Effect of longitudinal changes in visceral fat area and other anthropometric indices to the changes in metabolic risk factors in Japanese men: the Hitachi Health Study

OBJECTIVE

The effects of longitudinal changes in the visceral fat area (VFA), and other anthropometric indices, on the risk factors of metabolic syndrome were not studied. We calculated the changes in metabolic risk factors in relation to changes in certain anthropometric indices in a large-scale study of Japanese men.

RESEARCH DESIGN AND METHODS

The subjects were 1,106 men participating in the Hitachi Health Study who received a computed tomography examination in both 2004 and 2007. VFA, subcutaneous fat area (SFA), and waist circumference were measured using the computed tomography. We examined how longitudinal changes in each anthropometric index over a 3-year period influenced the value of each metabolic risk factor.

RESULTS

Changes (∆) over a 3-year period in body weight, SFA, and waist circumference strongly correlated, while the changes in body weight and VFA were weakly correlated. Changes in the VFA were associated with changes in metabolic risk factors, especially changes in triglyceride and HDL; we found these changes to be independent of the ∆body weight and ∆waist circumference.

CONCLUSIONS

Change in body weight is not a precise surrogate marker of ∆VFA, and repeated VFA measurements over time are useful. Adopting a lifestyle that does not increase the VFA is important in preventing metabolic syndrome.Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality in the world (1). Previous reports have shown that obesity plays a significant role in increasing cardiovascular risk (2). Certain indicators of obesity, such as the visceral fat area (VFA), or visceral adipose tissue, are more strongly associated with the risk of CVD than other indicators of obesity, such as waist circumference, BMI (3), or the subcutaneous fat area (SFA) (2). A large VFA is strongly related to a higher prevalence of impaired fasting glucose levels (4,5), diabetes (4,6,7), insulin resistance (4,8–10), hypertension (11,12), abnormality of lipid metabolism (13–16), and metabolic risk factors (14,17,18). Previous studies have examined the relationship between baseline VFA and metabolic risk factors. In a previous intervention study of 54 postmenopausal women, an increase in VFA strongly correlated with changes in triglyceride and HDL cholesterol levels compared with changes in the blood pressure and fasting blood glucose levels (19). In the current study, we examined the relationships between changes in the VFA, SFA, body weight, and waist circumference and changes in CVD risk factors to determine the relative contributions of the longitudinal changes in these anthropometric indices to the changes in metabolic risk factors over a 3-year period. Determining the relationships between the anthropometric indices and metabolic risk factors would be useful for preventing CVD in clinical settings.     

Adipose Dipeptidyl Peptidase-4 and Obesity: Correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro

OBJECTIVE

To study expression of the recently identified adipokine dipeptidyl peptidase-4 (DPP4) in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) of patients with various BMIs and insulin sensitivities, as well as to assess circulating DPP4 in relation to obesity and insulin sensitivity.

RESEARCH DESIGN AND METHODS

DPP4 expression was measured in SAT and VAT from 196 subjects with a wide range of BMIs and insulin sensitivities. DPP4 release was measured ex vivo in paired biopsies from SAT and VAT as well as in vivo from SAT of lean and obese patients. Circulating DPP4 was measured in insulin-sensitive and insulin-resistant BMI-matched obese patients.

RESULTS

DPP4 expression was positively correlated with BMI in both SAT and VAT, with VAT consistently displaying higher expression than SAT. Ex vivo release of DPP4 from adipose tissue explants was higher in VAT than in SAT in both lean and obese patients, with obese patients displaying higher DPP4 release than lean controls. Net release of DPP4 from adipose tissue was also demonstrated in vivo with greater release in obese subjects than in lean subjects and in women than in men. Insulin-sensitive obese patients had significantly lower circulating DPP4 than did obesity-matched insulin-resistant patients. In this experiment, DPP4 positively correlated with the amount of VAT, adipocyte size, and adipose tissue inflammation.

CONCLUSIONS

DPP4, a novel adipokine, has a higher release from VAT that is particularly pronounced in obese and insulin-resistant patients. Our data suggest that DPP4 may be a marker for visceral obesity, insulin resistance, and the metabolic syndrome.Obesity is an increasing health issue worldwide and an economical burden, and as the hallmark of the metabolic syndrome the obese state is frequently associated with the development of chronic diseases, including type 2 diabetes (1,2). The association between the epidemics of obesity and diabetes has promoted research on the endocrine link between lipid and glucose homeostasis, demonstrating that adipose tissue is an endocrine organ releasing various adipokines. A complex interorgan crosstalk scenario between adipose tissue and other central and peripheral organs underlies the progression of obesity-related metabolic disorders, with adipose tissue being a key player in this scenario (3). The current view of the role of expanded adipose tissue in obesity identifies adipokines as a potential link between obesity and insulin resistance (4). This link has stimulated a further characterization of the adipocyte secretome by means of diverse proteomic profiling approaches, leading to the discovery of such novel adipokines as dipeptidyl peptidase-4 (DPP4) (5).DPP4 is a transmembrane glycoprotein and exoprotease that cleaves N-terminal dipeptides from various substrates (6). Most importantly, DPP4 also cleaves and inactivates the incretins glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide. In this context, DPP4-inhibitors are in clinical use as antidiabetic drugs to improve glycemic control by stimulating pancreatic insulin secretion and suppressing glucagon production (7). We recently demonstrated that adipocytes release DPP4 in a differentiation-dependent manner (5). Circulating DPP4 concentrations are increased in obese subjects and correlate with fasting plasma insulin, leptin, and adipocyte size in subcutaneous adipose tissue (SAT); however, the tissue source of circulating DPP4 is not known. This study aimed to assess DPP4 expression and release in paired biopsies of SAT and visceral adipose tissue (VAT) of lean and obese patients and of patients with or without impaired glucose tolerance, as well as DPP4 release from adipose tissue in vivo. Because circulating DPP4 is increased in obese patients with the metabolic syndrome (5), we hypothesized that DPP4 expression and release in VAT are more prominent than in SAT and that VAT DPP4 could be a marker for insulin sensitivity.     

Abdominal Subcutaneous Adipose Tissue: A Protective Fat Depot?

OBJECTIVE

Obesity is associated with increased metabolic and cardiovascular risk. The ectopic fat hypothesis suggests that subcutaneous fat may be protective, but this theory has yet to be fully explored.

RESEARCH DESIGN AND METHODS

Participants from the Framingham Heart Study (n = 3,001, 48.5% women) were stratified by visceral adipose tissue (VAT) into sex-specific tertiles. Within these tertiles, age-adjusted abdominal subcutaneous adipose tissue (SAT) tertiles were examined in relation to cardiometabolic risk factors.

RESULTS

In the lowest VAT tertile, risk factor prevalence was low, although systolic blood pressure in women and rates of high triglycerides, impaired fasting glucose, hypertension, and the metabolic syndrome in men increased with increasing SAT tertile (all P < 0.04). In contrast, in the top VAT tertile, lower triglycerides were observed in men with increasing SAT (64.4% high triglycerides in SAT tertile 1 vs. 52.7% in SAT tertile 3, P = 0.03). Similar observations were made for women, although results were not statistically significant (50.6% high triglycerides in SAT tertile 1 vs. 41.0% in tertile 3, P = 0.10). Results in the highest VAT tertile were notable for a lack of increase in the prevalence of low HDL in men and women and in rates of impaired fasting glucose in men with increasing subcutaneous fat, despite sizable differences in BMI across SAT tertiles (27.1 to 36.3 kg/m²[women]; 28.1 to 35.7 kg/m²[men]).

CONCLUSIONS

Although adiposity increases the absolute risk of metabolic and cardiovascular disease, abdominal subcutaneous fat is not associated with a linear increase in the prevalence of all risk factors among the obese, most notably, high triglycerides.Obesity is associated with multiple cardiometabolic risk factors, including insulin resistance (1), diabetes (2), hypertension (3), and dyslipidemia (4). Variations in fat distribution may mediate such risks, with visceral adipose tissue (VAT) associated with more adverse risk factor profiles than abdominal subcutaneous adipose tissue (SAT) (5,6). The ectopic fat hypothesis proposes that obesity represents a failure of adipocyte growth and differentiation, resulting in “acquired lipodystrophy” and fat deposition in liver, skeletal muscle, and pancreatic β-cells (7). Such ectopic fat stores are hypothesized to contribute to the pathogenesis of impaired insulin secretion and insulin resistance and to mediate obesity-related cardiovascular disease (8).In addition to the detrimental effects of VAT, human and animal studies have suggested a possible protective role for subcutaneous fat. In humans, increased subcutaneous leg fat is associated with decreased risk of disturbed glucose metabolism and dyslipidemia, independent of abdominal fat (9). Thiazolidinedione treatment, which increases total fat mass, mostly in subcutaneous fat stores, improves insulin sensitivity (10). Removal of VAT by omentectomy results in decreased glucose and insulin levels in humans, (11), whereas removal of SAT by liposuction does not always result in improvements in glucose metabolism or lipid levels (12,13). Transplantation of subcutaneous fat into visceral compartments in mice produces decreases in body weight and total fat mass and improved glucose metabolism, suggesting that subcutaneous fat may be intrinsically different from visceral fat in ways that are beneficial (14).Therefore, the purpose of the present study was to test the hypothesis that abdominal subcutaneous fat is a protective fat depot in terms of cardiometabolic risk factor prevalence. We theorized that among those with similar levels of VAT, increasing SAT might be associated with decreases in cardiometabolic risk factor prevalence despite increasing BMI and total abdominal fat.     

In Vivo Insulin Sensitivity and Lipoprotein Particle Size and Concentration in Black and White Children

OBJECTIVE

To examine sex-specific black/white differences in lipoprotein profile and the role of visceral adiposity and to assess the relationship between insulin sensitivity and lipoprotein profiles in each group.

RESEARCH DESIGN AND METHODS

Fasting lipoprotein particle size and concentration and visceral adipose tissue (VAT) were determined in 226 children (117 black, 101 male) aged 8 to <18 years. The relationship between lipoproteins and insulin sensitivity was evaluated in a subset of 194 children (100 black, 88 male) who underwent a hyperinsulinemic-euglycemic clamp.

RESULTS

Black male children had smaller VLDL and black female children had larger HDL size than their white counterparts. Overall, blacks had larger LDL size with no sex-specific race differences. After adjusting for VAT and sex, only VLDL size and concentrations remained significantly favorable in blacks. Analysis of lipoprotein particle size and concentration across insulin sensitivity quartiles revealed that in both racial groups, the most insulin-resistant children had higher concentrations of small dense LDL, small HDL, and large VLDL and smaller LDL and HDL sizes than their more insulin-sensitive counterparts.

CONCLUSIONS

The previously reported favorable lipoprotein profiles in black versus white children is partly due to race differences in VAT. In both groups, however, the most insulin-resistant youths have a high-risk atherogenic profile of small dense LDL, small HDL, and large VLDL, akin to the atherogenic lipoprotein pattern in adults with coronary artery disease.Type 2 diabetes and insulin resistance in children are associated with dyslipidemia (1,2), characterized by elevated triglycerides and LDL cholesterol and low concentrations of HDL cholesterol (1–3). In addition to traditional lipid profiles, evidence suggests that insulin resistance and type 2 diabetes are associated with changes in lipoprotein particle size and subclass concentration (2,4). These are important to assess, as traditional lipid measurements only partially predict disease risk (5). Recently, the SEARCH for Diabetes in Youth study (2) reported that 36% of youth with type 2 diabetes and 62% of those with poorly controlled diabetes had small dense LDL. Similarly, low proportions of large and high proportions of small HDL particles are found in children with type 2 diabetes and overweight, insulin-resistant children (4). However, whereas some investigators reported associations between LDL (6,7), HDL (8), and VLDL (6) particle size and fasting insulin, others did not (9). High triglyceride and low HDL cholesterol concentrations together with small, dense LDL in children with type 2 diabetes and insulin resistance are similar to the atherogenic lipoprotein phenotype in adults with coronary artery disease (10,11).Black children, despite being insulin resistant and hyperinsulinemic (12,13) compared with their white counterparts, have favorable lipid concentrations including lower LDL and triglyceride and higher HDL concentrations (3,14,15), larger HDL and LDL and smaller VLDL particles, and favorable lipoprotein subclass concentrations (6,8). Why black children have favorable lipoprotein profiles despite insulin resistance is not clear. One explanation could be lower visceral adiposity in black than in white children despite similar overall adiposity (15). In black adults insulin resistance is not a good marker of triglyceride or HDL cholesterol concentrations or lipoprotein particle size (16). Thus, the relationship between in vivo insulin sensitivity and lipoprotein profiles in black and white children needs to be examined if at-risk children are to be identified for early treatments to improve lipoprotein profiles and if those treatments are to be pertinent in children of different ethnicity.In the present study, therefore, we determined lipoprotein particle size and subclass concentrations in black and white children and measured in vivo insulin sensitivity to test the following hypotheses: 1) the favorable lipoprotein phenotype in black children is probably due to lower visceral adipose tissue (VAT) than in whites and 2) the relationship between insulin sensitivity and lipoprotein profile is similar between black and white children.     

Relation of Abdominal Fat Depots to Systemic Markers of Inflammation in Type 2 Diabetes

OBJECTIVE

Both visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) have been linked to systemic inflammation in nondiabetic cohorts. We examined the relationships between VAT and SAT and systemic inflammatory markers in a large well-characterized cohort of subjects with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Three hundred eighty-two subjects with type 2 diabetes in the CHICAGO (Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone) study cohort underwent abdominal computed tomography to determine SAT and VAT distribution. Fasting blood was obtained for measurement of inflammatory markers. The relationships between inflammatory markers and BMI, SAT, and VAT were examined using regression models adjusted for age, sex, diabetes treatment, duration of diabetes, smoking, statin use, and A1C.

RESULTS

VAT was positively related to CRP, monocyte chemoattractant protein (MCP), intracellular adhesion molecule (ICAM)-1, and plasminogen activator inhibitor type 1 (PAI-1) antigen before adjustment for BMI. After adjustment for BMI, the relationship to CRP was lost but positive associations with MCP (P < 0.01), PAI-1 (P < 0.0001), ICAM-1 (P < 0.01), and vascular cell adhesion molecule (P = 0.01) were evident. BMI was positively related to CRP (P < 0.0001) and IL-6 (P < 0.01) even after adjustment for VAT and SAT. SAT was not related to any inflammatory marker after adjustment for BMI.

CONCLUSIONS

In this large group of subjects with type 2 diabetes, BMI was most strongly associated with CRP and IL-6 levels. SAT was not associated with markers of systemic inflammation. The size of the VAT depot provided information additional to that provided by BMI regarding inflammatory markers that are strongly related to vascular wall remodeling and coagulation. Our findings suggest that adipose tissue distribution remains an important determinant of systemic inflammation in type 2 diabetes.Obesity, especially of the abdominal type, is associated with a proinflammatory state. The association between obesity and inflammation was first reported by Hotamisligil et al. (1), who demonstrated expression of tumor necrosis factor-α (TNF-α) in adipose tissue, an increase in its expression in obesity, and its ability to induce insulin resistance. Since this report, adipose tissue has been recognized as an important source of a number of hormones and cytokines, including TNF-α, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1 (2). While adipokines such as leptin and adiponectin are exclusively produced by adipocytes, inflammatory cytokines can be produced by both adipocytes and adipose tissue macrophages (ATMs) (2). Obesity is associated with an increase in ATM infiltration (3) and activation (4). Epidemiological studies have demonstrated an increase in plasma levels of inflammatory markers such as C-reactive protein (CRP), IL-6, and TNF-α in obesity and a strong association with these levels and risk for type 2 diabetes and cardiovascular disease (2,5). Weight loss in humans has been associated with a reduction in ATM infiltration and levels of systemic inflammatory markers (6). There is also evidence that adipose tissue isolated from specific fat depots, such as visceral fat, may express higher levels of inflammatory markers such as IL-6 (7), MCP-1 (8), and plasminogen activator inhibitor type 1 (PAI-1) (9).For this report, we examined the association between abdominal fat compartments measured by computed tomography (CT) and markers of systemic inflammation in 382 subjects with type 2 diabetes who participated in the Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone (CHICAGO) study (10). To our knowledge, this is the largest cohort in which the relationship between adipose tissue distribution (using abdominal CT) and inflammation in subjects with type 2 diabetes has been examined. A recent study of mostly non-Hispanic whites with low prevalence of diabetes and cardiovascular disease showed that both visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) are associated with inflammatory markers, though the association for VAT was stronger (11). In this analysis, we determined whether adipose tissue distribution and specific adipose tissue depots remain important determinants of systemic inflammation in type 2 diabetes.     

Pericardial Adipose Tissue, Atherosclerosis, and Cardiovascular Disease Risk Factors: The Jackson Heart Study

OBJECTIVE

Pericardial adipose tissue (PAT), a regional fat depot that surrounds the heart, is associated with an unfavorable cardiometabolic risk factor profile. The associations among PAT, cardiometabolic risk factors, and coronary artery calcification (CAC) and abdominal aortic artery calcification (AAC) in African American populations have not been explored.

RESEARCH DESIGN AND METHODS

A total of 1,414 African Americans (35% men; mean ± SD age 58 ± 11 years) drawn from the Jackson Heart Study (JHS) underwent multidetector computed tomography assessment of abdominal visceral adipose tissue (VAT) and PAT between 2007 and 2009. Cardiometabolic risk factors, CAC, and AAC were examined in relation to increments of PAT and VAT.

RESULTS

PAT was significantly correlated with BMI, waist circumference, and VAT (r = 0.35, 0.46, and 0.69; all P < 0.0001). PAT (per 1-SD increase) was associated with elevated levels of systolic blood pressure (P < 0.04), fasting glucose, triglycerides, and C-reactive protein and lower levels of HDL (all P values<0.0001). PAT was also associated with metabolic syndrome (odds ratio [OR] 1.89; P < 0.0001), hypertension (1.48; P < 0.0006), and diabetes (1.40; P < 0.04); all associations were diminished after further adjustment for VAT (most P > 0.05). However, the association of PAT with CAC but not with AAC remained significant (OR 1.34 [95% CI 1.10–1.64]; P < 0.004) after multivariable and VAT adjustment.

CONCLUSIONS

PAT is significantly correlated with most cardiometabolic risk factors and CAC in the JHS cohort. The results suggest that PAT is an important VAT depot that may exert a local effect on the coronary vasculature.Pericardial adipose tissue (PAT) is an ectopic fat depot associated with measures of adiposity and metabolic risk factors and a predictor of coronary heart disease events (1–5). As a newly proposed marker of the visceral fat depot, PAT may exert a paracrine effect on nearby anatomic structures by actively secreting a number of proatherogenic and proinflammatory hormones, cytokines, and chemokines (1,6,7). However, the understanding of the relationship between the extra-abdominal visceral fat depot including PAT and cardiovascular disease (CVD) risk factors in nonwhite populations is lacking. In particular, African Americans have much higher rates of obesity and have experienced different levels of CVD risk in relation to obesity (8,9). Therefore, additional data are needed to clarify the role of PAT in relation to CVD in this population. Thus, to better understand the impact of obesity on metabolic risk factors in African Americans, the purpose of this study was to examine the associations of computed tomography (CT) measures of PAT with other measures of adiposity, such as BMI and abdominal visceral adipose tissue (VAT) as well as cardiometabolic risk factors.     

Abdominal Visceral Adiposity in the First Trimester Predicts Glucose Intolerance in Later Pregnancy

OBJECTIVE

To assess whether abdominal adiposity in early pregnancy is associated with a higher risk of glucose intolerance at a later gestational stage.

RESEARCH DESIGN AND METHODS

Subcutaneous and visceral fat was measured with ultrasonography at ∼12 weeks'' gestation. A 50-g glucose challenge test (GCT) was performed between 24 and 28 weeks'' gestation. The risk of having a positive GCT (≥7.8 mmol/l) was determined in association with subcutaneous and visceral adipose tissue depths above their respective upper-quartile values relative to their bottom three quartile values.

RESULTS

Sixty-two women underwent GCTs. A visceral adipose tissue depth above the upper quartile value was significantly associated with a positive GCT in later pregnancy (adjusted odds ratio 16.9 [95% CI 1.5–194.6]). No associations were seen for subcutaneous adipose tissue.

CONCLUSIONS

Measurement of visceral adipose tissue depth in early pregnancy may be associated with glucose intolerance later in pregnancy.Maternal obesity is associated with a higher risk of gestational diabetes mellitus (GDM) (1) and adverse perinatal outcomes (2,3). Visceral adiposity (4) may better predict the onset of type 2 diabetes, independent of BMI. Given that GDM and type 2 diabetes share the same risk factors (1) and GDM predates the onset of type 2 diabetes (5), it is logical to question whether high maternal visceral adiposity is associated with GDM.We determined the reliability of first-trimester ultrasonography for measuring subcutaneous and visceral adipose tissue in pregnancy and whether either is predictive of a positive glucose challenge test (GCT), which is commonly used to screen for GDM later in pregnancy.     

Visceral Fat Area and Markers of Insulin Resistance in Relation to Colorectal Neoplasia

OBJECTIVE

Although abdominal obesity and related metabolic abnormalities are hypothesized to promote colorectal carcinogenesis, direct confirmation of this effect is required. Here, we examined the relation of early-stage colorectal neoplasia to visceral fat area and markers of insulin resistance.

RESEARCH DESIGN AND METHODS

Subjects were participants in a comprehensive health screening conducted at the Hitachi Health Care Center, Ibaraki, Japan. During a 3-year period (2004–2007), a total of 108 patients with early-stage colorectal neoplasia, including 22 with early cancer, were identified among individuals who received both colorectal cancer screening and abdominal computed tomography scanning. Three control subjects matched to each case subject were randomly selected from those whose screening results were negative. Conditional logistic regression analysis was used to examine the association of measures of obesity and markers of insulin resistance with colorectal neoplasia, with adjustment for smoking and alcohol drinking.

RESULTS

Visceral fat area, but not subcutaneous fat area, was significantly positively associated with colorectal cancer, with odds ratios (95% CI) for the lowest to highest tertile of visceral fat area of 1 (reference), 2.17 (0.45–10.46), and 5.92 (1.22–28.65), respectively (P^trend = 0.02). Markers of insulin resistance, particularly fasting glucose, were also positively associated with colorectal cancer risk. In contrast, no associations were observed for colorectal adenomas.

CONCLUSIONS

These results suggest that visceral adipose tissue accumulation and insulin resistance may promote the development of early-stage cancer but not adenoma in the colorectum.Although the role of obesity as a strong predictor of various chronic diseases, including type 2 diabetes and cardiovascular disease, has been established, accumulating evidence also indicates the importance of obesity and its related metabolic disorders in the development of cancer (1). In Japan, the incidence of colorectal cancer has sharply increased over the last several decades and is now among the highest in the world (2). This time trend, as well as findings from migrant studies (3), suggests the involvement of environmental factors in colorectal carcinogenesis. Epidemiological studies (4,5) have shown that colorectal cancer risk is more strongly associated with waist circumference than with BMI, indicating the etiological importance of abdominal or visceral fat disposition, rather than overall adiposity. However, given that waist circumference is only a surrogate of visceral fat mass, more direct evidence is required before the link between visceral adiposity and cancer risk can be considered conclusive.Several studies have assessed the association between visceral fat area, as measured using computed tomography (CT) scanning, and colorectal neoplasia (6–10), but results have been mixed. For example, a Japanese study (7) demonstrated an increased prevalence of colorectal adenomas among individuals with higher visceral fat area, whereas a larger, more recent study (8) did not. Given that adenomatous polyps are common but only a minority progress to cancer (11), the association with cancer should also be explored, but evidence to date is sparse. In a Turkish study (10), patients with colorectal cancer tended to have a smaller rather than larger visceral fat area than that in control subjects. This unexpected finding may have been due to weight loss in the course of cancer development, however, a possibility that highlights the importance of assessing visceral fat before the diagnosis of cancer or development of symptoms.An insulin hypothesis has been proposed to explain the observed association between obesity or abdominal obesity and colorectal neoplasia (12,13). Accumulation of visceral fat is a strong determinant of insulin resistance and hyperinsulinemia (14) and, as experimental data show (15), insulin promotes colorectal carcinogenesis. Compatible with the insulin hypothesis, epidemiological data appear consistent in showing a positive association between colorectal neoplasia and markers of hyperinsulinemia or insulin resistance (rev. in 16). These findings notwithstanding, however, a role for insulin resistance in promoting the development of adenoma, cancer, or both in the colorectum has yet to be confirmed. To further explore these issues, we examined the relation of visceral fat mass assessed by CT and measures of insulin resistance to adenoma and cancer in the colorectum among asymptomatic individuals who underwent screening.     

Fat Distribution and Glucose Intolerance Among Greenland Inuit

OBJECTIVE

A high amount of subcutaneous fat is suggested to explain the observation of lower obesity-associated metabolic risk among Inuit than among Europeans. We examined the association between measures of obesity (visceral adipose tissue [VAT], subcutaneous adipose tissue [SAT], BMI, waist circumference [WC], and percentage of body fat) and the indices of glucose metabolism (fasting and 2-h glucose levels, insulin resistance per homeostasis model assessment [HOMA-IR], and the insulin sensitivity index [ISI_0,120]) among Greenland Inuit.

RESEARCH DESIGN AND METHODS

A total of 3,108 adult Inuit participated in a population-based study. The examination included a 75-g oral glucose tolerance test and anthropometric measurements. VAT and SAT were measured by ultrasound according to a validated protocol. Information on sociodemographic characteristics and health behaviors was obtained by interview.

RESULTS

Mean SATs were 1.8 and 3.5 cm in men and women, respectively. Mean VATs were 7.0 and 6.3 cm in men and women, respectively. The total prevalence of type 2 diabetes was 9%. Percentage of body fat generally was most strongly associated with all outcomes. Both SAT and VAT were significantly associated with glucose intolerance, fasting and 2-h plasma glucose levels, HOMA-IR, and ISI_0,120. VAT was more strongly associated with all outcomes than was SAT. After further adjustment for BMI or WC, VAT was associated with glucose intolerance and insulin resistance, whereas there was a trend toward a negative or no association with SAT.

CONCLUSIONS

High mean values of SAT may to a large extent explain the high WC in Inuit populations, and this is suggested to contribute to the lower observed metabolic risk for a given level of obesity.A growing body of evidence indicates that Inuit populations in the Arctic have high levels of obesity according to international guidelines for BMI and waist circumference (WC) (1–3). These populations are undergoing rapid social and health transitions, with the emergence of chronic diseases such as type 2 diabetes and ischemic heart disease (4,5). Among the Inuit, the mean levels of various cardiovascular risk factors increase with increasing levels of obesity, as they do in other populations. The metabolic impact of different levels of obesity, at least cross-sectionally, appears to be less pronounced among the Inuit than among Europeans, however, especially for indicators such as HDL cholesterol, triglycerides, blood pressure, and postprandial glucose and insulin levels (1,6). These population-specific differences in levels of cardiovascular risk factors presumably depend on interactions among environmental factors, lifestyle, and genetic factors that influence obesity and insulin sensitivity; however, an alternative explanation is that anthropometric measurements such as BMI, waist-to-hip ratio (WHR), and WC do not reflect the same amount of fat or the same pattern of fat distribution in different populations.Evidence is now emerging that particular patterns of abdominal fat distribution may confer increased metabolic risk. Specifically, excess visceral adipose tissue (VAT) is thought to be a marker of the relative inability of subcutaneous adipose tissue (SAT) to store more energy during continued positive caloric balance. Individuals who cannot store their energy surplus in the SAT would be characterized by accumulation of fat at undesired sites such as the liver, the heart, the skeletal muscle, and the pancreas (7–10).To elucidate the role of fat distribution in obesity-associated metabolic risk among Greenland Inuit, the overall aim of the current study was therefore to study the associations of ultrasound measures of fat distribution (visceral fat, subcutaneous fat, and the ratio of these two measures), anthropometric measurements (BMI, WC, and percentage of body fat [fat%]), and the following indices of glucose metabolism: type 2 diabetes, impaired fasting glycemia (IFG), impaired glucose tolerance (IGT), fasting and 2-h glucose values, insulin resistance per homeostasis model assessment (HOMA-IR), and the insulin sensitivity index (ISI_0,120).     

Long-Term Changes in Adiposity and Glycemic Control Are Associated With Past Adenovirus Infection

OBJECTIVE

Ad36, a human adenovirus, increases adiposity but improves glycemic control in animal models. Similarly, natural Ad36 infection is cross-sectionally associated with greater adiposity and better glycemic control in humans. This study compared longitudinal observations in indices of adiposity (BMI and body fat percentage) and glycemic control (fasting glucose and insulin) in Ad36-infected versus uninfected adults.

RESEARCH DESIGN AND METHODS

Baseline sera from Hispanic men and women (n = 1,400) were screened post hoc for the presence of Ad36-specific antibodies. Indices of adiposity and glycemic control at baseline and at ∼10 years past the baseline were compared between seropositive and seronegative subjects, with adjustment for age and sex. In addition to age and sex, indices of glycemic control were adjusted for baseline BMI and were analyzed only for nondiabetic subjects.

RESULTS

Seropositive subjects (14.5%) had greater adiposity at baseline, compared with seronegative subjects. Longitudinally, seropositive subjects showed greater adiposity indices but lower fasting insulin levels. Subgroup analyses revealed that Ad36-seropositivity was associated with better baseline glycemic control and lower fasting insulin levels over time in the normal-weight group (BMI ≤25 kg/m²) and longitudinally, with greater adiposity in the overweight (BMI 25–30 kg/m²) and obese (BMI >30 kg/m²) men. Statistically, the differences between seropositive and seronegative individuals were modest in light of the multiple tests performed.

CONCLUSIONS

This study strengthens the plausibility that in humans, Ad36 increases adiposity and attenuates deterioration of glycemic control. Panoptically, the study raises the possibility that certain infections may modulate obesity or diabetes risk. A comprehensive understanding of these under-recognized factors is needed to effectively combat such metabolic disorders.A deeper understanding of the factors that modulate adiposity or glycemic control may aid in the development of more effective treatment and prevention strategies for combating obesity or diabetes. Although the contribution of various behavioral and physiological risk factors for obesity or diabetes is extensively investigated, that of several putative factors remains under-investigated (1). Ad36, a human adenovirus, is one such putative factor originally described for its adipogenic property (2). Subsequent data indicated that Ad36 is likely to modulate both adiposity and glycemic control. In various animal models, experimental Ad36 infection significantly increases adiposity (3–7) and yet, seemingly paradoxically, improves glycemic control (6,7). In vitro and ex vivo mechanistic studies indicate that Ad36 expands adipose tissue by recruiting adipocyte progenitors and increasing their commitment, differentiation, and lipid accumulation (8–12). In agreement with these findings, fat cells of humans harboring Ad36 DNA in adipose tissue have greater adipogenic ability compared with fat cells of those without Ad36 DNA (10). In addition, Ad36 increases cellular glucose uptake in adipose tissue and skeletal (13,14), reduces hepatic lipid accumulation and glucose release from hepatocytes (7,15), and upregulates adiponectin, an insulin-sensitizing adipocytokine (7,16), which may collectively contribute to systemic glycemic control improved by Ad36 (6,7). An improvement in glycemic control via the expansion of adipose tissue has been recently documented in several animal models (17–19) and has been suggested in humans receiving some antidiabetic agents (20). Similarly, Ad36 may mediate its effect on glycemic control by increasing adiposity.In humans, Ad36 infection is prevalent globally (21), with a prevalence of ∼15% in United States adults (7,22). Because of the substantial prevalence, if Ad36 influences adiposity or glycemic control in humans, then the potential impact could be considerable. However, ethical considerations preclude experimental infection of humans to determine a causal role of Ad36 in modulating adiposity or glycemic control. Several cross-sectional studies show that natural Ad36 infection in humans is associated with greater adiposity but better glycemic control. Association of Ad36 infection with greater BMI or greater prevalence of obesity is reported in adults from the United States (22), Italy (23), and Korea (24), and in children from the United States (25) and Korea (26,27). Ad36 infected human twins are significantly heavier compared with their uninfected counterparts (22). However, two studies did not find an association of Ad36 with obesity in military recruits or Scandinavian subjects (2). In four cohorts totaling >1,500 white, black, and Hispanic men, women, and children from the United States, Ad36 infection significantly predicted better indices of glycemic control that were independent of race, sex, age, and adiposity (7). Other smaller studies also showed significantly lower HbA1c levels and higher adiponectin in Ad36-infected adults (13,16). In addition, Ad36 infection is associated with lower hepatic lipid levels in United States and Italian adults and children (7,28).Similar to the phenotype induced by Ad36 in experimentally infected animals, overall human cross-sectional studies show an association of Ad36 infection with greater adiposity, better glycemic control, and lower hepatic lipid levels. This congruence of data from animal and human studies supports a similar role for Ad36 in humans. However, causality cannot be established unequivocally because of the observational nature of these studies. A prospective approach could help elucidate the long-term association of Ad36 infection with adiposity and glycemic control within a person over time, and could markedly strengthen causal inferences by assessing temporality. Such determination may advance our understanding of multifactorial nature of obesity or diabetes, and may lead to novel prevention or treatment strategies.This study screened baseline serum samples of Hispanic adults enrolled in San Antonio Family Heart Study for a history of natural Ad36 infection, as indicated by neutralizing antibodies. Data on obesity and glycemic control were collected for ∼10 years past baseline, which allowed the comparison of changes in indices of adiposity (BMI and body fat percentage) and glycemic control (fasting glucose and insulin) in Ad36-seropositive vs. Ad36-seronegative individuals.     

TRAF-interacting Protein (TRIP): A Novel Component of the Tumor Necrosis Factor Receptor (TNFR)- and CD30-TRAF Signaling Complexes That Inhibits TRAF2-mediated NF-κB Activation

Through their interaction with the TNF receptor–associated factor (TRAF) family, members of the tumor necrosis factor receptor (TNFR) superfamily elicit a wide range of biological effects including differentiation, proliferation, activation, or cell death. We have identified and characterized a novel component of the receptor–TRAF signaling complex, designated TRIP (TRAF-interacting protein), which contains a RING finger motif and an extended coiled-coil domain. TRIP associates with the TNFR2 or CD30 signaling complex through its interaction with TRAF proteins. When associated, TRIP inhibits the TRAF2-mediated NF-κB activation that is required for cell activation and also for protection against apoptosis. Thus, TRIP acts as a receptor–proximal regulator that may influence signals responsible for cell activation/proliferation and cell death induced by members of the TNFR superfamily.Members of the TNF receptor (TNFR)¹ superfamily play important roles in the induction of diverse signals leading to cell growth, activation, and apoptosis (1). Whether the signals induced by a given receptor leads to cell activation or death is, however, highly cell-type specific and tightly regulated during differentiation of cells. For example, the TNFRs can exert costimulatory signals for proliferation of naive lymphocytes but also induce death signals required for deletion of activated T lymphocytes (1). The cytoplasmic domains of these receptors lack intrinsic catalytic activity and also exhibit no significant homology to each other or to other known proteins. Exceptions to this include Fas(CD95) and TNFR1 that share a significant homology within an 80–amino acid region of their cytoplasmic tails (called the “death domain”; 2, 3). Therefore, it is suggested that the TNFR family members can initiate different signal transduction pathways by recruiting different types of intracellular signal transducers to the receptor complex (1).Indeed, several types of intracellular signal transducers have been identified that initiate distinct signal transduction pathways when recruited to the members of TNFR superfamily (4–19). Recent biochemical and molecular studies showed that a class of signal-transducing molecules are recruited to Fas(CD95) or TNFR1 via interaction of the death domains (2, 3, 6, 12, 17, 20). For example, Fas(CD95) and TNFR1 recruit FADD(MORT1)/RIP or TRADD/FADD (MORT1)/RIP through the interactions of their respective death domains (2, 3, 6, 12, 17, 20, 21). Clustering of these signal transducers leads to the recruitment of FLICE/ MACH, and subsequently, to cell death (13, 14).The TNFR family members can also recruit a second class of signal transducers called TRAFs (TNFR-associated factor), some of which are responsible for the activation of NF-κB or JNK (9, 20, 22). TRAF proteins were identified by their biochemical ability to interact with TNFR2, CD40, CD30, or LT-βR (4, 5, 10, 11, 15, 23–27). These receptors interact directly with TRAFs via a short stretch of amino acids within their cytoplasmic tails, but do not interact with the death domain containing proteins (4, 5, 15, 24–27). To date, five members of the TRAF family have been identified as signaling components of the TNFR family members. All TRAF members contain a conserved TRAF domain, ∼230 amino acids in length, that is used for either homo- or heterooligomerization among the TRAF family, for interactions with the cytoplasmic regions of the TNFR superfamily, or for interactions with downstream signal transducers (4, 5, 8, 10, 11, 19, 23–25, 28). In addition to the TRAF domain, most of the TRAF family members contain an NH₂-terminal RING finger and several zinc finger structures, which appear to be important for their effector functions (4, 5, 10, 11, 23–25).Several effector functions of TRAFs were revealed by recent experiments based on a transfection system. TRAF2, first identified by its interaction with TNFR2 (4), was subsequently shown to mediate NF-κB activation induced by two TNF receptors, CD40 and CD30 (9, 28–30). TRAF5 was also implicated in NF-κB activation mediated by LTβR (10), whereas TRAF3 (also known as CRAF1, CD40bp, or LAP1; references 5, 11, 24, and 25) was shown to be involved in the regulation of CD40-mediated CD23 upregulation in B cells (5). The role of other TRAF members in the TNFR family–mediated signal transduction is not clear. They may possess some effector functions as yet to be revealed, or work as adapter proteins to recruit different downstream signal transducers to the receptor complex. For example, TRAF1 is required for the recruitment of members of the cellular inhibitor of apoptosis protein (c-IAP) family to the TNFR2-signaling complex (7). In addition to the signal transduction by the TNFR family members, TRAFs may regulate other receptor-mediated signaling pathways. For example, TRAF6 is a component of IL-1 receptor (IL1R)–signaling complex, in which it mediates the activation of NF-κB by IL-1R (31). Since TRAFs form homo- or heterooligomers, it is suggested that the repertoire of TRAF members in a given cell type may differentially affect the intracellular signals triggered by these receptors. This may be accomplished by the selective interaction of TRAFs with a specific set of downstream signal transducers. Although many aspects of TRAF-mediated effector functions leading to cellular activation have been defined, it needs to be determined whether TRAF proteins will also mediate the apoptotic signals induced by the “death-domain-less” members of the TNFR superfamily (1, 27, 32–36).Here we report the isolation and characterization of a novel component of the TNFR superfamily/TRAFs signaling complex, named TRIP (TRAF-interacting protein). TRIP associates with the receptor/TRAF signaling complex, and inhibits the TRAF2-mediated NF-κB activation. Biochemical studies indicate that TRIP associates with the TNFR2 or CD30 receptor complex via its interaction with TRAF proteins, suggesting a model which can explain why the ligation of these receptors can promote different cell fates: proliferation or death.     

A New Mechanism of NK Cell Cytotoxicity Activation: The CD40–CD40 Ligand Interaction

NK recognition is regulated by a delicate balance between positive signals initiating their effector functions, and inhibitory signals preventing them from proceeding to cytolysis. Knowledge of the molecules responsible for positive signaling in NK cells is currently limited. We demonstrate that IL-2–activated human NK cells can express CD40 ligand (CD40L) and that recognition of CD40 on target cells can provide an activation pathway for such human NK cells. CD40-transfected P815 cells were killed by NK cell lines expressing CD40L, clones and PBLderived NK cells cultured for 18 h in the presence of IL-2, but not by CD40L-negative fresh NK cells. Cross-linking of CD40L on IL-2–activated NK cells induced redirected cytolysis of CD40-negative but Fc receptor-expressing P815 cells. The sensitivity of human TAP-deficient T2 cells could be blocked by anti-CD40 antibodies as well as by reconstitution of TAP/MHC class I expression, indicating that the CD40-dependent pathway for NK activation can be downregulated, at least in part, by MHC class I molecules on the target cells. NK cell recognition of CD40 may be important in immunoregulation as well as in immune responses against B cell malignancies.NK cells represent a distinct lineage of lymphocytes that are able to kill a variety of tumor (1), virus-infected (2), bone marrow transplanted (3), and allogeneic target cells (4). NK cells do not express T cell receptors or immunoglobulins and are apparently normal in mice with defects in the recombinase machinery (5, 6).Our knowledge about NK cell specificity has increased considerably in the last years. NK cells can probably interact with target cells by a variety of different cell surface molecules, some involved in cell adhesion, some activating the NK cytolytic program (7, 8), and other ones able to inhibit this activation by negative signaling (as reviewed in reference 9).A common feature of several inhibitory NK receptors is the capability to bind MHC class I molecules (10, 11), as predicted by the effector inhibition model within the missing self hypothesis of recognition by NK cells (12–14). Interestingly, the MHC class I receptors identified so far belong to different gene families in mouse and man; these are the p58/p70/NKAT or killer cell inhibitory receptors (KIR)¹ of the immunoglobulin superfamily in man and the Ly49 receptors of the C-type lectin family in the mouse. There is also evidence that MHC class I molecules can be recognized as triggering signals in NK cells of humans, rats as well as mice (13). The inhibitory receptors allow NK cells to kill tumor or normal cell targets with deficient MHC class I expression (12, 14). This does not exclude that other activating pathways can override inhibition by MHC class I molecules (15) and, even in their absence, there must be some activating target molecules that initiate the cytolytic program. Several surface molecules are able to mediate positive signals in NK cells. Some of these structures, like NKRP1 (16), CD69 (17), and NKG2 (18) map to the NK complex region (NKC) of chromosome 6 in mice and of chromosome 12 in humans (13). CD2 (19) and CD16 (20) molecules can also play a role in the activation pathway.NK cells resemble T cells in many respects, both may arise from an immediate common progenitor (21, 22), and share the expression of several surface molecules (23). NK cells produce cytokines resembling those secreted by some helper T cell subsets (24) and contain CD3 components in the cytoplasm (21). The expression of some surface structures, involved in TCR-dependent T cell costimulation, like CD28 in human (25), has been described on NK cells, but the functional relevance of these molecules for NK activation processes has not been fully established.Another T cell molecule of interest is CD40L, which interacts with CD40, a 50-kD membrane glycoprotein expressed on B cells (26), dendritic cells (27), and monocytes (28). CD40 is a member of the tumor necrosis factor/nerve growth factor receptor family (29) which includes CD27 (30), CD30 (31), and FAS antigen (32). Murine and human forms of CD40L had been cloned and found to be membrane glycoproteins with a molecular mass of ∼39 kD induced on T cells after activation (33). Also mast cells (34), eosinophils (35), and B cells (36) can be induced to express a functional CD40L. The CD40L–CD40 interaction has been demonstrated to be necessary for T cell–dependent B cell activation (33, 37). Mutations in the CD40L molecule cause a hyper-IgM immunodeficiency condition in man (38, 39, 40). On the other hand, CD40–CD40L interactions also orchestrate the response of regulatory T cells during both their development (41, 42) and their encounter with antigen (43, 44).NK cells have also been suggested to play a role in B cell differentiation and immunoglobulin production (45). Therefore, it was of interest to investigate whether NK cells could use a CD40-dependent pathway in their interactions with other cells. Therefore, we have investigated the ability of target cells expressing CD40 to induce activation of NK cytotoxicity.     

Intima-Media Thickness in Severe Obesity: Links with BMI and metabolic status but not with systemic or adipose tissue inflammation

OBJECTIVE

Obesity is associated with cardiovascular risk and a low-grade inflammatory state in both blood and adipose tissue (AT). Whether inflammation contributes to vascular alteration remains an open question. To test this hypothesis, we measured arterial intima-media thickness (IMT), which reflects subclinical atherosclerosis, in severely obese subjects and explored associations with systemic inflammation and AT inflammation.

RESEARCH DESIGN AND METHODS

IMT of the carotid artery (C-IMT) and IMT of the femoral artery (F-IMT) were measured in 132 nonobese (control) subjects (BMI 22.3 kg/m²; mean age 44.8 years) and 232 subjects who were severely obese without diabetes (OB/ND; n = 146; BMI 48.3 kg/m²; age 38.2 years) or severely obese with type 2 diabetes (OB/D; n = 86; BMI 47.0; age 49.4 years). In 57 OB/ND subjects, circulating soluble E-selectin, matrix metalloproteinase 9, myeloperoxidase, soluble intracellular adhesion molecule 1, soluble vascular cell adhesion molecule 1, tissue plasminogen activator inhibitor 1, cystatin C, cathepsin S, and soluble CD14 were measured in serum. AT macrophages were quantified by CD68 immunochemistry.

RESULTS

Both C-IMT and F-IMT increased in OB/ND and OB/D patients. In OB/ND patients, age was the sole independent determinant of IMT. No significant association was found with circulating inflammation-related molecules, number of CD68⁺ cells, or the presence of crown-like structures in visceral or subcutaneous AT of OB/ND patients.

CONCLUSIONS

IMT increased with severe obesity but was not influenced by the degree of systemic inflammation or AT macrophage accumulation.Obesity is well-recognized as a major risk factor for the development of metabolic disorders and cardiovascular disease (CVD), such as heart failure, myocardial infarction, and stroke (1–4). Two recent studies have identified an increased risk of cardiovascular events in subjects with extreme BMI (4,5), and the number of these subjects is increasing rapidly (6,7). As shown in the Prospective Studies Collaboration (4), cardiovascular risk factors (CV-RFs) increase with BMI. In a French study conducted using the general population (6), the proportion of subjects treated for three CV-RFs (dyslipidemia, diabetes, and hypertension) was 14-fold higher for obese subjects compared with subjects of normal weight. In addition to BMI, altered body-fat distribution and ectopic fat deposition are strongly associated with mortality and morbidity attributable to CVD (8,9). It is well-established that visceral fat accumulation is associated with CV-RFs, such as hypertension, hypertriglyceridemia, or low HDL cholesterol (HDL-c), and with insulin resistance, type 2 diabetes, prothrombotic and proinflammatory states, sleep apnea, and cardiac hypertrophy, which can have potentially deleterious effects on the cardiovascular system.Although the association between obesity and increased CV-RFs is recognized, the pathophysiological pathways that link expansion of fat mass (FM) to atherosclerosis are less clearly established. Growing evidence attributes a major role to the altered biology of adipose tissue (AT) as a cause of comorbidities in obesity. Part of the systemic inflammation that characterizes obesity originates from AT, where inflammatory cells, mainly macrophages, accumulate and create local inflammation (10,11). Adipose-derived inflammatory factors produced by enlarged adipocytes or AT macrophages (or both) are often increased in the serum of obese subjects and thought to contribute to the metabolic complications of obesity, including insulin resistance and liver disease (12). In this context, it is tempting to hypothesize that products released by AT impinge on vascular cells to promote the development of atherosclerotic lesions in obesity. In line with this hypothesis, recent studies of humans report a positive association between AT inflammation, as assessed by the presence of macrophages in crown-like structures (CLS), and endothelial dysfunction, as evaluated by brachial artery flow-mediated dilatation in obese subjects (13,14).The measure of intima-media thickness (IMT) is a noninvasive marker for subclinical atherosclerosis and provides a reliable and predictive value for later cardiovascular events (15–17). Previous studies of humans have shown correlations between BMI and increased IMT (18–22). However, only one previous study (23) has investigated IMT in morbidly obese subjects and only in a limited sample.The objectives of our study were to describe the relationships between obesity-related phenotypes and IMT values at two arterial sites in a large group of massively obese subjects and to assess the potential links between systemic inflammation and AT inflammation.     

Associations of Visceral and Subcutaneous Fat Areas With the Prevalence of Metabolic Risk Factor Clustering in 6,292 Japanese Individuals: The Hitachi Health Study

OBJECTIVE

We examined the relationships of visceral fat area (VFA), subcutaneous fat area, and waist circumference, determined using computed tomography (CT), and BMI with metabolic risk factors in a large Japanese population.

RESEARCH DESIGN AND METHODS

Study subjects comprised 6,292 men and women who participated in the Hitachi Health Study and received CT examinations in 2007 and 2008.

RESULTS

Regarding the clustering of metabolic risk factors, the odds ratios (ORs) for the VFA quintiles were 1.0 (ref.), 2.4, 3.4, 5.0, and 9.7 for men and 1.0 (ref.), 1.5, 2.6, 4.6, and 10.0 for women (P < 0.001 for trends in both sexes). For the highest quintiles, the OR for VFA was 1.5 to 2 times higher than those of the other anthropometric indexes in both sexes.

CONCLUSIONS

We demonstrated a superior performance of VFA to predict the clustering of metabolic risk factors compared with other anthropometric indexes.Metabolic syndrome (MS) has been growing globally with the clusters of obesity, high blood pressure, impaired lipid metabolism, and hyperglycemia. Individuals with MS have a higher risk of cardiovascular disease and a subsequent increase in disease mortality or morbidity (1–3). For the diagnosis of MS, waist circumference (WC) is almost always used as one of the criteria, and this measure is typically used as a simplified measure of the visceral fat area (VFA) (4–7). Visceral fat is regarded as an endocrine organ that secretes adipocytokines and other vasoactive substances that can influence the risk of developing traits of MS (8). A few studies have shown the impact of visceral fat on MS and its components in large-scale epidemiological research efforts (9). The present study analyzed the epidemiological impact of VFA compared with that of subcutaneous fat area (SFA), WC, and BMI against the clustering of metabolic risk factors and its components.     

The Relative Contribution of Prepregnancy Overweight and Obesity,Gestational Weight Gain,and IADPSG-Defined Gestational Diabetes Mellitus to Fetal Overgrowth

OBJECTIVE

The International Association of Diabetes in Pregnancy Study Groups (IADPSG) criteria for diagnosis of gestational diabetes mellitus (GDM) identifies women and infants at risk for adverse outcomes, which are also strongly associated with maternal overweight, obesity, and excess gestational weight gain.

RESEARCH DESIGN AND METHODS

We conducted a retrospective study of 9,835 women who delivered at ≥20 weeks’ gestation; had a prenatal, 2-h, 75-g oral glucose tolerance test; and were not treated with diet, exercise, or antidiabetic medications during pregnancy. Women were classified as having GDM based on IADPSG criteria and were categorized into six mutually exclusive prepregnancy BMI/GDM groups: normal weight ± GDM, overweight ± GDM, and obese ± GDM.

RESULTS

Overall, 5,851 (59.5%) women were overweight or obese and 1,892 (19.2%) had GDM. Of those with GDM, 1,443 (76.3%) were overweight or obese. The prevalence of large-for-gestational-age (LGA) infants was significantly higher for overweight and obese women without GDM compared with their normal-weight counterparts. Among women without GDM, 21.6% of LGA infants were attributable to maternal overweight and obesity, and the combination of being overweight or obese and having GDM accounted for 23.3% of LGA infants. Increasing gestational weight gain was associated with a higher prevalence of LGA in all groups.

CONCLUSIONS

Prepregnancy overweight and obesity account for a high proportion of LGA, even in the absence of GDM. Interventions that focus on maternal overweight/obesity and gestational weight gain, regardless of GDM status, have the potential to reach far more women at risk for having an LGA infant.Both International Association of Diabetes in Pregnancy Study Groups (IADPSG)–defined gestational diabetes mellitus (GDM) (1,2) and maternal overweight and obesity (2–4) are associated with increased risk for adverse maternal and perinatal outcomes, such as fetal overgrowth, shoulder dystocia and birth injury, pre-eclampsia, and preterm delivery. Although most studies addressing the effects of maternal BMI on adverse outcomes include women with GDM (2–6), a few have reported these associations in overweight or obese women with normal glucose tolerance (7–9). Scant data exist that demonstrate associations between GDM and adverse outcomes in the absence of overweight or obesity (9).Although it is currently estimated that 10–25% of pregnant women develop GDM by IADPSG criteria (1,2,10), 50–60% of women are overweight or obese at the start of their pregnancies (6,7,11,12). Prepregnancy overweight and obesity are also associated with GDM development, as 65–75% of women with GDM are also overweight or obese (11,13). As such, the relative impact of prepregnancy BMI and maternal glycemia during pregnancy on adverse maternal and perinatal outcomes is difficult to tease apart. Moreover, excess gestational weight gain complicates a large number of pregnancies and is highly correlated with maternal overweight and obesity, as well as the development of GDM (14–16). Despite the fact that studies have reported increases in the risk of adverse outcomes with increasing gestational weight gain (13,15–18), many studies examining the effects of maternal obesity and/or glucose levels have not accounted for this important factor.The purpose of this study was to examine the effects of prepregnancy overweight and obesity among women with and without IADPSG-defined GDM on clinically important adverse outcomes, focusing primarily on fetal overgrowth, one of the most prevalent adverse conditions associated with maternal and neonatal morbidity. In addition to magnitude of association, we determine the proportion of large-for-gestational-age (LGA) infants attributable to each risk factor and combinations thereof. We also examine the relative contribution of increasing gestational weight gain to the development of LGA.     

Inflammatory genes in epicardial fat contiguous with coronary atherosclerosis in the metabolic syndrome and type 2 diabetes: changes associated with pioglitazone

OBJECTIVE

To determine changes in gene expression in epicardial adipose tissue (EAT) associated with coronary atherosclerosis (CAD) and effects of pioglitazone therapy.

RESEARCH DESIGN AND METHODS

Genes were quantified by RT-PCR in EAT and thoracic subcutaneous adipose tissue (SAT) obtained during surgery in CAD patients with metabolic syndrome (MS) or type 2 diabetes and control subjects with minimal or no CAD and no MS or type 2 diabetes.

RESULTS

Increased expression of interleukin-1 receptor antagonist (IL-1Ra) and IL-10, a trend for higher IL-1β, and no change in peroxisome proliferator–activated receptor-γ (PPARγ) was found in EAT from MS or type 2 diabetes. Only PPARγ mRNA was reduced in SAT. Pioglitazone therapy in type 2 diabetes was associated with decreased expression of IL-1β, IL-1Ra, and IL-10 in EAT; decreased IL-10 in SAT; and increased PPARγ in SAT.

CONCLUSIONS

In MS and type 2 diabetes with CAD, proinflammatory and anti-inflammatory genes were differentially increased in EAT and selectively reduced in association with pioglitazone treatment.In patients with multiple risk factors for coronary atherosclerosis (CAD), including type 2 diabetes, interleukin (IL)-1β and other proinflammatory genes and proteins are higher in epicardial adipose tissue (EAT) than subcutaneous adipose tissue (SAT) from the same patients (1) or EAT from patients without CAD (2), whereas anti-inflammatory IL-10 is increased (2) and anti-inflammatory adiponectin is reduced (3).The relative expression of pro- and anti-inflammatory mediators may determine whether EAT contributes in a harmful or protective paracrine manner to CAD (4), which might be therapeutically relevant (5).IL-1β is secreted by classically activated M1 macrophages, whereas anti-inflammatory IL-1 receptor antagonist (IL-1Ra) and IL-10 are secreted by resident M2 or “alternatively activated” macrophages (6). IL-1Ra inhibits binding of IL-1β to and activation of its target cell receptor (7). IL-1Ra was identified in human visceral abdominal fat (VAT) and SAT by Juge-Aubry et al. (8). The balance between IL-1β and IL-1Ra (the IL-1Ra:IL-1β ratio) is considered to determine the severity of the chronic inflammatory disease (7), of which CAD is an example. Murine IL-1Ra gene knockout (9) and human IL-1Ra gene association studies (10) indicate an important role for IL-1Ra in atherosclerosis. To our knowledge, IL1-Ra has not been reported in EAT. The peroxisome proliferator–activated receptor-γ (PPARγ) mediates the anti-inflammatory action of thiazolidinediones in macrophages (6).Our objectives were to determine inflammatory gene expression in EAT contiguous with CAD in patients with metabolic syndrome (MS) and type 2 diabetes and changes associated with pioglitazone therapy.     

Insulin Clearance and the Incidence of Type 2 Diabetes in Hispanics and African Americans: The IRAS Family Study

OBJECTIVE

We aimed to identify factors that are independently associated with the metabolic clearance rate of insulin (MCRI) and to examine the association of MCRI with incident type 2 diabetes in nondiabetic Hispanics and African Americans.

RESEARCH DESIGN AND METHODS

We investigated 1,116 participants in the Insulin Resistance Atherosclerosis Study (IRAS) Family Study with baseline examinations from 2000 to 2002 and follow-up examinations from 2005 to 2006. Insulin sensitivity (S_I), acute insulin response (AIR), and MCRI were determined at baseline from frequently sampled intravenous glucose tolerance tests. MCRI was calculated as the ratio of the insulin dose over the incremental area under the curve of insulin. Incident diabetes was defined as fasting glucose ≥126 mg/dL or antidiabetic medication use by self-report.

RESULTS

We observed that S_I and HDL cholesterol were independent positive correlates of MCRI, whereas fasting insulin, fasting glucose, subcutaneous adipose tissue, visceral adipose tissue, and AIR were independent negative correlates (all P < 0.05) at baseline. After 5 years of follow-up, 71 (6.4%) participants developed type 2 diabetes. Lower MCRI was associated with a higher risk of incident diabetes after adjusting for demographics, lifestyle factors, HDL cholesterol, indexes of obesity and adiposity, and insulin secretion (odds ratio 2.01 [95% CI 1.30–3.10], P = 0.0064, per one-SD decrease in log_e-transformed MCRI).

CONCLUSIONS

Our data showed that lower MCRI predicts the incidence of type 2 diabetes.Insulin clearance is an integral component of insulin metabolism, as it regulates the cellular response to the hormone by decreasing insulin availability and mediates certain aspects of insulin action (1). The liver is the primary site of insulin clearance. Approximately 80% of endogenous insulin is removed by the liver, and the remainder is cleared by the kidneys and muscles (2). Clearance rates for insulin decrease in glucose intolerance (3), obesity (4), in particular abdominal obesity (5), hypertension (6), hepatic cirrhosis (7), and nonalcoholic fatty liver disease (8).Although the plasma concentration of insulin is largely determined by its rate of secretion and clearance, existing evidence suggests that increased insulin resistance is associated with reduced insulin clearance (9–12). Reduced insulin clearance has important physiological functions; for example, animal models have shown that decreased insulin clearance serves as a compensatory mechanism to preserve β-cell function and to maintain peripheral insulin levels in the states of insulin resistance (13,14). In addition, insulin clearance has been found to be a highly heritable trait in Mexican Americans, and specific haplotypes in the AMPD1 gene were associated with variation in insulin clearance (15).Despite its potential role in the etiology of diabetes, little is known about the factors that are independently associated with decreased insulin clearance. In addition, no previous study has investigated whether decreased insulin clearance predicts the risk of type 2 diabetes. In this study, we aimed to identify demographic and metabolic factors that are independently associated with the metabolic clearance rate of insulin (MCRI), and to examine its association with the 5-year risk of incident type 2 diabetes, using the data from a large, well-characterized cohort of Hispanics and African Americans with direct measurements of insulin metabolism (secretion, sensitivity, and clearance) and adipose tissue (visceral and subcutaneous) in the Insulin Resistance Atherosclerosis Study (IRAS) Family Study.     

Plasma Lipopolysaccharide Is Closely Associated With Glycemic Control and Abdominal Obesity: Evidence from bariatric surgery

OBJECTIVE

It is of vital importance to elucidate the triggering factors of obesity and type 2 diabetes to improve patient care. Bariatric surgery has been shown to prevent and even cure diabetes, but the mechanism is unknown. Elevated levels of lipopolysaccharide (LPS) predict incident diabetes, but the sources of LPS are not clarified. The objective of the current study was to evaluate the potential impact of plasma LPS on abdominal obesity and glycemic control in subjects undergoing bariatric surgery.

RESEARCH DESIGN AND METHODS

This was a prospective observational study involving a consecutive sample of 49 obese subjects undergoing bariatric surgery and 17 controls. Main assessments were plasma LPS, HbA_1c, adipose tissue volumes (computed tomography), and quantified bacterial DNA in adipose tissue compartments.

RESULTS

Plasma levels of LPS were elevated in obese individuals compared with controls (P < 0.001) and were reduced after bariatric surgery (P = 0.010). LPS levels were closely correlated with HbA_1c (r = 0.56; P = 0.001) and intra-abdominal fat volumes (r = 0.61; P < 0.001), but only moderately correlated with subcutaneous fat volumes (r = 0.33; P = 0.038). Moreover, there was a decreasing gradient (twofold) in bacterial DNA levels going from mesenteric via omental to subcutaneous adipose tissue compartments (P = 0.041). Finally, reduced LPS levels after bariatric surgery were directly correlated with a reduction in HbA_1c (r = 0.85; P < 0.001).

CONCLUSIONS

Our findings support a hypothesis of translocated gut bacteria as a potential trigger of obesity and diabetes, and suggest that the antidiabetic effects of bariatric surgery might be mechanistically linked to, and even the result of, a reduction in plasma levels of LPS.Obesity and type 2 diabetes are rapidly emerging as major public health problems worldwide. This growing pandemic is often associated with other prevalent diseases, such as insulin resistance, metabolic syndrome, and cardiovascular disease, which are disease states that are potentially linked to chronic low-grade inflammation (1). Obesity per se facilitates a proinflammatory state, characterized by increased levels of proinflammatory cytokines, and it has been proposed that adipose tissue, particularly intra-abdominal adipose tissue, might be a major source of inflammation (2,3). However, the triggering factors of adipose tissue inflammation, obesity, and type 2 diabetes remain to be determined.Interestingly, mesenteric fat, which is localized in close proximity to the gut wall, in mice has been shown to express higher levels of proinflammatory chemokines than other types of adipose tissue (4). The gut flora or microbiota contains 10-fold the number of cells and 150-times the number of genes compared with the human body and is currently being characterized in the Human Microbiome Project and in the MetaHIT program (5). An altered gut microbiota has been linked to several chronic disease states, including obesity (6) and type 2 diabetes (7).Translocation of gut microbiota, particularly endotoxins or lipopolysaccharides (LPSs) on the surface of gram-negative bacteria to the systemic circulation, has been proposed to be an early trigger of inflammation and obesity (8). Endotoxins normally circulate at low levels in healthy individuals (9), and 80–97% of circulating endotoxin is bound to lipoproteins (10). LPS promotes inflammation mainly by signaling through Toll-like receptor (TLR) 4 on macrophages, monocytes, and other cells of the innate immune system, and CD14 plays a central role by transferring LPS to the TLR4 complex (11).An increase in plasma LPS occurs in healthy individuals after a high-fat meal (12), whereas a chronic state of low-grade endotoxemia as measured by plasma LPS (8) or LPS-binding protein (13) is evident in patients with obesity and insulin resistance. Furthermore, low-grade endotoxemia predicts incident diabetes, but the sources of LPS are unknown because LPS can translocate both from the oral cavity and the gut (14). Interestingly, in a mouse model, commensal gut bacteria translocate to mesenteric adipose tissue, initiating low-grade inflammation before the onset of insulin resistance and type 2 diabetes (15). To our knowledge, these mechanisms have not been studied in humans.Bariatric surgery has been shown to prevent and potentially cure diabetes (16–18), but the mechanism is unknown. We hypothesized that adipose tissue in proximity to the gut would have a relatively higher quantity of bacterial DNA than other types of adipose tissue, that circulating plasma LPS would be associated with the amount of intra-abdominal adipose tissue and HbA_1c, and that a reduction of LPS after bariatric surgery would correlate with improved glycemic control.