linear regression analysis. In summary, circulating IL-6 levels, by inducing either hypertension in women or insulin resistance in men, constitute a significant proatherogenic cytokine. The mechanisms of these associations should be further investigated.     

Post-heparin lipolytic enzyme activities, sex hormones and sex hormone-binding globulin (SHBG) in men and women: The HERITAGE Family Study

We tested the hypothesis that androgen, estrogen, and sex hormone-binding globulin (SHBG) levels would be significantly related to post-heparin hepatic lipase (HL) and lipoprotein lipase (LPL) activities in a sample of Caucasian men (n = 233) and women (n = 235) aged 17-64 years from the HERITAGE Family Study. Body composition (hydrostatic weighing), abdominal adipose tissue distribution (computed tomography), plasma lipid-lipoprotein and hormone levels, and post-heparin lipases activities were measured. HL activity was significantly higher in males, whereas LPL activity was higher in women (P < 0.005). In women only, HL activity was positively associated with body fat mass (r = 0.17, P < 0.05) and intra-abdominal adipose tissue area (r = 0.18, P < 0.05). Significant associations were also found between fasting insulin and LPL activity (r = -0.16, P < 0.05 and r = -0.18, P < 0.005) as well as HL activity (r = 0.22, P < 0.005, and r = 0.27, P < 0.0001) in men and women, respectively. A positive association between total testosterone and HL activity was noted in men (r = 0.13, P = 0.05). In women, plasma SHBG levels were negatively associated with HL activity (r = -0.48, P < 0.0001), and statistical adjustment for body fat mass, visceral adipose tissue area, and fasting insulin did not attenuate this correlation. In multivariate analyses with models including adiposity variables and measurements of the hormonal profile, insulin, and testosterone levels were both independent positive predictors of HL activity in men. In women, hormone use was a significant positive predictor, and SHBG level a strong negative predictor of HL activity, independent of plasma estradiol and testosterone concentrations. Fasting insulin was the only significant predictor of LPL activity in men (negative association), whereas menstrual status, fasting insulin (negative associations), and plasma SHBG levels (positive association) were all independent predictors of LPL activity in women. These results suggest that the postulated sensitivity of lipolytic enzymes to androgens and estrogens is reflected by a strong negative association between SHBG levels and HL, and a lower magnitude positive association of this hormonal parameter to LPL activity in women. These associations appear to be independent from concomitant variation in total adiposity or body fat distribution.     

Association between diet, lifestyle, metabolic cardiovascular risk factors, and plasma C-reactive protein levels

Increased C-reactive protein (CRP) levels have been associated with several of the components of the metabolic syndrome, but the direct influence of diet and lifestyle factors on CRP levels remains largely unknown. The purpose of the present study was to investigate the association between CRP and diet and lifestyle factors. Plasma CRP levels were determined by a highly sensitive enzyme-linked immunosorbent assay (ELISA) in 760 participants in the beta-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS). In accordance with previous findings, increased levels of CRP were associated with high body mass index (BMI) (P = .012), triglycerides (P = .001), systolic blood pressure (P = .019), cholesterol/high-density lipoprotein (HDL) ratio (P = .009), and low HDL cholesterol (P = .001). CRP was also increased in smokers (P = .023) and in subjects with a low vitamin C intake (P = .018). When men and women were analyzed together, there were no significant associations between CRP and dietary intake of total calories, total fat, saturated fat, monounsaturated fat, polyunsaturated fat, n-3 polyunsaturated fatty acids, n-6 polyunsaturated fatty acids, fiber, vitamin E, carotene, or selen, or in physical activity. However, in the female subgroup weak inverse relations were observed between CRP and the intake of total fat (r = -0.13, P = .011), saturated fat (r = -0.13, P = .011), monounsaturated fat (r = -0.13, P = .010), polyunsaturated fat (r = -0.14, P = .007), and n-3 PUFA (r = -0.14, P = .004). Stratified factor analyses in smoking subgroups, obese, and in under-reporters of energy, largely confirmed the results although in male never-smokers a combination of high fiber vitamin C/beta carotene intake was associated with low CRP levels. These observations suggest that CRP levels are only marginally associated with individual dietary and lifestyle factors. Surprisingly, a higher intake of fat tended to be associated with lower CRP values among women.     

Relation of abdominal obesity to hyperinsulinemia and high blood pressure in men.

The relationships between body fatness, adipose tissue distribution, plasma glucose, insulin levels, lipoprotein levels, and resting blood pressure were studied in 81 men aged 36.0 +/- 3.3 years (mean +/- s.d.) (body mass index (BMI): 27.4 +/- 3.8 kg/m2, percentage body fat: 26.4 +/- 6.6%). Systolic and diastolic blood pressures (BP) were significantly associated with the BMI (r = 0.31, r = 0.33, P < 0.01), the waist circumference (r = 0.33, r = 0.27; P < 0.01) as well as with adipose tissue areas measured by computerized tomography (CT) (0.27 < or = r < or = 0.36, P < 0.01). Furthermore, the relative accumulation of subcutaneous abdominal fat, as estimated by the ratio of abdominal to femoral adipose tissue areas measured by CT, was positively correlated with systolic and diastolic BP (P < 0.01). Fasting plasma insulin level (r = 0.30, P < 0.01) as well as the insulin area measured during an oral glucose tolerance test (0.34 < or = r < or = 0.37, P < 0.01) were significantly correlated with blood pressure. Systolic and diastolic BP were significantly associated with HDL2-cholesterol (C) as well as with the HDL2-C/HDL3-C ratio (-0.24 < or = r < or = -0.34), whereas triglycerides (r = 0.23) and the HDL-C/C ratio (r = -0.23) were significantly correlated with diastolic BP only (P < 0.05). Multivariate analysis indicated that the insulin area was the most important variable associated with blood pressure and that this association was independent of total body fatness and regional adipose tissue distribution. Plasma insulin levels explained 14% and 11% of the variance observed in the systolic and diastolic blood pressures respectively. These results suggest that most of the association between abdominal obesity and high blood pressure is mediated by the hyperinsulinemia and/or the related insulin resistant state.     

Relationship between generalized and upper body obesity to insulin resistance in Asian Indian men.

It has been proposed that excessive insulin resistance in Asian Indians living in urban areas or migrated to western countries is responsible for the higher incidence of type 2 diabetes and coronary heart disease observed in this population. To evaluate whether Asian Indians are more insulin resistant than Caucasians and to define the role of generalized and truncal adiposity, we performed hydrodensitometry, skinfold measurements, and euglycemic-hyperinsulinemic clamps in 21 healthy Asian Indian men and 23 Caucasian men of similar age and body fat content. The glucose disposal rate (Rd) was significantly lower in the Asian Indians than in the Caucasians (3.7+/-1.3 vs. 5.3+/-2.0 mg/min x kg lean body mass, respectively; P = 0.003). Despite similar total body fat content, Asian Indians had higher truncal adiposity than Caucasians (sum of truncal skinfolds, 117+/-37 and 92.4+/-38 mm, respectively). In both Asian Indians and Caucasians, the insulin sensitivity index (Rd/plasma insulin concentrations) was inversely correlated with both total body fat (r = -0.49; P<0.03 and r = -0.67; P<0.001, respectively) and sum of truncal skinfold thickness (r = -0.55; P<0.001 and r = -0.61; P<0.002, respectively). After adjustment for total body fat and truncal skinfold thickness, Asian Indians still had a significantly lower glucose disposal rate (P = 0.04). These results show that Asian Indian men are more insulin resistant than Caucasian men independently of generalized or truncal adiposity. The excessive insulin resistance in Asian Indians is probably a primary metabolic defect and may account for the excessive morbidity and mortality from diabetes and coronary heart disease in this population.     

Inflammatory cardiovascular risk markers in women with hypopituitarism.

Patients with hypopituitarism have increased cardiovascular mortality. A high prevalence of conventional cardiovascular risk factors, including obesity, central fat distribution, insulin resistance, and dyslipidemia, have been described in these patients. The inflammatory markers C-reactive protein (CRP) and IL-6 are predictors of cardiovascular events, and high levels of CRP have been reported in men with hypopituitarism and GH deficiency. However, little is known about inflammatory cardiovascular risk markers in women with hypopituitarism. We therefore investigated whether inflammatory and traditional cardiovascular risk markers are elevated in women with hypopituitarism. Fifty-three women with hypopituitarism and 111 healthy control women were included in this cross-sectional study. Morning blood samples were drawn after an overnight fast. Serum was assayed for CRP, IL-6, glucose, insulin, IGF-I, triglycerides, total cholesterol, low density lipoprotein cholesterol, high density lipoprotein (HDL) cholesterol, lipoprotein(a), E2, total testosterone (total T) and free testosterone (free T), and dehydroepiandrosterone sulfate. IL-6 and CRP levels were higher in women with hypopituitarism than in healthy controls (P < 0.0001 for comparison between groups). In a multivariate model, CRP levels depended on hypopituitarism, body mass index (BMI), and estrogen use. There was an interaction between the effect of BMI and hypopituitarism on CRP levels, such that the importance of hypopituitarism in determining CRP levels disappeared at high BMIs. In a similar multivariate model, IL-6 levels depended on hypopituitarism and BMI. Total cholesterol, the total to HDL cholesterol ratio, and triglycerides were higher in hypopituitary patients, but only triglycerides and the total to HDL cholesterol ratio depended on hypopituitarism when controlling for BMI. There was no significant difference in lipoprotein(a) levels between hypopituitary women and control subjects. However, when controlling for estrogen use, lipoprotein(a) levels showed a trend toward being lower in the hypopituitary group (P = 0.075). In patients with hypopituitarism, CRP correlated negatively with IGF-I (r = -0.35; P = 0.010), total T (r = -0.42; P = 0.0020), and free T (r = -0.30; P = 0.031). Similarly, IL-6 correlated negatively with total T (r = -0.39; P = 0.0040) and androstenedione (r = -0.27; P = 0.048) in hypopituitary patients. In conclusion, hypopituitary women have increased levels of IL-6 and CRP, both of which are inflammatory markers of atherosclerosis. GH deficiency and androgen deficiency may contribute to these findings. Chronic inflammation may contribute to the high cardiovascular risk seen in this population.     

Oxidative stress is associated with adiposity and insulin resistance in men

To investigate the direct relationship of oxidative stress with obesity and insulin resistance in men, we measured the plasma levels of 8-epi-prostaglandin F2alpha (PGF2alpha) in 14 obese and 17 nonobese men and evaluated their relationship with body mass index; body fat weight; visceral, sc, and total fat areas, measured by computed tomography; and glucose infusion rate during a euglycemic hyperinsulinemic clamp study. Obese men had significantly higher plasma concentrations of 8-epi-PGF2alpha than nonobese men (P < 0.05). The plasma levels of 8-epi-PGF2alpha were significantly correlated with body mass index (r = 0.408; P < 0.05), body fat weight (r = 0.467; P < 0.05), visceral (r = 0.387; P < 0.05) and total fat area (r = 0.359; P < 0.05) in all (obese and nonobese) men. There was also a significant correlation between the plasma levels of 8-epi-PGF2alpha and glucose infusion rate in obese men (r = -0.552; P < 0.05) and all men (r = -0.668; P < 0.01). In all subjects, the plasma levels of 8-epi-PGF2alpha were significantly correlated with fasting serum levels of insulin (r = 0.487; P < 0.01). In brief, these findings showed that the circulating levels of 8-epi-PGF2alpha are related to adiposity and insulin resistance in men. Although correlation does not prove causation, the results of this study suggest that obesity is an important factor for enhanced oxidative stress and that this oxidative stress triggers the development of insulin resistance in men.     

Serum adiponectin is related to plasma high-density lipoprotein cholesterol but not to plasma insulin-concentration in healthy children: the FLVS II study

Although low levels of plasma adiponectin were associated with an increase in cardiovascular risk in adults, few data investigated that relationship in children. The aim of this study was to investigate the relationship between plasma adiponectin and cardiovascular risk factors in healthy children. This cross-sectional population-based study was conducted in Fleurbaix and Laventie, 2 cities in the north of France. The main outcome measure was the correlations between plasma adiponectin and adiposity variables (the body mass index, the sum of 4 skinfolds, waist circumference [WC], and percent body fat [bioimpedance]), blood pressure, plasma glucose, triglycerides, high-density lipoprotein (HDL) cholesterol and insulin. In 398 children of both sexes, adiponectin was not significantly related to age and pubertal stage. In boys only, adiponectin correlated with WC (r = -0.19; P = .008) and body mass index (r = -0.15; P = .04) but not with other adiposity variables. After taking into account WC, adiponectin was positively correlated with HDL-cholesterol in boys (r = 0.14; P = .05) and girls (r = 0.25; P = .0004), but was not correlated with insulin and homeostasis model assessment index for insulin resistance in both sexes. These results suggest that, in apparently healthy children, adiponectin is related to the level of HDL-cholesterol independently of fat mass. The relationship between adiponectin and insulin resistance previously reported in obese or diabetic children was not apparent in these subjects and may therefore occur only at later age with fat accumulation.     

Relationship of regional adiposity to insulin resistance and serum triglyceride levels in nonobese Japanese type 2 diabetic patients

The aim of this study was to investigate the relationships between insulin resistance and regional abdominal fat area, body mass index (BMI), and serum lipid profile in nonobese Japanese type 2 diabetic patients. A total of 63 nonobese Japanese type 2 diabetic patients aged 45 to 83 years were examined. The duration of diabetes was 8.4 +/- 0.8 years. BMI, glycosylated hemoglobin (HbA(1c)) levels, and fasting concentrations of plasma glucose, serum lipids (total cholesterol, high-density lipoprotein [HDL] cholesterol, and triglycerides), and serum insulin were measured. The low-density lipoprotein (LDL) cholesterol level was calculated using the Friedewald formula (LDL cholesterol = total cholesterol - HDL cholesterol - 1/5 triglycerides). Insulin resistance was estimated by the homeostasis model assessment (HOMA-IR). Computed tomography (CT) was used to measure cross-sectional abdominal subcutaneous and visceral fat areas in all the patients. Adipose tissue areas were determined at the umbilical level. Subcutaneous and visceral abdominal fat areas were 136.5 +/- 6.0 and 86.0 +/- 4.1 cm(2), respectively. Univariate regression analysis showed that insulin resistance was positively correlated with subcutaneous (r =.544, P <.001) and visceral (r =.408, P =.001) fat areas, BMI (r =.324, P =.009), HbA(1c) (r =.254, P =.001), serum triglycerides (r =.419, P <.001), and serum LDL cholesterol (r =.290, P =.019) levels and was negatively correlated with serum HDL cholesterol level (r =.254, P =.041). Multiple regression analyses showed that insulin resistance was independently predicted by the areas of subcutaneous (F = 6.76, P <.001) and visceral (F = 4.61, P <.001) abdominal fat and serum triglycerides (F = 8.88, P <.001) level, which explained 36.9% of the variability of insulin resistance. Moreover, the present study demonstrated that whereas BMI was positively correlated with visceral (r =.510, P <.001) and subcutaneous (r =.553, P <.001) fat areas, serum triglyceride level was positively associated with visceral (r =.302, P =.015), but not with subcutaneous (r =.222, P =.074) fat area. From these results, it can be suggested that (1) both subcutaneous and visceral abdominal fat areas are independently associated with insulin resistance and (2) visceral fat area, but not the subcutaneous one, is associated with serum triglyceride levels in our nonobese Japanese type 2 diabetic patients.     

Changes in high-density lipoprotein-cholesterol subfractions with exercise training may be dependent on cholesteryl ester transfer protein (CETP) genotype

We sought to determine if a cholesteryl ester transfer protein (CETP) gene locus variation contributes to the variability in the responses of plasma high-density lipoprotein-cholesterol (HDL-C) and its subfractions to endurance exercise training. Middle- to older-aged men and women with at least 1 lipoprotein-lipid risk factor underwent 6 months of endurance exercise training while on a low-fat diet. Plasma lipid levels were measured by nuclear magnetic resonance (NMR). Initial age, body composition, lipoprotein-lipid profiles, and VO(2)max did not differ between the 2 CETP genotype groups (B1B1, n = 16; B1B2, n = 14). With exercise training, VO(2)max increased, and body weight, total body fat, and computed tomographic (CT) intra-abdominal visceral fat decreased similarly in both CETP genotype groups. Plasma total cholesterol and low-density lipoprotein-cholesterol (LDL-C) levels did not change significantly with training in either genotype group. HDL(2NMR)-C levels increased with exercise training in CETP B1B1 (P <.05), but did not change in CETP B1B2 genotype individuals. HDL(3NMR)-C levels tended to decrease with training in CETP B1B1 persons and HDL(4NMR)-C levels tended to increase with training somewhat more in CETP B1B2 individuals, but these differences were not significant. HDL(5NMR)-C levels increased similarly with exercise training in the 2 groups. The integrated HDL(3-5NMR)-C levels increased with exercise training in CETP B1B2 (P <.05), but did not change in CETP B1B1 genotype individuals. Apolipoprotein E (APO E) or lipoprotein lipase (LPL) PvuII genotype did not associate with HDL-C subfraction changes with training. Thus, CETP genotype may contribute to the interindividual differences in plasma HDL-C subfraction changes occurring with endurance exercise training in sedentary middle- to older-aged men and women.     

Plasma levels of agouti-related protein are increased in obese men

To investigate the relationship between peripheral blood levels of agouti-related protein (AGRP) and various parameters of obesity, we measured the plasma level of AGRP in 15 obese and 15 nonobese men and evaluated its relationship with body mass index (BMI), body fat weight, and visceral, sc, and total fat areas measured by computed tomography, fasting insulin levels, glucose infusion rate during an euglycemic hyperinsulinemic clamp study, serum leptin, and plasma alpha-MSH. Obese men had significantly higher plasma concentrations of AGRP than nonobese men (P < 0.01). Univariate analysis showed that the plasma levels of AGRP are proportionally correlated with BMI, body fat weight, and sc fat area in obese men (BMI: r = 0.732, P < 0.01; body fat weight: r = 0.603, P < 0.02; sc fat area: r = 0.668, P < 0.01) and in all men (BMI: r = 0.839, P < 0.0001; body fat weight: r = 0.818, P < 0.0001; sc fat area: r = 0.728, P < 0.0001). In all men, the plasma levels of AGRP were significantly correlated with the visceral fat area (r = 0.478, P < 0.01), total fat area (r = 0.655, P < 0.0001), fasting insulin level (r = 0.488, P < 0.01), glucose infusion rate (r = -0.564, P < 0.01), serum level of leptin (r = 0.661, P < 0.0001), and the plasma level of alpha-MSH (r = 0.556, P < 0.01). In all subjects, multiple regression analysis showed that the plasma levels of AGRP are significantly (F = 15.522, r = 0.801, P < 0.03) correlated with the plasma levels of alpha-MSH, independently from the total fat area. However, the correlation between plasma levels of AGRP and serum levels of leptin was found to be dependent on the total fat area. In brief, these findings showed that the circulating levels of AGRP are increased in obese men and that they are correlated with various parameters of obesity. Although correlation does not prove causation, the results of this study suggest that peripheral AGRP may play a role in the pathogenesis of obesity.     

Androgenicity and obesity are independently associated with insulin sensitivity in postmenopausal women

An increase in androgenicity may contribute to the development of insulin resistance in postmenopausal women. Increased androgenicity in women has been found to be associated with the development of type 2 diabetes. In addition, obesity and central obesity are associated with greater androgenicity. Insulin sensitivity, androgenicity, and body composition were characterized in 34 nondiabetic postmenopausal women age 72 +/- 1 years (mean +/- SEM) to test the hypothesis that androgenicity is a predictor of insulin sensitivity independent of measures of obesity. Androgenicity was measured using levels of sex hormone-binding globulin (SHBG), total and free testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, and free androgen index (FAI). Insulin sensitivity (S(I)) was determined from a frequently sampled intravenous glucose tolerance test. Body composition measures included body mass index (BMI) and dual energy x-ray absorptiometry measurements of total and central fat mass. S(I) was found to be associated with total fat mass (r = -.51, P =.002), central fat mass (r = -.62, P =.0001), BMI (r = -.55, P =.0008), SHBG levels (r =.65, P =.0001), and FAI (r = -.41, P =.01). SHBG levels were inversely correlated with central fat mass (r = -.59, P =.0002). Using multiple regression, SHBG and central fat mass were the only significant independent predictors of S(I), accounting for 50% of its variance (r =.71, P =.0001); total fat mass, BMI, total and free testosterone, DHEA-S, androstenedione, and FAI did not enter the model. We conclude that there is a significant association between insulin sensitivity and androgenicity in postmenopausal women that is independent of obesity. Interventions to decrease androgenicity may therefore be useful in improving insulin sensitivity in postmenopausal women.     

Impaired subcutaneous adipocyte lipogenesis is associated with systemic insulin resistance and increased apolipoprotein B/AI ratio in men and women

OBJECTIVES: To study the association between subcutaneous fat cell lipogenesis and components of the metabolic syndrome (systemic insulin resistance, dyslipidaemia and hypertension). DESIGN AND SETTING: A university hospital-based cross-sectional study of 383 subjects (303 women and 80 men) with a wide range of BMI (18-53 kg m(-2)). RESULTS: Strong negative correlations between in vitro fat cell lipogenesis (basal and after maximal insulin stimulation) and HOMA-IR were present in both genders (r = -0.42 to -0.56, P < 0.0001 and r = -0.37 to -0.44, P < 0.001, for women and men respectively). Insulin sensitivity measured using the insulin tolerance test (K(ITT)) was also correlated with adipocyte lipogenesis (r = 0.47-0.57, P < 0.0001, women, r = 0.52-0.70, P < 0.001, men). Plasma apolipoprotein B/AI-ratio negatively associated with fat cell lipogenesis in women (r = -0.41 to-0.51, P < 0.0001,) and men (r = -0.49 to -0.55, P < 0.0001). The negative relationship of fat cell lipogenesis with blood pressure was significant in women (r = -0.27 to -0.28, P < 0.0002,) but not in men (P = 0.08-0.09). All correlations remained significant after adjusting for differences in fat cell volume, body mass index, waist- to hip- ratio or age (P < 0.01). CONCLUSIONS: Subcutaneous adipocyte lipogenesis is negatively associated with systemic insulin resistance, plasma apolipoprotein B/AI-ratio and blood pressure supporting the view that impaired fat cell function per se may contribute to the development of the metabolic syndrome.     

Relationship of visceral adipose tissue to metabolic risk factors for coronary heart disease: is there a contribution of subcutaneous fat cell hypertrophy?

Visceral adipose tissue (VAT) accumulation is an important correlate of the metabolic complications found in obese patients. The aim of this study was to evaluate the respective contribution of VAT deposition versus subcutaneous abdominal or femoral fat cell hypertrophy as correlates of the metabolic risk profile in 69 men and 65 premenopausal women (aged 35+/-5 years) with a wide range of fatness (body mass index, 18 to 57 kg/m2). In both genders, VAT accumulation was positively correlated with fasting plasma insulin, triglyceride (TG), and low-density lipoprotein (LDL)-apolipoprotein B (apo B) levels and the cholesterol (CHOL)/high-density lipoprotein (HDL)-CHOL ratio (.24 < or = r < or = .71, P < .05). A similar pattern of positive relationships was found between subcutaneous abdominal fat cell weight and metabolic risk variables in men and women (.33 < or = r < or = .60, P < .01). Positive associations were also observed in women between femoral fat cell weight and fasting plasma insulin, TG, and CHOL levels and the CHOL/HDL-CHOL ratio (.29 < or = r < or = .42, P < .05). However, only plasma TG concentrations and the CHOL/HDL-CHOL ratio were positively correlated with femoral fat cell weight in men (r = .30, P < .05). To better investigate the relationships between the metabolic risk profile and hypertrophic subcutaneous obesity, individuals with small versus large subcutaneous abdominal adipocytes were matched according to VAT accumulation. Men with large abdominal fat cells displayed higher plasma TG and LDL-apo B levels compared with men characterized by small abdominal adipocytes (P < .05). Stepwise multiple regression analyses showed that subcutaneous abdominal fat cell weight was the best independent variable predicting plasma TG and LDL-apo B levels in men. No significant difference was found in the metabolic profile of subjects displaying small versus large femoral adipocytes. Taken together, these results suggest that for a given VAT deposition, the presence of hypertrophied subcutaneous abdominal adipocytes in men appears to be associated with further deterioration in the metabolic risk profile. On the other hand, the hypertrophy of femoral adipocytes does not further alter the metabolic complications generally related to obesity in both men and women.     

Interrelationships of spontaneous growth hormone axis activity, body fat, and serum lipids in healthy elderly women and men

Aging is associated with decreased growth hormone (GH) secretion and plasma insulin-like growth factor-I (IGF-I) levels, increased total and abdominal fat, total and low-density lipoprotein (LDL) cholesterol, and triglycerides, and reduced high-density lipoprotein (HDL) cholesterol. Similar changes in lipids and body composition occur in nonelderly GH-deficient adults and are reversed with GH administration. To examine whether GH/IGF-I axis function in the elderly is related to the lipid profile independently of body fat, we evaluated GH secretion, serum IGF-I and IGF binding protein-3 (IGFBP-3) levels, adiposity via the body mass index (BMI), waist to hip ratio (WHR), dual-energy x-ray absorptiometry (DEXA), and magnetic resonance imaging (MRI), and circulating lipids in 101 healthy subjects older than 65 years. Integrated nocturnal GH secretion (log IAUPGH) was inversely related (P < .005) to DEXA total and abdominal fat and MRI visceral fat in both genders. Log IAUPGH was inversely related to visceral fat in women (P < .005) and men (P < .0001), but was not significantly related to total fat in either gender. In women, log IAUPGH was related inversely to total and LDL cholesterol and positively to HDL cholesterol (P < .008). In men, log IAUPGH was inversely related to total cholesterol and triglycerides (P < .005). In women, HDL cholesterol was inversely related to the WHR (P < .005). In men, triglycerides were positively related (P < .001) to the WHR and DEXA abdominal and MRI visceral fat. Multivariate regression revealed log IAUPGH, but not DEXA total body fat, to be an independent determinant of total (P < .001 for women and P = .01 for men) and LDL (P < .007 and P = .05) cholesterol in both sexes and of HDL cholesterol (P < .005) and triglycerides (P < .03) in women. Log IAUPGH, but not DEXA abdominal fat, was related to total (P < .005 and P < .03) and LDL (P < .03 and P = .05) cholesterol in both genders and to HDL in women (P < .05). Log IAUPGH, but not MRI visceral fat, was related to total cholesterol (P < .03 and P = .05) in women and men. Age, IGF-I, and IGFBP-3 were not significantly related to any body fat or lipid measures, except for a positive correlation of IGF-I with triglycerides in men. Thus, endogenous nocturnal GH secretion predicts total, LDL, and HDL cholesterol levels independently of total or abdominal fat, suggesting that it is an independent cardiometabolic risk factor in healthy elderly people.     

Ghrelin levels correlate with insulin levels, insulin resistance, and high-density lipoprotein cholesterol, but not with gender, menopausal status, or cortisol levels in humans

The gut peptide, ghrelin, may participate in the control of energy homeostasis and pituitary hormone secretion in humans, stimulating both food intake and, at pharmacological doses, ACTH and cortisol secretion. Meal consumption and weight loss regulate ghrelin levels, but less is known about the relationship of ghrelin to body composition, aging, menopausal status, and lipid metabolism. Therefore, 60 adult men and women of widely varying ages and weights were characterized in terms of body composition and levels of ghrelin, glucose, insulin, lipids, and cortisol. Fasting ghrelin levels correlated positively with age and negatively with BMI and fat cell size, but were not related to fat mass, intraabdominal fat, or lean mass. Fasting ghrelin levels correlated most strongly with insulin levels (r = -0.39; P = 0.002), insulin resistance as determined by the quantitative insulin sensitivity check index (r = 0.38; P = 0.003), and high-density lipoprotein cholesterol levels (r = 0.33; P = 0.009). Meal-induced ghrelin suppression correlated with the postprandial rise in insulin (r = 0.39; P < 0.05). Ghrelin levels were similar in men and women and did not vary by menopausal status or in association with cortisol levels. Our data are consistent with the hypotheses that insulin may negatively regulate ghrelin and that high-density lipoprotein may be a carrier particle for circulating ghrelin.