Association of Pericardial Fat With Liver Fat and Insulin Sensitivity After Diet‐Induced Weight Loss in Overweight Women

Pericardial adipose tissue (PAT) is positively associated with fatty liver and obesity‐related insulin resistance. Because PAT is a well‐known marker of visceral adiposity, we investigated the impact of weight loss on PAT and its relationship with liver fat and insulin sensitivity independently of body fat distribution. Thirty overweight nondiabetic women (BMI 28.2–46.8 kg/m², 22–41 years) followed a 14.2 ± 4‐weeks low‐calorie diet. PAT, abdominal subcutaneous (SAT), and visceral fat volumes (VAT) were measured by magnetic resonance imaging (MRI), total fat mass, trunk, and leg fat by dual‐energy X‐ray absorptiometry and intrahepatocellular lipids (IHCL) by (¹)H‐magnetic resonance spectroscopy. Euglycemic hyperinsulinemic clamp (M) and homeostasis model assessment of insulin resistance (HOMA_IR) were used to assess insulin sensitivity or insulin resistance. At baseline, PAT correlated with VAT (r = 0.82; P < 0.001), IHCL (r = 0.46), HOMA_IR (r = 0.46), and M value (r = ?0.40; all P < 0.05). During intervention, body weight decreased by ?8.5%, accompanied by decreases of ?12% PAT, ?13% VAT, ?44% IHCL, ?10% HOMA2‐%B, and +24% as well as +15% increases in HOMA2‐%S and M, respectively. Decreases in PAT were only correlated with baseline PAT and the loss in VAT (r = ?0.56; P < 0.01; r = 0.42; P < 0.05) but no associations with liver fat or indexes of insulin sensitivity were observed. Improvements in HOMA_IR and HOMA2‐%B were only related to the decrease in IHCL (r = 0.62, P < 0.01; r = 0.65, P = 0.002) and decreases in IHCL only correlated with the decrease in VAT (r = 0.61, P = 0.004). In conclusion, cross‐sectionally PAT is correlated with VAT, liver fat, and insulin resistance. Longitudinally, the association between PAT and insulin resistance was lost suggesting no causal relationship between the two.     

Adipokines,Ghrelin and Obesity‐Associated Insulin Resistance in Nondiabetic Patients with Acute Coronary Syndrome

Altered glucose metabolism negatively modulates outcome in acute coronary syndromes (ACS). Insulin resistance is commonly associated with increasing BMI in the general population and these associations may involve obesity‐related changes in circulating ghrelin and adipokines. We aimed at investigating interactions between BMI, insulin resistance and ACS and their associations with plasma ghrelin and adipokine concentrations. Homeostasis model assessment of insulin resistance (HOMA_IR)‐insulin resistance index, plasma adiponectin, leptin, total (T‐Ghrelin), acylated (Acyl‐Ghrelin), and desacylated ghrelin (Desacyl‐Ghrelin) were measured in 60 nondiabetic ACS patients and 44 subjects without ACS matched for age, sex, and BMI. Compared with non‐ACS, ACS patients had similar HOMA_IR and plasma adipokines, but lower T‐ and Desacyl‐Ghrelin and higher Acyl‐Ghrelin. Obesity (BMI > 30) was associated with higher HOMA_IR, lower adiponectin, and higher leptin (P < 0.05) similarly in ACS and non‐ACS subjects. In ACS (n = 60) HOMA_IR remained associated negatively with adiponectin and positively with leptin independently of BMI and c‐reactive protein (CRP) (P < 0.05). On the other hand, low T‐ and Desacyl‐Ghrelin with high Acyl‐Ghrelin characterized both obese and non‐obese ACS patients and were not associated with HOMA_IR. In conclusion, in ACS patients, obesity and obesity‐related changes in plasma leptin and adiponectin are associated with and likely contribute to negatively modulate insulin resistance. ACS per se does not however enhance the negative impact of obesity on insulin sensitivity. High acylated and low desacylated ghrelin characterize ACS patients independently of obesity, but are not associated with insulin sensitivity.     

Insulin Resistance is the Best Predictor of the Metabolic Syndrome in Subjects With a First‐Degree Relative With Type 2 Diabetes

Although obesity is associated with insulin resistance and the metabolic syndrome (MetS), some obese individuals are metabolically healthy. Conversely, some lean individuals are insulin resistant (IR) and at increased cardiometabolic risk. To determine the relative importance of insulin sensitivity, BMI and waist circumference (WC) in predicting MetS, we studied these two extreme groups in a high‐risk population. One thousand seven hundred and sixty six subjects with a first‐degree relative with type 2 diabetes were stratified by BMI and homeostasis model assessment of insulin resistance (HOMA_IR) into groups. IR groups had higher triglycerides, fasting glucose, and more diabetes than their BMI‐group insulin sensitive (IS) counterparts. Within both IS and IR groups, obesity was associated with higher HOMA_IR and diastolic blood pressure (BP), but no difference in other metabolic variables. MetS (Adult Treatment Panel III (ATPIII)) prevalence was higher in IR groups (P < 0.001) and more subjects met each MetS criterion (P < 0.001). Within each BMI category, HOMA_IR independently predicted MetS (P < 0.001) whereas WC did not. Within IS and IR groups, age and WC, but not BMI, were independent determinants of MetS (P < 0.001). WC was a less meaningful predictor of MetS at higher values of HOMA_IR. HOMA_IR was a better predictor of MetS than WC or BMI (receiver operating characteristic (ROC) area under the curve 0.76 vs. 0.65 vs. 0.59, P < 0.001). In conclusion, insulin sensitivity rather than obesity is the major predictor of MetS and is better than WC at identifying obese individuals with a healthier metabolic profile. Further, as many lean individuals with a first‐degree relative with type 2 diabetes are IR and metabolically unhealthy, they may all benefit from metabolic testing.     

Association of Long‐term Change in Waist Circumference With Insulin Resistance

Recent studies have shown that fat accumulation is associated with insulin resistance; however, the risks associated with long‐term changes and fluctuations in central fatness are less clear. This study examined the longitudinal relationship between waist circumference (WC) and insulin resistance using three dimensions of WC: baseline WC, slope of linear changes in WC, and fluctuation of WC around the slope during 20 years of follow‐up. Anthropometry, insulin resistance (homeostasis model assessment (HOMA_IR)), and lifestyle factors were obtained in a population‐based, prospective observational study (Coronary Artery Risk Development in Young Adults (CARDIA)) during 1985–2006, excluding participants who had been diagnosed with diabetes at any examination. After adjusting for socio‐demographic and lifestyle factors, the evolution of HOMA_IR from CARDIA year 15 to 20 was 6.9% higher per standard deviation of year 0 WC (P trend <0.0001) and 6.3% higher per standard deviation increase in the change in WC over the long term (P trend <0.0001). However, WC fluctuations around the linear change were not associated with insulin resistance or its evolution. The level of HOMA_IR increased substantially with steeper linear WC slope among initially thinner participants at baseline, whereas this association tended to be weaker in those with higher initial WC (P interaction <0.0001). We conclude that year 0 WC and long‐term increment in WC are associated with worsening insulin resistance. However, the association of HOMA_IR with slope of WC change may vary across the range of initial WC.     

Both Subcutaneous and Visceral Adipose Tissue Correlate Highly with Insulin Resistance in African Americans

Objective: The contribution of visceral adipose tissue (VAT) to insulin resistance is well‐established; however, the role of subcutaneous abdominal adipose tissue (SAT) in insulin resistance remains controversial. Sex may determine which of these two components of abdominal obesity is more strongly related to insulin resistance and its consequences. The aim of this study was to determine whether both VAT and SAT contribute to insulin resistance in African Americans and to examine the effects of sex on this relationship. Research Methods and Procedures: This was a cross‐sectional study of 78 nondiabetic African‐American volunteers (44 men, 35 women; age 33.8 ± 7.3 years; BMI 30.9 ± 7.4 kg/m²). VAT and SAT volumes were measured using serial computerized tomography slices from the dome of the diaphragm to the iliac crest. The insulin sensitivity index (S_I) was determined from the minimal model using data obtained from the frequently sampled intravenous glucose tolerance test. Results: In men, both VAT and SAT were negatively correlated with S_I (r for both correlations = ?0.57; p < 0.01). In women, the correlation coefficient between VAT and S_I was ?0.50 (p < 0.01) and between SAT and S_I was ?0.67 (p < 0.01). In women, the correlation coefficient for S_I with SAT was significantly greater than the correlation coefficient with VAT (p = 0.02). Discussion: Both SAT and VAT are strongly correlated with insulin resistance in African Americans. For African‐American women, SAT may have a greater effect than VAT on insulin resistance.     

Insulin Resistance and Oxidative Stress Influence Colony‐Forming Unit‐Endothelial Cells Capacity in Obese Patients

The aim of this study was to investigate the relationship between a sub‐population of endothelial progenitor cells (EPC), namely colony‐forming unit‐endothelial cells (CFU‐EC), their colony‐forming capacity and variable clinical parameters, including insulin resistance and oxidative stress, in obese individuals. Thirty‐eight obese adults (aged 42.5 ± 12.7), with BMI 32.3 ± 4.0 and 13 normal‐weight controls (aged 48.2 ± 12.9; BMI 23.2 ± 2.3) were studied. CFU‐EC colony‐forming capacity was impaired in the group of obese individuals compared to the normal‐weight controls (P = 0.001). The inverse correlation between homeostasis model assessment‐insulin resistance (HOMA_IR) index and CFU‐EC number (r = ?0.558, P < 0.0001) as well as positive total antioxidant status of plasma (TAS)/CFU‐EC relation were noticed during the study. Additionally, correlations between the concentration of triglycerides (TG), high‐density lipoproteins (HDLs), and body composition parameters in the obese participants were established. Our results demonstrate that insulin resistance and oxidative stress have a significant impact on the CFU‐EC colony formation in obesity. Moreover, in multivariate regression analysis, in both studied groups, the HOMA_IR index and HDL concentration were independent predictors of the number of CFU‐EC. Endothelium dysfunction, which can be present in obesity, may in part be caused by EPC function impairment in this condition.     

Early Detrimental Metabolic Outcomes of rs17300539‐A Allele of ADIPOQ Gene Despite Higher Adiponectinemia

Minor allele A of single‐nucleotide polymorphism (SNP) 11391 G/A of ADIPOQ gene (rs17300539) has been consistently associated with higher adiponectin levels in adults and children. The aim of this study was to investigate the metabolic role of this variant in a large cohort of children of European origin. A total of 1,852 children from two general populations in Verona and in Fleurbaix–Laventie and from the Lille childhood obesity cohort, were genotyped and pooled together after checking for the absence of genetic heterogeneity for rs17300539 between Italian and French children. The genotype of rs17300539 was studied in relation to circulating adiponectin levels, BMI, fasting plasma glucose, fasting serum insulin (FSI), insulin resistance index (homeostasis model assessment of insulin resistance (HOMA_IR)), high‐density lipoprotein cholesterol, and triglycerides. After adjustment for known confounders, rs17300539 GA+AA carriers had 1.6 µg/ml higher adiponectin levels (P = 6 × 10^?8) than GG carriers. They also showed higher BMI (B = 0.97, P = 0.015) and higher prevalence of obesity (OR = 1.35 (1.06–1.85), P = 0.015) than GG carriers. Before adjusting for obesity status, GA+AA carriers had higher FSI (B = 1.10, P = 0.040) and higher HOMA_IR (B = 0.31, P = 0.020) than GG carriers. After adjustment for obesity status, they did not differ from GG carriers for any metabolic parameter, either among obese or nonobese children. The rs17300539‐A variant, though consistently associated with higher adiponectin levels, does not exert any appreciable protective metabolic effect in children, either in the presence or absence of obesity. In contrast, this SNP may increase the risk for childhood obesity and related insulin resistance.     

Appetite‐Regulating Hormone Changes in Patients With Craniopharyngioma

Patients with craniopharyngioma (CP), an embryological tumor located in the hypothalamic and/or pituitary region, often suffer from uncontrolled eating and severe obesity. We aimed to compare peripherally secreted hormones involved in controlling food intake in normal weight and obese children and adolescents with CP vs. controls. Plasma insulin, glucose, total ghrelin, and peptide‐YY (PYY) levels were assessed under fasting conditions as well as 60 min after liquid mixed meal in four groups: Normal weight (n = 12) and obese (n = 15) CP patients, and 12 normal weight and 15 obese otherwise healthy BMI‐, gender‐ and age‐matched controls. Homeostasis model assessment of insulin resistance (HOMA_IR), as well as quantitative insulin sensitivity check index (QUICKI) were calculated. Obese CP subjects had significantly higher HOMA_IR, higher baseline and postmeal insulin but lower ghrelin levels, weaker postmeal changes for PYY, and lower QUICKI compared to obese controls. QUICKI data from all CP patients correlated positively with ghrelin and PYY % postmeal changes (ghrelin: r = 0.38, P = 0.023; PYY r = 0.40, P = 0.017) and negatively with standard deviation score‐BMI (SDS‐BMI: r = ?0.49, P = 0.002). Tumor growth of 87% obese and 58% of normal weight CP patients affected the hypothalamic area which was associated with higher SDS‐BMI and weaker % postmeal ghrelin changes (P = 0.014) compared to CP patients without hypothalamic tumor involvement. Blunted postmeal ghrelin and PYY responses in obese CP subjects are likely due to their higher degree of insulin resistance and lower insulin sensitivity compared to matched obese controls. Thus, insulin resistance in CP patients seems to affect eating behavior by affecting meal responses of gut peptides.     

Decreased Liver Fatty Acid Δ‐6 and Δ‐5 Desaturase Activity in Obese Patients

Steatosis in obese nonalcoholic fatty liver disease (NAFLD) patients is a clinicopathological condition associated with depletion of n‐3 polyunsaturated fatty acids (PUFA), a feature that may be related to PUFA desaturation. Liver Δ‐6 and Δ‐5 desaturase (Δ‐6D and Δ‐5D) activities, homeostasis model assessment of insulin resistance (HOMA_IR), and ferric reducing ability of plasma (FRAP) were evaluated in 13 obese patients who underwent subtotal gastrectomy with gastro‐jejunal anastomosis in Roux‐en‐Y and 15 nonobese patients who underwent laparoscopic cholecystectomy (controls). Liver Δ‐6D and Δ‐5D activities in obese patients were 87% and 66% lower than controls (P < 0.001), respectively, with a 62% diminution in the Δ‐6D/Δ‐5D activity ratio (P < 0.02). Δ‐6D inversely correlated with both HOMA_IR (r = ?0.70, P < 0.0001) and oxidative stress assessed as the reciprocal value of FRAP (r = ?0.40, P < 0.05). Δ‐5D negatively correlated with HOMA_IR (r = ?0.48, P < 0.01) but not with FRAP^?1 (r = ?0.13, not significant). In conclusion, liver PUFA desaturation is diminished in obese NAFLD patients, in association with underlying insulin resistance and oxidative stress, which may play a role in altering lipid metabolism favoring fatty infiltration.     

Effects of Weight Reduction on Serum Vaspin Concentrations in Obese Subjects: Modification by Insulin Resistance

Visceral adipose tissue‐derived serpin (vaspin) has been regarded as a novel adipokine with potential insulin sensitizing properties. We investigated the changes of serum vaspin concentration in response to weight reduction, and the associations between changes in serum vaspin concentrations and changes of anthropometric and metabolic variables in obese subjects after weight reduction. We performed a longitudinal clinical intervention study on 63 obese persons enrolled in a 12‐week weight reduction program that included lifestyle modification and adjuvant treatment with the antiobesity agent orlistat. Anthropometric variables, lipid profiles, fasting glucose, fasting insulin, and serum vaspin concentrations were measured. Statistical analyses were performed according to the homeostasis model assessment of insulin resistance (HOMA_IR). Serum vaspin concentrations decreased significantly in responders (≥2% reduction in baseline weight), but not in nonresponders (<2% reduction in baseline weight). Changes in serum vaspin concentrations were significantly correlated with body weight, BMI, waist circumference, and hip circumference in the higher, but not in the lower, HOMA_IR group. In multivariate linear regression analysis, change in serum vaspin concentrations in the higher, but not in the lower, HOMA_IR group was positively correlated with change in BMI and negatively correlated with initial HOMA_IR level. The associations between changes in serum vaspin concentrations and changes in anthropometric and metabolic parameters differed according to insulin resistance status in obese subjects. These relationships were more prominent in the higher HOMA_IR group. Insulin resistance may influence the correlations between changes in serum vaspin concentration and related metabolic variables.     

Visceral and Subcutaneous Adiposity and Brachial Artery Vasodilator Function

Endothelial dysfunction may link obesity to cardiovascular disease (CVD). We tested the hypothesis that visceral abdominal tissue (VAT) as compared with subcutaneous adipose tissue (SAT) is more related to endothelium‐dependent vasodilation. Among Framingham Offspring and Third Generation cohorts (n = 3,020, mean age 50 years, 47% women), we used multivariable linear regression adjusted for CVD and its risk factors to relate computed tomography (CT)‐assessed VAT and SAT, BMI, and waist circumference (WC), with brachial artery measures. In multivariable‐adjusted models, BMI, WC, VAT, and SAT were positively related to baseline artery diameter and baseline mean flow velocity (all P < 0.001), but not hyperemic mean flow velocity. In multivariable‐adjusted models, BMI (P = 0.002), WC (P = 0.001), and VAT (P = 0.01), but not SAT (P = 0.24) were inversely associated with percentage of flow‐mediated dilation (FMD%). However, there was little incremental increase in the proportion of variability explained by VAT (R² = 0.266) as compared to SAT (R² = 0.265), above and beyond traditional risk factors. VAT, but not SAT was associated with FMD% after adjusting for clinical covariates. Nevertheless, the differential association with VAT as compared to SAT was minimal.     

Effect of Glucose Tolerance Status on PAI‐1 Plasma Levels in Overweight and Obese Subjects

Objective: The aim of our study was to examine whether plasminogen activator inhibitor‐1 (PAI‐1) plasma levels varied as a function of differences in glucose tolerance status independently of body fatness, body‐fat distribution, and insulin sensitivity. Research Methods and Procedures: Plasma PAI‐1 antigen levels, along with insulin resistance [measured by homeostatic model assessment (HOMA_IR)], central fat accumulation, body composition, blood pressure, and fasting concentrations of glucose, insulin, and lipids, were measured in 229 overweight and obese [body mass index (BMI) ≥25 kg/m²) subjects with normal glucose tolerance (NGT) and in 44 age‐ and BMI‐matched subjects with impaired glucose tolerance (IGT). Results: Plasma PAI‐1 antigen levels were significantly higher in IGT than in NGT subjects. Log PAI‐1 was positively correlated with BMI, HOMA_IR, and log insulin, and inversely associated with high‐density lipoprotein‐cholesterol both in IGT and in NGT individuals. On the other hand, log PAI‐1 was positively correlated with waist circumference, fat mass (FM), fat‐free mass, systolic and diastolic blood pressure, and log triglycerides only in the NGT group. After multivariate analyses, the strongest determinants of PAI‐1 levels were BMI, FM, waist circumference, and high‐density lipoprotein cholesterol in the NGT group and only HOMA_IR in the IGT cohort. Discussion: This study demonstrates that PAI‐1 concentrations are higher in IGT than in NGT subjects. Furthermore, we suggest that the influences of total adiposity, central fat, and insulin resistance, main determinants of PAI‐1 concentrations, are different according to the degree of glucose tolerance.     

Effect of Family History of Type 2 Diabetes on White Blood Cell Count in Adult Women

Objective: To evaluate the effect of a first‐degree family history of type 2 diabetes on white blood cell (WBC) count, a risk factor for atherosclerotic vascular disease, in glucose‐tolerant adult women Research Methods and Procedures: WBC count was measured in 174 normal weight, overweight, and obese female offspring of type 2 diabetic patients (FH⁺) and 174 age‐ and BMI‐matched female controls with no family history of type 2 diabetes (FH^?). Other measurements included fat mass (FM), measured by body impedance analysis; central fat accumulation, evaluated by waist circumference; insulin resistance, estimated by homeostatic model assessment for insulin resistance (HOMA_IR); systolic and diastolic blood pressure; and fasting concentrations of glucose, insulin, and lipids. Results: WBC count, waist circumference, systolic blood pressure, and fasting levels of glucose, insulin, and triglycerides were significantly higher in FH⁺ than in FH^? subjects. In FH⁺ individuals, WBC count was positively associated with BMI, FM, waist circumference, HOMA_IR, and triglyceride and insulin concentrations, and negatively correlated with age and high‐density lipoprotein‐cholesterol. In FH^? subjects, WBC count was directly associated with BMI, FM, waist circumference, and triglyceride and insulin concentrations, and inversely correlated with age and high‐density lipoprotein‐cholesterol. After multivariate analyses, WBC count maintained a significant association with age, systolic blood pressure, and HOMA_IR in FH⁺ subjects and with age, BMI, FM, and triglycerides in FH^? individuals. Discussion: This study indicates that WBC count is increased in adult women with genetic predisposition to type 2 diabetes, and its main correlates are insulin resistance in FH⁺ and adiposity in FH^? individuals.     

Adipose tissue R2* signal is increased in subjects with obesity: A preliminary MRI study

Objective : Circulating and adipose tissue markers of iron overload are increased in subjects with obesity. The aim is to study iron signals in adipose tissue. Methods: Adipose tissue R2* values and hepatic iron concentration (HIC) were evaluated using magnetic resonance imaging (MRI) in 23 middle‐aged subjects with obesity and 20 subjects without obesity. Results: Subcutaneous (SAT) and visceral adipose tissue (VAT) R2* were increased in subjects with obesity (P = 0.004 and P = 0.008) and correlated significantly and positively with HIC in all subjects. Strikingly, most of the associations of liver iron with metabolic parameters were replicated with SAT and VAT R2*. BMI, waist circumference, fat mass, HOMA value, and C‐reactive protein positively correlated with HIC and SAT and VAT R2*. BMI or percent fat mass (but not insulin resistance) contributed independently to 26.8‐34.8% of the variance in sex‐ and age‐adjusted SAT or VAT R2* (β > 0.40, P < 0.005). Within subjects with obesity, total cholesterol independently contributed to 14.8% of sex‐ and age‐adjusted VAT iron variance (β = 0.50, P = 0.025). Conclusions: Increased R2* in adipose tissue, which might indicate iron content, runs in parallel to liver iron stores of subjects with obesity. VAT iron seems also associated with serum cholesterol within subjects with obesity.     

Sphingolipid Content of Human Adipose Tissue: Relationship to Adiponectin and Insulin Resistance

Ceramides (Cer) are implicated in obesity‐associated skeletal muscle and perhaps adipocyte insulin resistance. We examined whether the sphingolipid content of human subcutaneous adipose tissue and plasma varies by obesity and sex as well as the relationship between ceramide content and metabolic indices. Abdominal subcutaneous adipose biopsies were performed on 12 lean adults (males = 6), 12 obese adults (males = 6) for measurement of sphingolipid content and activity of the main ceramide metabolism enzymes. Blood was sampled for glucose, insulin (to calculate homeostasis model assessment‐estimated insulin resistance (HOMA_IR)) adiponectin, and interleukin‐6 (IL‐6) concentrations. Compared to lean controls, total ceramide content (pg/adipocyte) was increased by 31% (P < 0.05) and 34% (P < 0.05) in obese females and males, respectively. In adipocytes from obese adults sphingosine, sphinganine, sphingosine‐1‐phosphate, C14‐Cer, C16‐Cer, and C24‐Cer were all increased. C18:1‐Cer was increased in obese males and C24:1‐Cer in obese females. For women only, there was a negative correlation between C16‐Cer ceramide and plasma adiponectin (r = ?0.77, P = 0.003) and a positive correlation between total ceramide content and HOMA_IR (r = 0.74, P = 0.006). For men only there were significant (at least P < 0.05), positive correlations between adipocyte Cer‐containing saturated fatty acid and plasma IL‐6 concentration. We conclude that the sexual dimorphism in adipose tissue behavior in humans extends to adipose tissue sphingolipid content its association with adiponectin, IL‐6 and insulin resistance.     

INSIG2 SNPs Associated With Obesity and Glucose Homeostasis Traits in Hispanics: The IRAS Family Study

The genome‐wide association study by Herbert et al. identified the INSIG2 single‐nucleotide polymorphism (SNP) rs7566605 as contributing to increased BMI in ethnically distinct cohorts. The present study sought to further clarify the matter, by testing whether SNPs of INSIG2 influenced quantitative adiposity or glucose homeostasis traits in Hispanics of the Insulin Resistance Atherosclerosis Family Study (IRASFS). Using a tagging SNP approach, rs7566605 and 31 additional SNPs were genotyped in 1,425 IRASFS Hispanics. SNPs were tested for association with six adiposity measures: BMI, waist circumference (WAIST), waist‐to‐hip ratio (WHR), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and VAT to SAT ratio (VSR). SNPs were also tested for association with fasting glucose (GFAST), fasting insulin (FINS), and three measures obtained from the frequently sampled intravenous glucose tolerance test: insulin sensitivity (S_I), acute insulin response (AIR), and disposition index (DI). Most prominent association was observed with direct computed tomography (CT)‐measured adiposity phenotypes, including VAT, SAT, and VSR (P values range from 0.007 to 0.044 for rs17586756, rs17047718, rs17047731, rs9308762, rs12623648, and rs11673900). Multiple SNP associations were observed with all glucose homeostasis traits (P values range from 0.001 to 0.031 for rs17047718, rs17047731, rs2161829, rs10490625, rs889904, and rs12623648). Using BMI as a covariate in evaluation of glucose homeostasis traits slightly reduced their association. However, association with adiposity and glucose homeostasis phenotypes is not significant following multiple comparisons adjustment. Trending association after multiple comparisons adjustment remains suggestive of a role for genetic variation of INSIG2 in obesity, but these results require validation.     

Increased Soluble Leptin Receptor Levels in Morbidly Obese Patients With Insulin Resistance and Nonalcoholic Fatty Liver Disease

The adipocyte hormone, leptin has been demonstrated to have profibrogenic actions in vitro and in animal models. However, no correlation was found between plasma leptin levels and fibrosis stage in humans. Thus, our aim was to study whether soluble leptin receptor (SLR) or free leptin index (FLI; calculated as the ratio of leptin to SLR), may correlate better with the features of metabolic syndrome and with the histological grade and stage of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). We studied a population (n = 104) of morbidly obese patients undergoing bariatric surgery. Data including BMI, type 2 diabetes mellitus, hypertension, and hyperlipidemia were obtained. Plasma fasting leptin and SLR, fasting glucose and insulin were measured, and homeostasis model of assessment insulin resistance (HOMA_IR) index and FLI were calculated. All patients had intraoperative liver biopsies. Leptin levels correlated with the BMI. The multiple regression analysis indicated that increasing HOMA and decreasing FLI were predictors of steatosis in the liver (P < 0.0003). SLR levels were positively correlated with the presence of diabetes mellitus and the stage of fibrosis. In conclusion, increased SLR levels in morbidly obese patients with diabetes are correlated with the stage of liver fibrosis, and may reflect progressive liver disease.     

Adiponectin and leptin in African Americans

Objective: African Americans (AAs) have less visceral and more subcutaneous fat than whites, thus the relationship of adiponectin and leptin to body fat and insulin sensitivity in AA may be different from that in whites. Methods and Procedures: Sixty‐nine non‐diabetic AA (37 men and 32 women), aged 33 ± 1 year participated. The percent fat was determined by dual‐energy X‐ray absorptiometry, abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volume by computerized tomography (CT), and insulin sensitivity by homeostasis model assessment (HOMA). Results: VAT was greater in men (1,619 ± 177 cm³ vs. 1,022 ± 149 cm³; P = 0.01); women had a higher percentage of body fat (34.1 ± 1.4 vs. 24.0 ± 1.2; P < 0.0001), adiponectin (15.8 ± 1.2 μg/ml vs. 10.4 ± 0.8 μg/ml; P = 0.0004) and leptin (23.2 ± 15.8 ng/ml vs. 9.2 ± 7.2 ng/ml; P < 0.0001). SAT and HOMA did not differ because of the sex. Adiponectin negatively correlated with VAT (r = ?0.41, P < 0.05) in men, and with VAT (r = ?0.55, P < 0.01), and SAT (r = ?0.35, P < 0.05) in women. Adiponectin negatively correlated with HOMA in men (r = ?0.38, P < 0.05) and women (r = ?0.44, P < 0.05). In multiple regression, sex (P = 0.02), HOMA (P = 0.03) and VAT (P = 0.003) were significant predictors of adiponectin (adj R ² = 0.38, P < 0.0001). Leptin positively correlated with VAT, SAT, percent fat and HOMA in men (r = 0.79, r = 0.86, r = 0.89, and r = 0.53; P < 0.001) and women (r = 0.62, r = 0.75, r = 0.83, and r = 0.55; P < 0.01). In multiple regression VAT (P = 0.04), percent body fat (P < 0.0001) and sex (P = 0.01), but not HOMA were significant predictors of serum leptin (adj R ²= 0.82, P < 0.0001). Discussion: The relationship of adiponectin and leptin to body fat content and distribution in AA is dependent on sex. Although VAT and insulin sensitivity are significant determinants of adiponectin, VAT and percent body fat determine leptin.     

Metabolic syndrome is not a risk factor for kidney dysfunction in obese non-diabetic subjects

Objective: To investigate whether insulin resistance (IR) and the metabolic syndrome (MS) are associated with kidney dysfunction in obese non‐diabetic (OND) subjects. Methods and Procedures: Three‐hundred and eighty (113M/267F; age = 41 ± 14 years) OND subjects (BMI ≥ 30 kg/m²; range = 43 ± 8 kg/m²) were studied. Anthropometric measures, blood pressure, fasting glucose, insulin, lipid profile, and serum creatinine were evaluated. Glomerular filtration rate (GFR) was estimated (e‐GFR) with the Modification of Diet in Renal Disease equation. Chronic kidney disease (CKD) was defined as e‐GFR <60 ml/min/1.73 m². Results: e‐GFR was associated with gender (being lower in women) (P = 0.001) and age (P < 0.0001). CKD was present in 32 subjects (8.4%), who were older (P < 0.0001) and more frequently affected by hypertension (P = 0.04) as compared to subjects without CKD. MS was present in 212 (55.8%) subjects. They were older (P< 0.001), had lower e‐GFR (P = 0.02) and were more frequently affected by CKD (odds ratio (OR), 95% confidence interval (CI) = 2.3, 1.1–5.1) than those without MS. However, differences in e‐GFR values and in the risk of CKD were no longer statistically significant after adjusting for age (P = 0.99 for e‐GFR and OR, 95% CI = 1.2, 0.5–2.8 for the risk of CKD, respectively). Homeostasis model assessment of IR (HOMA_IR) index was neither higher in subject with CKD (P = 0.1) nor inversely correlated with e‐GFR (r = 0.1, P = 0.1). Discussion: In OND individuals the risk of CKD is independent of the MS and related abnormalities. This suggests that these individuals are not susceptible to a further deleterious role on kidney function on the top of that played by obesity itself.