Visceral adipose tissue cutoffs associated with metabolic risk factors for coronary heart disease in women

OBJECTIVE: This study determined whether there is a critical level of visceral adipose tissue (VAT) associated with elevated coronary heart disease (CHD) risk factors in a cohort of women >45 years of age. RESEARCH DESIGN AND METHODS: Measurements of body composition (dual-energy X-ray absorptiometry), body fat distribution (computed tomography), fasting and 2-h postprandial (75-g) glucose concentrations, and fasting lipoprotein lipid and insulin concentrations were performed in 233 perimenopausal (9%) and postmenopausal women (age 59 +/- 6 years, 79% Caucasian, 16% on hormone replacement therapy). RESULTS: Women in the lowest VAT quintile (< or =105 cm(2)) had higher concentrations of HDL and HDL(2) cholesterol, lower LDL/HDL cholesterol ratios and triglyceride concentrations, and lower fasting glucose and insulin concentrations than women in the remaining four quintiles (P values <0.05-0.001). Women in the second lowest VAT quintile (106-139 cm(2)) had higher HDL and HDL(2) cholesterol and lower LDL/HDL ratios than women with a VAT > or =163 cm(2) (P < 0.05). Logistic regression analyses showed that women with a VAT of 106-162 cm(2) are 2.5 times more likely to have a low HDL cholesterol (P < 0.05), while women with a VAT > or =163 cm(2) are 5.5 times more likely to have a low HDL cholesterol (P < 0.01) and approximately 4.0 times more likely to have a high LDL/HDL ratio (P < 0.05) compared with women with a VAT < or =105 cm(2). Women with a VAT > or =163 cm(2) are at a higher risk of having impaired glucose tolerance (P < 0.01). CONCLUSIONS: A VAT > or =106 cm(2) is associated with an elevated risk, and a VAT > or =163 cm(2) with an even greater risk, for these metabolic CHD risk factors compared with women with a VAT < or =105 cm(2). These values may prove useful for defining "visceral obesity" and for identifying women most likely to benefit from preventative interventions.     

Influence of age and visceral fat area on plasma adiponectin concentrations in women with normal glucose tolerance

BACKGROUND: Age-related adiponectin concentration has been discrepantly reported. We investigated the distribution of adiponectin by age in healthy women with normal glucose tolerance (NGT) and the relationship of adiponectin with visceral fat area (VFA). METHODS: Three-hundred fifty-nine women (age: 38+/-0.6 years, BMI: 26.5+/-0.2 kg/m(2)) were categorized into 4 age-groups: 20-29, 30-39, 40-49, and 50-64 years. Computed tomography was performed to measure abdominal fat area and adiponectin, TNF-alpha, interleukin-6 (IL-6), CRP, insulin, free fatty acid (FFA), and blood urea nitrogen (BUN) were determined. RESULTS: No significant differences were observed in BMI, total body fat percent and concentrations of insulin, IL-6 and CRP among age-groups. Waist circumference, total fat area at L4, and FFA were significantly higher only in postmenopausal women than in previous decades of premenopausal women. VFA, adiponectin and TNF-alpha concentrations are significantly higher in older women than in younger women. Higher adiponectin concentration in older women was clearly shown even after adjustment for VFA (P<0.05). Age per se was positively correlated with plasma adiponectin concentrations (r=0.21, P<0.001) and these relationship became stronger (r=0.36, P<0.001) after controlled for VFA. VFA was negatively correlated with adiponectin (r=-0.16, P<0.01) in total studied population. However, when analyzed subgroups separately, a strong negative correlation (r=-0.37, P<0.001) was found in younger women (<40 years), while a weak significant relationship (r=-0.18, P<0.05) was found in older women (> or =40 years). In a multiple stepwise regression model to predict adiponectin, only age and VFA remained in the model at P<0.001. CONCLUSIONS: We observed a significant positive relationship between plasma adiponectin and age, even after adjustment for visceral adiposity. These associations suggest that adiponectin concentrations are affected by visceral adiposity, with additional independent effects of age.     

Effect of weight loss on cardiac synchronization and proinflammatory cytokines in premenopausal obese women

OBJECTIVE: Obesity is an important risk factor for heart failure in both women and men. Dyssynchrony between right and left ventricular contraction and relaxation has been identified as an independent predictor of heart failure. We examined the relationship of ventricular synchronization abnormalities with the concentration of proinflammatory cytokines in obese women at baseline and after sustained weight loss. RESEARCH DESIGN AND METHODS: Echocardiographic parameters of ventricular dyssynchrony, circulating levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-18, and C-reactive protein (CRP) were investigated in 67 healthy, premenopausal obese women and 40 age-matched normal-weight women. RESULTS: Compared with nonobese women, obese women had increased concentrations of CRP (P < 0.01), TNF-alpha (P < 0.01), IL-6 (P < 0.01), and IL-18 (P < 0.01). Moreover, obese women had a higher myocardial performance index (P < 0.02) and lower transmitral Doppler flow (P < 0.05), pulmonary venous flow analysis (P < 0.02), and ejection fraction (P < 0.05), indicating ventricular dyssynchrony. Concentrations of CRP, TNF-alpha, and IL-6 were related to anthropometric indexes of obesity and to echocardiographic parameters of ventricular dyssynchrony. After 1 year of a multidisciplinary program of weight reduction, obese women lost at least 10% of their original weight. This was associated with reduction of cytokine (P < 0.01) and CRP (P < 0.02) concentrations and with improvement of echocardiographic parameters of ventricular dyssynchrony, which correlated with changes in adiposity, particularly visceral adiposity. CONCLUSIONS: In obese women, ventricular dyssynchrony correlates with body fat, possibly through inappropriate secretion of cytokines. Weight loss represents a safe method for downregulating the inflammatory state and ameliorating cardiac function in obese women.     

Contribution of insulin-stimulated glucose uptake and basal hepatic insulin sensitivity to surrogate measures of insulin sensitivity

OBJECTIVE: The goal of this study was to evaluate the performance of surrogate measures of insulin sensitivity and insulin secretion. RESEARCH DESIGN AND METHODS: The homeostasis model assessment (HOMA) of insulin resistance (IR) and the insulin sensitivity index (S(i)) from oral glucose tolerance test (OGTT) were compared with the M value from a hyperinsulinemic-euglycemic clamp in 467 subjects with various degrees of glucose tolerance. Endogenous glucose production (EGP) and hepatic insulin sensitivity were determined in a subset (n = 143). Insulin secretion was estimated as the HOMA beta-cell index and as the insulinogenic index from the first 30 min of the OGTT (I/G30) and compared with the first-phase insulin response (FPIR) to an intravenous glucose tolerance test (n = 218). RESULTS: The M value correlated with the HOMA-IR (r = -0.591, P < 0.0001) and the S(i) (r = 0.533, P < 0.0001) indexes in the total study group. HOMA-IR correlated with basal EGP in the total study group (r = 0.378, P < 0.0005) and in subjects with diabetes (r = 0.330, P = 0.01). However, neither HOMA-IR nor S(i) correlated significantly with the M value in subjects with impaired fasting glucose (IFG) (r = -0.108, P = 0.5; r = 0.01, P = 0.9) or IFG/impaired glucose tolerance (IGT) (r = -0.167, P = 0.4; r = 0.09, P = 0.6). The HOMA-IR correlated with hepatic insulin sensitivity in the whole study group (r = -0.395, P < 0.005) as well as in the IFG/IGT subgroup (r = -0.634, P = 0.002) and in the diabetic subgroup (r = -0.348, P = 0.008). In subjects with IFG/IGT, hepatic insulin sensitivity was the most important determinant of HOMA-IR, explaining 40% of its variation. The HOMA beta-cell index showed a weak correlation with FPIR in the whole study group (r = 0.294, P = 0.001) but not in the subgroups. In contrast, the I/G30 correlated with FPIR in the whole study group (r = 0.472, P < 0.0005) and in the IFG/IGT subgroup (r = 0.493, P < 0.005). CONCLUSIONS: HOMA-IR is dependent upon both peripheral and hepatic insulin sensitivity, the contribution of which differs between subjects with normal and elevated fasting glucose concentrations. These discrepancies develop as a consequence of a nonparallel deterioration of the variables included in the equations with worsening of glucose tolerance.     

Relation of C-reactive protein to insulin resistance and cardiovascular risk factors in youth

OBJECTIVE: Insulin resistance and C-reactive protein (CRP) levels are strongly correlated in adults. This study explored the relationship in youth. RESEARCH DESIGN AND METHODS: Associations between CRP levels, cardiovascular risk, and insulin resistance measured by the euglycemic clamp were investigated in 342 healthy Minneapolis youth. RESULTS: There was no difference in mean CRP levels among boys (n = 189, CRP 1.10 +/- 0.46 mg/l) and girls (n = 153, CRP 1.16 +/- 0.63 mg/l; P = 0.32). There was also no difference between CRP and Tanner stage. CRP, adjusted for BMI, was significantly greater in black subjects compared with white subjects (P = 0.03). CRP was strongly related to adiposity in both girls and boys. CRP levels were related to fasting insulin levels (r = 0.16, P = 0.003) but this association was not significant after adjustment for BMI (r = 0.07, P = 0.21). Similarly, M, the euglycemic clamp measurement of insulin sensitivity, was significantly related to CRP levels (r = -0.13, P = 0.02) but not when M was normalized to lean body mass (M(lbm)) (r = -0.10, P = 0.09). There was a significant inverse correlation between M(lbm) and CRP quartiles, which disappeared after adjustment for BMI. There was no significant association between CRP levels and lipids, blood pressure, physical activity, or left ventricular mass. CONCLUSIONS: In contrast to adult subjects, after adjustment for adiposity, CRP levels in children age 10-16 years were not significantly associated with insulin resistance or with other factors comprising the metabolic syndrome. This is consistent with the concept that insulin resistance may precede the development of CRP elevation in the evolution of the metabolic syndrome.     

Additive effect of interleukin-6 and C-reactive protein (CRP) single nucleotide polymorphism on serum CRP concentration and other cardiovascular risk factors

BACKGROUND: Serum C-reactive protein (CRP) levels, closely associated with cardiovascular disease (CVD) risk are influenced by CRP or interleukin-6 (IL-6) single nucleotide polymorphism (SNPs). However, it is still controversial. Therefore, we investigated the association of IL-6/CRP SNPs and serum CRP levels or other CVD risk factors in healthy adult Korean men. METHODS: In healthy adult men (age>or=20 years, n=677), we genotyped IL-6-572C>G and CRP SNPs (-717G>A, 1444C>T, 2147A>G) and measured anthropometric parameters, lipid profile, serum levels of CRP and IL-6 and insulin resistance. RESULTS: At IL-6-572C>G (n=677), subjects with G/G genotype (n=42) showed higher concentrations of CRP (P=0.027) and IL-6 (P=0.028) as compared with C allele carriers after age-adjustment (C/C: n=371, C/G: n=264). Fasting insulin and homeostatis model assessment insulin resistance (HOMA-IR) were also higher in G/G genotype. However, there were no significant differences in other metabolic biomarkers. Among 677 study subjects, 676 were genotyped at CRP-717G>A (G/G: n=513, G/A: n=150, A/A: n=13), 672 at CRP+1444C>T (C/C: n=580, C/T: n=85, T/T: n=7), and 668 at CRP+2147A>G (A/A: n=273, A/G: n=296, G/G: n=99). There were no significant differences in CRP concentrations and other markers related to CVD risk according to each CRP SNP genotype. However, we could find the additive gene-gene interaction between IL-6-572C>G and CRP SNPs on CRP concentration; subjects with the 'G/G' at IL-6-572 showed the highest CRP levels when they have variant allele at CRP SNPs after adjusted for age, body mass index, cigarette smoking and alcohol drinking (-717G>A: F=7.806, P=0.005; CRP+1444C>T: F=8.398, P=0.004; and CRP+2147A>G: F=7.564, P=0.006, respectively) Particularly, G allele carriers at CRP+2147A>G in subjects with IL-6-572G/G showed highest HOMA-IR (F=9.092, P=0.003). CONCLUSION: The present data showed that serum CRP levels and other CVD risk factors appeared more influenced by IL-6-572C>G rather than CRP SNPs (-717G>A, 1444C>T, and 2147A>G), however CRP levels and insulin resistance may be additively affected by IL-6-572 and CRP SNP, particularly when subjects with G/G genotype at IL-6-572 have allele variant at CRP SNPs.     

Insulin action and insulinemia are closely related to the fasting complement C3, but not acylation stimulating protein concentration

OBJECTIVE: An elevated C3 concentration has been reported in people with obesity, type 2 diabetes, hypertension, and dyslipidemia, and has been proposed to play a role in the development of atherosclerosis. We hypothesized that an elevated C3 concentration might be linked to insulin resistance and/or hyperinsulinemia, abnormalities commonly observed in association with the above conditions. RESEARCH DESIGN AND METHODS: Fasting concentrations of C3 and acylation stimulating protein (ASP, C3adesarg), a cleavage product of C3 recently found to stimulate glucose uptake in vitro, were measured in 33 healthy nondiabetic Pima Indians (14 women and 19 men; age 27 +/- 1 and body fat 33 +/- 1%, means +/- SEM). Subjects were characterized for body composition dual-energy X-ray absorptiometry, insulin action (insulin-stimulated glucose disposal [M], hyperinsulinemic glucose clamp), and glucose tolerance (75-g oral glucose tolerance test). RESULTS: Fasting C3 and ASP concentrations were positively correlated (r = 0.43, P < 0.05). Fasting C3 concentration was closely related to percent body fat (r = 0.77), M (r = -0.75), and fasting insulin concentration (r = 0.72) (all P < 0.0001). Fasting C3 concentrations remained significantly related to M and fasting insulin after adjusting for percent body fat (partial r = -0.53 and 0.33, both P < 0.05). In subjects with impaired glucose tolerance, fasting C3 concentrations were higher than in those with normal glucose tolerance--a difference that remained after adjustment for percent body fat and M. We found that fasting ASP concentrations were significantly related to percent body fat (r = 0.37, P < 0.05), but not to M or fasting insulin. CONCLUSIONS: In Pima Indians, fasting C3 concentration is closely related to adiposity, insulin action, and fasting insulin levels and may thus be a mediator for the postulated link between obesity, insulin resistance, hyperinsulinemia, and possibly atherosclerosis.     

Hormone replacement therapy, insulin sensitivity, and abdominal obesity in postmenopausal women.

OBJECTIVE: The purpose of this study was to determine whether insulin sensitivity differs between postmenopausal women taking estradiol, women on estrogen plus progesterone hormone replacement therapy (HRT), and women not on HRT and whether differences are explained by the differences in total and/or abdominal adiposity and fat deposition in the muscle. RESEARCH DESIGN AND METHODS: We studied 28 obese, sedentary postmenopausal Caucasian women. Women taking oral estrogen (n = 6) were matched for age (57 +/- 3 vs. 58 +/- 2 years), weight (87.9 +/- 6.0 vs. 83.0 +/- 3.9 kg), and BMI (33.9 +/- 1.7 vs. 33.9 +/- 1.9 kg/m(2)) with women not on HRT (n = 6). Eight women taking oral estrogen plus progesterone were matched with eight different women not on HRT for age (59 +/- 2 vs. 60 +/- 2 years), weight (82.8 +/- 3.7 vs. 83.7 +/- 4.1 kg), and BMI (30.7 +/- 1.0 vs. 29.9 +/- 1.3 kg/m(2)). RESULTS: VO(2max) (maximal aerobic capacity), percentage of fat, total body fat mass, and fat-free mass (FFM) were similar between groups. Visceral fat, subcutaneous abdominal fat, sagittal diameter, and mid-thigh low-density lean tissue (intramuscular fat) did not differ by hormone status. Basal carbohydrate and fat utilization was not different among groups. Fasting plasma glucose and insulin did not differ by hormone use. Glucose utilization (M) was measured during the last 30 min of a 3-h hyperinsulinemic-euglycemic clamp (40 mU. m(2). min(-1)). Postmenopausal women taking oral estrogen had a 31% lower M than women not on HRT (42.7 +/- 4.0 vs. 61.7 +/- 4.7 micromol. kg(FFM). min(-1), P < 0.05). M was 26% lower in women taking estrogen plus progesterone (44.0 +/- 3.5 vs. 59.7 +/- 6.2 micromol. kg(FFM). min(-1), P < 0.05) than women not on HRT. M/I, the amount of glucose metabolized per unit of plasma insulin (I), an index of insulin sensitivity, was 36% lower in women taking estrogen compared with matched women not on HRT (P < 0.05) and 28% lower in women taking estrogen plus progesterone compared with matched women not on HRT (P < 0.05). CONCLUSIONS: Postmenopausal women taking oral estrogen or those taking a combination of estrogen and HRT are more insulin-resistant than women not on HRT, even when women are of comparable total and abdominal adiposity.     

Effect of calorie restriction with or without exercise on insulin sensitivity, beta-cell function, fat cell size, and ectopic lipid in overweight subjects

OBJECTIVE: The purpose of this article was to determine the relationships among total body fat, visceral adipose tissue (VAT), fat cell size (FCS), ectopic fat deposition in liver (intrahepatic lipid [IHL]) and muscle (intramyocellular lipid [IMCL]), and insulin sensitivity index (S(i)) in healthy overweight, glucose-tolerant subjects and the effects of calorie restriction by diet alone or in conjunction with exercise on these variables. RESEARCH DESIGN AND METHODS: Forty-eight overweight volunteers were randomly assigned to four groups: control (100% of energy requirements), 25% calorie restriction (CR), 12.5% calorie restriction +12.5% energy expenditure through structured exercise (CREX), or 15% weight loss by a low-calorie diet followed by weight maintenance for 6 months (LCD). Weight, percent body fat, VAT, IMCL, IHL, FCS, and S(i) were assessed at baseline and month 6. RESULTS: At baseline, FCS was related to VAT and IHL (P < 0.05) but not to IMCL. FCS was also the strongest determinant of S(i) (P < 0.01). Weight loss at month 6 was 1 +/- 1% (control, mean +/- SE), 10 +/- 1% (CR), 10 +/- 1% (CREX), and 14 +/- 1% (LCD). VAT, FCS, percent body fat, and IHL were reduced in the three intervention groups (P < 0.01), but IMCL was unchanged. S(i) was increased at month 6 (P = 0.05) in the CREX (37 +/- 18%) and LCD (70 +/- 34%) groups (P < 0.05) and tended to increase in the CR group (40 +/- 20%, P = 0.08). Together the improvements in S(i) were related to loss in weight, fat mass, and VAT, but not IHL, IMCL, or FCS. CONCLUSIONS: Large adipocytes lead to lipid deposition in visceral and hepatic tissues, promoting insulin resistance. Calorie restriction by diet alone or with exercise reverses this trend.     

Adiponectin in youth: relationship to visceral adiposity, insulin sensitivity, and beta-cell function

OBJECTIVE: Adiponectin is an adipose tissue protein that enhances insulin sensitivity and has antiatherogenic properties. The present study investigated the relationship of adiponectin levels in adolescents to 1) obesity and body fat distribution and 2) insulin sensitivity and the components of syndrome X. RESEARCH DESIGN AND METHODS: Twenty-three normal-weight and 26 obese adolescents had fasting adiponectin, lipid profile, and proinsulin measurements performed. Hepatic and peripheral insulin sensitivity were assessed with constant-rate [6,6-(2)H(2)]glucose infusion and a 3-h hyperinsulinemic-euglycemic clamp, respectively. Body composition was evaluated by dual-energy X-ray absorptiometry, and visceral adipose tissue (VAT) and subcutaneous adipose tissue were measured by computed tomography scan at the L(4)-L(5) level. RESULTS: Obese adolescents had approximately 50% lower adiponectin than normal-weight adolescents. Moreover, obese adolescents with high (111.8 +/- 9.3 cm(2)) versus low (55.4 +/- 2.1 cm(2)) VAT had lower adiponectin levels (6.2 +/- 0.9 vs. 9.0 +/- 1.0 microg/ml, P = 0.05). Plasma adiponectin correlated positively with peripheral and hepatic insulin sensitivity (r = 0.67, P < 0.001 and r = 0.54, P < 0.001, respectively) and HDL (r = 0.52, P < 0.001) and negatively with fasting proinsulin and the proinsulin-to-insulin ratio (r = -0.64, P < 0.001 and r = -0.43, P = 0.003, respectively). In a multiple regression analysis, adiponectin, independently and together with BMI, explained 73% (R(2) = 0.73, P < 0.001) of the variance in insulin sensitivity. Adiponectin, but not adiposity, was the significant independent determinant of the proinsulin-to-insulin ratio (R(2) = 0.18, P = 0.008) and of HDL (R(2) = 0.45, P < 0.001). CONCLUSIONS: In summary, hypoadiponectinemia in youth is a strong and independent correlate of insulin resistance, beta-cell dysfunction, visceral adiposity, and syndrome X. The antidiabetogenic and antiatherogenic properties of adiponectin are evident early in life and compromised in youth-onset obesity.     

Islet dysfunction in insulin resistance involves impaired insulin secretion and increased glucagon secretion in postmenopausal women with impaired glucose tolerance

OBJECTIVE: To characterize in detail the association between insulin sensitivity and islet function in relation to glucose tolerance in nondiabetic subjects. RESEARCH DESIGN AND METHODS: The study included 108 postmenopausal women, aged 57-59 years, with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) and measured glucose tolerance (World Health Organization, 75 g glucose), insulin sensitivity (euglycemic-hyperinsulinemic clamp), and islet function (the 2-5 min insulin responses [AIR] and glucagon [AGR] responses to 5 g intravenous arginine at fasting, 14 and >25 mmol/l glucose levels). The product of insulin sensitivity and secretion was calculated (disposition index [DI]) and used to study the relationship between the two parameters. RESULTS: Insulin sensitivity and insulin secretion were highly inversely correlated in a hyperbolic manner (r > 0.64, P < 0.001) in women with NGT (n = 71). Women with IGT (n = 37) had reduced insulin sensitivity compared with women with NGT (P = 0.011). The AIRs were not appropriately increased in relation to the reduced insulin sensitivity in the IGT women, demonstrated as reduced DI in IGT compared with NGT (P < 0.001). Further, women with IGT had an increased AGR (P < 0.001) and a reduced glucose inhibition of glucagon secretion (slopeAGR, P = 0.014) compared with women with NGT. In a multivariate regression model including all of the 108 women, 2-h glucose was independently determined by the DI, the AGR, and the slopeAGR (r = 0.63, P < 0.001). CONCLUSIONS: We have shown that both the individual ability to adapt insulin secretion to the ambient insulin sensitivity and the level of glucagon secretion are important parameters for maintenance of NGT. Therefore, islet dysfunction in IGT involves low insulin and high glucagon secretion, which present potential targets for correcting impaired glycemia.     

Insulin resistance, hepatic lipid and adipose tissue distribution in HIV-infected men

BACKGROUND: A large proportion of HIV-infected patients on antiretroviral medication develop insulin resistance, especially in the context of fat redistribution. This study investigates the interrelationships among fat distribution, hepatic lipid content, and insulin resistance in HIV-infected men. METHODS: We performed a cross-sectional analysis of baseline data from 23 HIV-infected participants in three prospective clinical studies. Magnetic resonance spectroscopy was used to quantify hepatic lipid concentrations. Magnetic resonance imaging was used to quantify whole-body adipose tissue compartments: that is, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes, as well as the intermuscular adipose tissue (IMAT) subcompartment and the omental-mesenteric adipose tissue (OMAT) and retroperitoneal adipose tissue (RPAT) subcompartments of VAT. The homeostasis model for assessment of insulin resistance (HOMA-IR) was calculated from fasting glucose and insulin concentrations. RESULTS: Hepatic lipid content correlated significantly with total VAT (r = 0.62, P = 0.0014), but not with SAT (r = 0.053, P = 0.81). In univariate analysis, hepatic lipid content was associated with the OMAT (r = 0.67, P = 0.0004) and RPAT (r = 0.53, P = 0.009) subcompartments; HOMA-IR correlated with both VAT and hepatic lipid contents (r = 0.61, P = 0.057 and r = 0.68, P = 0.0012, respectively). In stepwise linear regression models, hepatic lipid had the strongest associations with OMAT and with HOMA-IR. CONCLUSION: Hepatic lipid content is associated with VAT volume, especially the OMAT subcompartment, in HIV-infected men. Hepatic lipid content is associated with insulin resistance in HIV-infected men. Hepatic lipid content might mediate the relationship between VAT and insulin resistance among treated, HIV-infected men.     

LDL particle size in relation to insulin, proinsulin, and insulin sensitivity. The Insulin Resistance Atherosclerosis Study.

OBJECTIVE: LDL particles are heterogeneous in terms of size and density; small dense LDL particles are considered more atherogenic than larger LDL particles. The aim of this study was to investigate the interrelationships among LDL size, insulin, proinsulin (intact and split), and insulin sensitivity in a tri-ethnic population with varying degrees of glucose tolerance (n = 1,549) in the Insulin Resistance Atherosclerosis Study. RESEARCH DESIGN AND METHODS: Insulin sensitivity was assessed by a frequently sampled intravenous glucose tolerance test with minimal model analysis. Proinsulin levels were measured using highly sensitive assays without detectable cross-reactivity with insulin, and LDL size was determined by gradient-gel electrophoresis. RESULTS: In univariate analyses, LDL size was related to various features of the insulin resistance syndrome, including fasting insulin (r = -0.18), intact proinsulin (r = -0.24), split proinsulin (r = -0.24), the proinsulin-to-insulin ratio (r = -0.14), and insulin sensitivity (r = 0.21; all P < 0.0001). In a multivariate regression model (adjusted for age, BMI, ethnicity, and clinic), triglyceride levels (P = 0.0001), HDL cholesterol (P = 0.0001), sex (P = 0.002), and proinsulin (P = 0.01) were significantly related to LDL size. In the same model stratified by sex, LDL size was significantly inversely related to proinsulin in men (P = 0.005 and P = 0.04 after further adjustment for the glucose tolerance status), but not in women (P > 0.15). CONCLUSIONS: We found an inverse relation of proinsulin to LDL particle size in a large tri-ethnic population with varying degrees of glucose tolerance. This relation was independent of age, BMI, and triglyceride and HDL cholesterol concentrations, and was more pronounced in men than in women.     

Inflammation, insulin resistance, and adiposity: a study of first-degree relatives of type 2 diabetic subjects

OBJECTIVE: Inflammatory markers such as C-reactive protein (CRP) are associated with insulin resistance, adiposity, and type 2 diabetes. Whether inflammation causes insulin resistance or is an epiphenomenon of obesity remains unresolved. We aimed to determine whether first-degree relatives of type 2 diabetic subjects differ in insulin sensitivity from control subjects without a family history of diabetes, whether first-degree relatives of type 2 diabetic subjects and control subjects differ in CRP, adiponectin, and complement levels, and whether CRP is related to insulin sensitivity independently of adiposity. RESEARCH DESIGN AND METHODS: We studied 19 young normoglycemic nonobese first-degree relatives of type 2 diabetic subjects and 22 control subjects who were similar for age, sex, and BMI. Insulin sensitivity (glucose infusion rate [GIR]) was measured by the euglycemic-hyperinsulinemic clamp. Dual-energy X-ray absorptiometry determined total and abdominal adiposity. Magnetic resonance imaging measured abdominal adipose tissue volumes. RESULTS: First-degree relatives of type 2 diabetic subjects had a 20% lower GIR than the control group (51.8 +/- 3.9 vs. 64.9 +/- 4.6 micromol x min(-1) x kg fat-free mass(-1), P = 0.04). However, first-degree relatives of subjects with type 2 diabetes and those without a family history of diabetes had normal and comparable levels of CRP, adiponectin, and complement proteins. When the cohort was examined as a whole, CRP was inversely related to GIR (r = -0.33, P = 0.04) and adiponectin (r = -0.34, P = 0.03) and positively related to adiposity (P < 0.04). However, CRP was not related to GIR independently of fat mass. In contrast to C3 (r = 0.41, P = 0.009) and factor B (r = 0.43, P = 0.005), CRP was unrelated to factor D. CONCLUSIONS: The insulin-resistant state is not associated with changes in inflammatory markers or complement proteins in subjects at high risk of type 2 diabetes. Our study confirms a strong relationship between CRP and fat mass. Increasing adiposity and insulin resistance may interact to raise CRP levels.     

Plasma adiponectin, insulin sensitivity, and subclinical inflammation in women with prior gestational diabetes mellitus

OBJECTIVE: Women with prior gestational diabetes mellitus (pGDM) are at increased risk of developing type 2 diabetes and associated vasculopathy. Because increased fat mass and inflammatory processes are angiopathic risk factors, the relationship between insulin sensitivity, parameters of subclinical inflammation, and plasma concentrations of adipocytokines was investigated in pGDM both at 3 months and 12 months after delivery. RESEARCH DESIGN AND METHODS: Insulin sensitivity (through a frequently sampled intravenous glucose tolerance test) and plasma concentrations of ultrasensitive C-reactive protein (CRP), adiponectin, plasminogen activator inhibitor (PAI)-1, tumor necrosis factor-alpha, leptin, and interleukin-6 were measured in 89 pGDM (BMI 26.9 +/- 0.5 kg/m(2), age 32 +/- 0.5 years) and in 19 women with normal glucose tolerance during pregnancy (NGT) (23.7 +/- 0.9 kg/m(2), 31 +/- 1.3 years). RESULTS: pGDM showed lower (P < 0.0001) plasma adiponectin (6.7 +/- 0.2 microg/ml) than NGT (9.8 +/- 0.6 microg/ml) and a decreased (P < 0.003) insulin sensitivity index (S(i)) and disposition index (P < 0.03), but increased plasma leptin (P < 0.003), PAI-1 (P < 0.002), and CRP (P < 0.03). After adjustment for body fat mass, plasma adiponectin remained lower in pGDM (P < 0.004) and correlated positively with S(i) (P < 0.003) and HDL cholesterol (P < 0.0001) but negatively with plasma glucose (2-h oral glucose tolerance test [OGTT]) (P < 0.0001), leptin (P < 0.01), CRP (P < 0.007), and PAI-1 (P < 0.0001). On regression analysis, only HDL cholesterol, postload (2-h OGTT) plasma glucose, and S(i) remained significant predictors of plasma adiponectin, explaining 42% of its variability. Of note, adiponectin further decreased (P < 0.05) only in insulin-resistant pGDM despite unchanged body fat content and distribution after a 1-year follow-up. CONCLUSIONS: Lower plasma adiponectin concentrations characterize women with previous GDM independently of the prevailing insulin sensitivity or the degree of obesity and are associated with subclinical inflammation and atherogenic parameters.     

Are the reductions in triacylglycerol and insulin levels after exercise related?

Moderate exercise improves insulin sensitivity and reduces triacylglycerol (triglyceride; TG) concentrations. We hypothesized that changes in insulin sensitivity are an important determinant of exercise-induced changes in postprandial TG concentrations. Altogether, 38 men and 43 women, all of whom were normotriglyceridaemic and normoglycaemic, each underwent two oral fat tolerance tests with different pre-conditions: control (no exercise) and prior exercise (90 min of exercise at 60% of maximal O(2) uptake the day before). Venous blood samples were obtained in the fasting state and for 6 h after a high-fat mixed meal. In the control trial there were significant correlations between log fasting TG concentration and log fasting insulin concentration (r=0.42, P<0.0005) and between log postprandial TG response (area under the curve) and log postprandial insulin response (r=0.48, P<0.0005). Prior exercise reduced the fasting TG concentration by 18.2 +/- 2.2% (mean +/- S.E.M.) (P<0.0005), the postprandial TG response by 21.5 +/-1.9% (P<0.0005), the fasting insulin concentration by 3.8 +/- 3.1% (P<0.01) and the postprandial insulin response by 11.9 +/- 2.5% (P<0.0005). However, there was no relationship between the exercise-induced changes in log fasting TG and log fasting insulin (r=0.08, P=0.50), nor between the exercise-induced changes in log postprandial TG response and log postprandial insulin response (r=0.04, P=0.70). These data suggest that the reductions in fasting and postprandial TG levels elicited by a session of moderate-intensity exercise are not mediated by an increase in insulin sensitivity.     

Cereal fiber improves whole-body insulin sensitivity in overweight and obese women

OBJECTIVE: Cereal fiber intake is linked to reduced risk of type 2 diabetes in epidemiological observations. The pathogenic background of this phenomenon is unknown. Based on recent findings, we hypothesized that intake of purified insoluble oat fiber may improve whole-body insulin sensitivity. RESEARCH DESIGN AND METHODS: A randomized, controlled, single-blind, cross-over study was performed, and 17 overweight or obese subjects with normal glucose metabolism were analyzed. After consumption of nine macronutrient-matched portions of fiber-enriched bread (white bread enriched with 31.2 g insoluble fiber/day) or control (white bread) over a time period of 72 h, whole-body insulin sensitivity was assessed by euglycemic-hyperinsulinemic clamp. Energy intake was individually adjusted by providing standardized liquid meals. Hydrogen breath tests were performed to control for dietary adherence. RESULTS: When analyzing the entire cohort, whole-body glucose disposal was improved after fiber consumption (M value 6.56 +/- 0.32 vs. 6.07 +/- 0.27 mg . min(-1) . kg(-1); P = 0.043). Thirteen subjects had increased hydrogen breath test concentrations after fiber consumption, indicating probable dietary adherence. Restricting analysis to these subjects, improvements in M value (6.85 +/- 0.34 vs. 6.06 +/- 0.32 mg . min(-1) . kg(-1); P = 0.003) and insulin sensitivity, expressed as M/I ratio (M value divided by mean serum insulin at steady state: 3.73 +/- 0.23 vs. 3.21 +/- 0.27; P = 0.02), after fiber consumption were more pronounced. Plasma lipids, serum magnesium, ghrelin, and adiponectin concentrations, as well as substrate utilization and body weight, were not significantly changed by fiber intake (P > 0.15). CONCLUSIONS: Increased insoluble dietary fiber intake for 3 days significantly improved whole-body insulin sensitivity. These data suggest a potential mechanism linking cereal fiber intake and reduced risk of type 2 diabetes.     

Inflammatory markers,adiponectin, and risk of type 2 diabetes in the Pima Indian

OBJECTIVE: To examine the association between adiponectin, a known predictor of diabetes in Pima Indians, and markers of inflammation and endothelial function in nondiabetic subjects and to assess whether these markers predict later diabetes in a case-control study within a longitudinal health study in Pima Indians. RESEARCH DESIGN AND METHODS: Participants with normal glucose tolerance at baseline were selected. Case subjects (who later developed type 2 diabetes), and control subjects (n = 71 pairs) were matched for BMI, age, and sex. Adiponectin, C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor-alpha, phospholipase A2 (sPLA2), soluble E-selectin (SE-selectin), soluble intracellular adhesion molecule-1, soluble vascular adhesion molecule-1, and von Willebrand factor (vWF) were measured in baseline samples. RESULTS: Adiponectin was negatively correlated with CRP (r = -0.25, P < 0.05), IL-6 (r = -0.20, P < 0.05), sPLA2 (r = -0.22, P < 0.05), and SE-selectin (r = -0.20, P < 0.05). CRP and IL-6 did not predict diabetes. Only vWF predicted the development of diabetes (incidence rate ratio 0.67 for a 1-SD difference, 95% CI 0.41-1.00, P = 0.05), but this was not significant after adjustment for age, glucose, HbA(1c), waist circumference, and fasting insulin (hazard rate ratio 0.73, 95% CI 0.46-1.16, P = 0.18). CONCLUSIONS: Adiponectin is negatively correlated with markers of inflammation in vivo. In case and control subjects matched for BMI, with the exception of vWF, none of the inflammatory markers predicted diabetes. Adiponectin may be the link between adiposity, inflammation, and type 2 diabetes.     

The glucoregulatory and antilipolytic actions of insulin in abdominal obesity with normal or impaired glucose tolerance: an in vivo and in vitro study

To evaluate the effects of obesity and impaired glucose tolerance on insulin sensitivity, we performed a euglycaemic-hyperinsulinemic clamp at about 350 pmol l-1, combined with 3H-glucose infusion, in 14 obese patients, BMI 36.5 +/- 1.2 and in 12 matched controls, BMI 23.9 +/- 0.4. Six obese patients had normal glucose tolerance (oNGT), and eight had impaired glucose tolerance (oIGT). The ability of insulin to inhibit lipolysis in isolated adipocytes was also studied. Insulin-mediated glucose utilization was more severely impaired in oIGT than in oNGT with respect to the controls (621 +/- 51 vs. 897 +/- 83 vs. 1298 +/- 55 mumol m-2 min-1, P < 0.001). Plasma glycerol was higher in oIGT than in oNGT and in the controls, both fasting (238 +/- 12 vs. 179 +/- 14 vs. 112 +/- 8 mumol l-1, P < 0.001) and during the clamp (175 +/- 21 vs. 120 +/- 12 vs. 36 +/- 6 mumol l-1, P < 0.001). The correlation between glucose utilization and the percent reduction of plasma glycerol during the clamp was significant in the study group as a whole (r = 0.809, P = 0.0001), and in each of the groups separately (oIGT: r = 0.929, P = 0.002; oNGT: r = 0.943, P = 0.036; controls: r = 0.902, P = 0.0001). Inhibition by insulin of noradrenaline-stimulated lipolysis in isolated adipocytes was more severely impaired in oIGT than in oNGT compared with the controls (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

In vitro insulin resistance of human adipocytes isolated from subjects with noninsulin-dependent diabetes mellitus.

To assess possible cellular mechanisms of in vitro resistance in noninsulin-dependent diabetes mellitus (NIDDM), maximum insulin-stimulated glucose transport and utilization and insulin binding were measured in adipocytes isolated from weight-matched normal glycemic subjects and patients with NIDDM. Glucose transport rate was determined by measuring the amount of [U-14C]-D-glucose taken up by incubating adipocytes at trace concentrations of glucose (300 nM), and glucose metabolism by estimating the amount of lactate, CO2, triglyceride, and total glucose carbons retained in the cells following incubating at 5.5 mM glucose. Insulin binding was measured at 50, 100, and 200 pM [mono125I-tyrosinyl A14]insulin. Both maximum insulin-stimulated glucose transport and utilization in adipocytes from diabetic subjects were 40% (P less than 0.01) and 32% (P less than 0.05) lower, respectively, than values obtained for subjects with normal glucose tolerance. In addition, the maximum capacity of glucose transport was correlated with the maximum capacity of glucose utilization (r = 0.81, P less than 0.001). Furthermore, fasting plasma glucose concentrations of diabetic subjects were negatively correlated with both maximum insulin-stimulated glucose transport (r = -0.56, P less than 0.05) and glucose utilization (r = -0.67, P less than 0.05). Since basal glucose transport in adipocytes from diabetic subjects was also 33% lower than in adipocytes from normal subjects, there was no change in the relative ability of insulin to stimulate glucose transport. However, there was a 64% decrease in the sensitivity of the glucose transport system to insulin (P less than 0.05), unrelated to concomitant changes in insulin binding. These results demonstrate that both maximal insulin-stimulated glucose transport and utilization, and the sensitivity of the glucose transport system to insulin, was decreased in adipocytes isolated from subjects with NIDDM. These in vitro defects were associated with impaired glucose metabolism in vivo, consistent with the view that the metabolic alterations observed at the cellular level may contribute to the in vivo insulin resistance of NIDDM.