Association of built environment characteristics with adiposity and glycaemic measures.

OBJECTIVE: This study examined the cross-sectional and longitudinal relationships of built environment characteristics with adiposity and glycaemic measures. METHOD: Longitudinal study sample consisted of 4,010 Framingham Heart Study Offspring (baseline: 1998-2001; follow-up: 2005-2008) and Generation Three (baseline: 2002-2005; follow-up: 2008-2011) participants (54.8% women, baseline mean age 48.6 years). Built environment characteristics (intersection density, greenspace, recreation land and food stores) at baseline were collected. Adiposity and glycaemic measures (body mass index [BMI], waist circumference, abdominal subcutaneous and visceral adipose tissue, and fasting plasma glucose) at baseline and changes during 6.4-year follow-up were measured. RESULTS: In cross-sectional models, higher intersection density and food store density (total food stores, fast food restaurants and supermarkets) were linearly associated with higher BMI (all p < 0.05). Higher greenspace was associated with lower BMI, waist circumference, fasting plasma glucose, prevalent obesity and prevalent diabetes (all p < 0.05). Longitudinally, higher intersection density and food store density, and lower greenspace were associated with smaller increases in abdominal visceral adipose tissue (all p < 0.05). Higher densities of intersections, fast food restaurants and supermarkets were associated with smaller increases in fasting plasma glucose (all p < 0.05). CONCLUSIONS: Collectively, built environment characteristics are associated with adiposity and glycaemic traits, suggesting the potential mechanisms by which built environment influences cardiometabolic health.

Longitudinal association between dairy consumption and changes of body weight and waist circumference: the Framingham Heart Study.

BACKGROUND: Dairy foods are nutrient dense and may be protective against long-term weight gain. OBJECTIVE: We aimed to examine the longitudinal association between dairy consumption and annualized changes in weight and waist circumference (WC) in adults. METHODS: Members of the Framingham Heart Study Offspring Cohort who participated in the fifth through eighth study examinations (1991-2008) were included in these analyses (3440 participants with 11 683 observations). At each exam, dietary intake was assessed by a validated food frequency questionnaire, and weight and WC were assessed following standardized procedures. Repeated measures models were used for the longitudinal analyses of annualized weight and waist circumference changes, adjusting for time-varying or invariant covariates. RESULTS: On average, participants gained weight and WC during follow-up. Dairy intake increased across exams. After adjusting for demographic and lifestyle factors (including diet quality), participants who consumed ≥3 servings per day of total dairy had 0.10 kg (±0.04) smaller annualized increment of weight (P(trend)=0.04) than those consuming <1 serving per day. Higher total dairy intake was also marginally associated with less WC gain (P(trend)=0.05). Similarly, participants who consumed ≥3 servings per week of yogurt had a 0.10 kg (±0.04) and 0.13 cm (±0.05) smaller annualized increment of weight (P(trend)=0.03) and WC (P(trend)=0.008) than those consuming <1 serving per week, respectively. Skim/low-fat milk, cheese, total high-fat or total low-fat dairy intake were not associated with long-term change in weight or WC. CONCLUSION: Further longitudinal and interventional studies are warranted to confirm the beneficial role of increasing total dairy and yogurt intake, as part of a healthy and calorie-balanced dietary pattern, in the long-term prevention of gain in weight and WC.

The ratio of visceral to subcutaneous fat, a metric of body fat distribution, is a unique correlate of cardiometabolic risk.

AIMS/HYPOTHESIS: The anatomic location of excess body fat has an impact on associated cardiometabolic morbidity, and visceral adipose tissue (VAT) is more pathogenic than subcutaneous adipose tissue (SAT). However, VAT or SAT alone provides little information regarding the relative distribution of body fat. We hypothesised that the propensity to store energy in VAT relative to SAT depots may be a correlate of cardiometabolic risk, and tested this hypothesis using the VAT/SAT ratio as a metric of fat distribution. METHODS: We investigated associations of the VAT/SAT ratio with cardiometabolic traits in 3,223 participants (48% women) from the Framingham Heart Study. Fat depots were quantified by multidetector computed tomography (CT) scanning. RESULTS: In women and men, higher VAT/SAT ratio was associated (p < 0.05) with most assessed cardiovascular risk factors reflecting blood pressure, dyslipidaemia and insulin resistance. Additional adjustment for BMI did not materially change the findings in women, and generally strengthened associations in men. Further adjustment for VAT attenuated some associations in women, but those with lower HDL-cholesterol, higher triacylglycerol (both p < 0.0001) and higher prevalence of hypertension (p = 0.02), diabetes (p = 0.01) and the metabolic syndrome (p = 0.005) remained significant. Similarly, in men, associations with higher systolic (p = 0.006) and diastolic blood pressure (p = 0.03), higher fasting glucose (p = 0.0005), lower HDL-cholesterol and higher triacylglycerol (both p < 0.0001) and higher prevalence of diabetes (p = 0.006) remained significant. CONCLUSIONS/INTERPRETATION: VAT/SAT ratio is a correlate of cardiometabolic risk, above and beyond BMI and VAT. The propensity to store fat viscerally versus subcutaneously may be a unique risk factor independent of absolute fat volumes.

Common genetic variants differentially influence the transition from clinically defined states of fasting glucose metabolism.

AIMS/HYPOTHESIS: Common genetic variants have been associated with type 2 diabetes. We hypothesised that a subset of these variants may have different effects on the transition from normal fasting glucose (NFG) to impaired fasting glucose (IFG) than on that from IFG to diabetes. METHODS: We identified 16 type 2 diabetes risk variants from the Illumina Broad Candidate-gene Association Resource (CARe) array genotyped in 26,576 CARe participants. Participants were categorised at baseline as NFG, IFG or type 2 diabetic (n = 16,465, 8,017 or 2,291, respectively). Using Cox proportional hazards and likelihood ratio tests (LRTs), we compared rates of progression by genotype for 4,909 (NFG to IFG) and 1,518 (IFG to type 2 diabetes) individuals, respectively. We then performed multinomial regression analyses at baseline, comparing the risk of assignment to the NFG, IFG or diabetes groups by genotype. RESULTS: The rate of progression from NFG to IFG was significantly greater in participants carrying the risk allele at MTNR1B (p = 1 × 10(-4)), nominally greater at GCK and SLC30A8 (p < 0.05) and nominally smaller at IGF2BP2 (p = 0.01) than the rate of progression from IFG to diabetes by the LRT. Results of the baseline, multinomial regression model were consistent with these findings. CONCLUSIONS/INTERPRETATION: Common genetic risk variants at GCK, SLC30A8, IGF2BP2 and MTNR1B influence to different extents the development of IFG and the transition from IFG to type 2 diabetes. Our findings may have implications for understanding the genetic contribution of these variants to the development of IFG and type 2 diabetes.

Insulin resistance influences the association of adiponectin levels with diabetes incidence in two population-based cohorts: the Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 study and the Framingham Offspring Study.

AIMS/HYPOTHESIS: Lower adiponectin levels are associated with higher risk of incident type 2 diabetes. Most analyses have been adjusted for confounding factors, but few have taken into account insulin resistance per se. We tested the hypothesis that the association of adiponectin levels with incident type 2 diabetes differs between insulin-resistant and insulin-sensitive individuals. METHODS: We studied two prospective cohorts: the Framingham Offspring Study (n = 2,023) and the Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 study (n = 887) cohorts. Insulin resistance was estimated by HOMA-insulin resistance (HOMA-IR). We used logistic regression analysis to test the association between adiponectin and incident type 2 diabetes overall and in insulin-resistant vs insulin-sensitive individuals (defined by ≥ vs <75th percentile of HOMA-IR). RESULTS: At baseline, Framingham's participants were 60 ± 9 years old and 56% were women; KORA's participants were 63 ± 5 years old and 49% were women. Type 2 diabetes incidence was 5.4% over 6.5 years (n = 109) in Framingham and 10.5% over 8 years (n = 93) in KORA. Lower adiponectin levels were associated with type 2 diabetes incidence in both cohorts. In insulin-resistant individuals, lower adiponectin levels were associated with higher risk of type 2 diabetes incidence (OR 1.60 [95% CI 1.10-2.31] per SD decrease in Framingham, p = 0.01; and OR 2.34 [95% CI 1.16-4.73] in KORA, p = 0.02); while this was not observed in insulin-sensitive individuals (OR 1.10 [95% CI 0.73-1.67] in Framingham, p = 0.64; and OR 1.34 [95%CI: 0.88-2.03] in KORA, p = 0.18). CONCLUSIONS/INTERPRETATION: We conclude that lower adiponectin levels are associated with higher risk of type 2 diabetes in insulin-resistant but not in insulin-sensitive individuals. This suggests that some level of insulin resistance is needed to see deleterious effects of low adiponectin.

Association between single-slice measurements of visceral and abdominal subcutaneous adipose tissue with volumetric measurements: the Framingham Heart Study.

OBJECTIVE: Volumetric visceral abdominal adipose tissue (VAT) and subcutaneous abdominal adipose tissue (SAT) as measured by computed tomography (CT) are associated with metabolic risk factors. We sought to identify the correlations of VAT and SAT between area-based measures at different anatomic locations with volumetric measurements to identify the optimal anatomic site, and to relate measurements at this site with metabolic risk factors. METHODS: We measured SAT and VAT volumes across the total imaging volume, whereas we measured SAT and VAT area at seven predefined anatomic landmarks in 200 participants from the Framingham Heart Study (mean age 54 years, 50% women) who underwent abdominal multi-detector CT. Correlation coefficients were used to assess the association between area measurements and volumes as well as metabolic risk factors stratified by gender. RESULTS: Area-based measurements of SAT and VAT obtained at all anatomic landmarks were strongly associated with SAT and VAT volumes (all r>0.93, P<0.0001 and r>0.87, P<0.0001, for women and men; respectively). Consistently, area-based measurements of SAT and VAT obtained at L(3/4) were most strongly associated with volumetric measured VAT and SAT independent of age (both r=0.99 in men, r=0.96 for SAT and r=0.99 for VAT in women, all P-value <0.0001) and were similarly correlated with risk factors compared with SAT and VAT volumes (all P<0.05 for fasting plasma glucose, triglycerides, high-density lipoprotein, systolic blood pressure). CONCLUSION: Among area-based measurements of SAT and VAT, those obtained at the level of L(3/4) were strongly associated with SAT and VAT volumes and cardio-metabolic risk factors in both men and women.

TCF7L2 variants are associated with increased proinsulin/insulin ratios but not obesity traits in the Framingham Heart Study.

AIMS/HYPOTHESIS: Common variants in the TCF7L2 gene are associated with type 2 diabetes via impaired insulin secretion. One hypothesis is that variation in TCF7L2 impairs insulin processing in the beta cell. In contrast, the association of related TCF7L2 polymorphisms with obesity is controversial in that it has only been shown in cohorts susceptible to ascertainment bias. We reproduced the association of diabetes-associated variants with proinsulin/insulin ratios, and also examined the association of a TCF7L2 haplotype with obesity in the Framingham Heart Study (FHS). METHODS: We genotyped the TCF7L2 single nucleotide polymorphisms rs7903146 and rs12255372 (previously associated with type 2 diabetes) and rs10885406 and rs7924080 (which tag haplotype A [HapA], a haplotype reported to be associated with obesity) in 2,512 FHS participants. We used age- and sex-adjusted linear mixed-effects models to test for association with glycaemic traits, proinsulin/insulin ratios and obesity measures. RESULTS: As expected, the T risk allele of rs7903146 was associated with higher fasting plasma glucose (p = 0.01). T/T homozygotes had a 23.5% increase in the proinsulin/insulin ratio (p = 1 x 10(-7)) compared with C/C homozygotes. There was no association of HapA with BMI (p = 0.98), waist circumference (p = 0.89), subcutaneous adipose tissue (p = 0.32) or visceral adipose tissue (p = 0.92). CONCLUSIONS/INTERPRETATION: We confirmed that the risk allele of rs7903146 is associated with hyperglycaemia and a higher proinsulin/insulin ratio. We did not detect any association of the TCF7L2 HapA with adiposity measures, suggesting that this may have been a spurious association from ascertainment bias, possibly induced by the evaluation of obesity in separate groups of glycaemic cases and controls.

Novel measurements of periaortic adipose tissue in comparison to anthropometric measures of obesity, and abdominal adipose tissue.

BACKGROUND: Perivascular adipose tissue may be associated with the amount of local atherosclerosis. We developed a novel and reproducible method to standardize volumetric quantification of periaortic adipose tissue by computed tomography (CT) and determined the association with anthropometric measures of obesity, and abdominal adipose tissue. METHODS: Measurements of adipose tissue were performed in a random subset of participants from the Framingham Heart Study (n=100) who underwent multidetector CT of the thorax (ECG triggering, 2.5 mm slice thickness) and the abdomen (helical CT acquisition, 2.5 mm slice thickness). Abdominal periaortic adipose tissue (AAT) was defined by a 5 mm cylindrical region of interest around the aortic wall; thoracic periaortic adipose tissue (TAT) was defined by anatomic landmarks. TAT and AAT were defined as any voxel between -195 and -45 HU and volumes were measured using dedicated semiautomatic software. Measurement reproducibility and association with anthropometric measures of obesity, and abdominal adipose tissue were determined. RESULTS: The intra- and inter-observer reproducibility for both AAT and TAT was excellent (ICC: 0.97 and 0.97; 0.99 and 0.98, respectively). Similarly, the relative intra- and inter-observer difference was small for both AAT (-1.85+/-1.28% and 7.85+/-6.08%; respectively) and TAT (3.56+/-0.83% and -4.56+/-0.85%, respectively). Both AAT and TAT were highly correlated with visceral abdominal fat (r=0.65 and 0.77, P<0.0001 for both) and moderately correlated with subcutaneous abdominal fat (r=0.39 and 0.42, P<0.0001 and P=0.009), waist circumference (r=0.49 and 0.57, P<0.0001 for both) and body mass index (r=0.47 and 0.58, P<0.0001 for both). CONCLUSION: Standardized semiautomatic CT-based volumetric quantification of periaortic adipose tissue is feasible and highly reproducible. Further investigation is warranted regarding associations of periaortic adipose tissue with other body fat deposits, cardiovascular risk factors and clinical outcomes.

Comparison of anthropometric, area- and volume-based assessment of abdominal subcutaneous and visceral adipose tissue volumes using multi-detector computed tomography.

PURPOSE: Cross-sectional imaging may enable accurate localization and quantification of subcutaneous and visceral adipose tissue. The reproducibility of multi-detector computed tomography (MDCT)-based volumetric quantification of abdominal adipose tissue and the ability to depict age- and gender-related characteristics of adipose tissue deposition have not been reported. METHODS: We evaluated a random subset of 100 Caucasian subjects (age range: 37-83 years; 49% women) of the Framingham Heart Study offspring cohort who underwent MDCT scanning. Two readers measured subcutaneous and visceral adipose tissue volumes (SAV and VAV; cm(3)) and areas (SAA and VAA; cm(2)) as well as abdominal sagital diameter (SD) and waist circumference (WC). RESULTS: Inter-reader reproducibility was excellent (relative difference: -0.34+/-0.52% for SAV and 0.59+/-0.93% for VAV, intra-class correlation (ICC)=0.99 each). The mean SAA/VAA ratio was significantly different from the mean SAV/VAV ratio (2.0+/-1.2 vs 1.7+/-0.9; P<0.001). The ratio of SAV/VAV was only weakly inversely associated with SD (ICC=-0.32, P=0.01) and not significantly associated with WC (ICC=-0.14, P=0.14) or body mass index (ICC=-0.17, P=0.09). The mean SAV/VAV ratio was significantly different between participants <60 vs >60 years (1.9+/-1.0 vs 1.5+/-0.7; P<0.001) and between men and women (1.2+/-0.5 vs 2.2+/-0.9; P<0.001). CONCLUSION: This study demonstrates that MDCT-based volumetric quantification of abdominal adipose tissue is highly reproducible. In addition, our results suggest that volumetric measurements can depict age- and gender-related differences of visceral and subcutaneous abdominal adipose tissue deposition. Further research is warranted to assess whether volumetric measurements may substantially improve the predictive value of obesity measures for insulin resistance, type 2 diabetes mellitus and other diseases.

Cross-sectional relations of serum aldosterone and urine sodium excretion to urinary albumin excretion in a community-based sample.

Experimental models suggest that increased aldosterone and sodium intake are associated with renovascular damage and resultant proteinuria. We hypothesized that serum aldosterone and urinary sodium would be associated with urinary albumin excretion, an indicator of kidney damage. We evaluated 2700 participants (53% women, mean age 58 years) from the Framingham Offspring Study who attended a routine examination between 1995 and 1998, who were free of heart failure and renal failure, and underwent testing for serum aldosterone, spot urinary sodium, and urinary albumin excretion (urine albumin/creatinine ratio, UACR), the latter two indexed to urinary creatinine. Stepwise multivariable linear regression was used to evaluate the relations between UACR with urinary sodium index and serum aldosterone. In multivariable regression, log urinary sodium index was associated positively with log-UACR (P<0.0001). UACR levels in the fourth and fifth quintiles of urinary sodium index were 24% (95% confidence interval (CI) 3-49%), and twofold higher (95% CI 72-150%), respectively, relative to the lowest quintile (P-value for trend across quintiles <0.001). In multivariable models, log-transformed aldosterone was not related to log-UACR. The top quintile of serum aldosterone levels was associated with a 21% higher (95% 1-44%) UACR levels relative to the lowest quintile. Urinary albumin excretion was strongly and positively associated in a continuous fashion with urinary sodium excretion, whereas a weaker nonlinear positive relation with serum aldosterone was noted. Our cross-sectional observations raise the possibility that dietary salt intake may be associated with early renovascular damage.

Undertreatment of hyperlipidemia in a cohort of United States kidney dialysis patients.

BACKGROUND: Application of national guidelines regarding cardiovascular disease risk reduction to kidney dialysis patients is complicated by the conflicting observations that dialysis patients have a high risk of atherosclerotic cardiovascular disease (ASCVD), but dialysis patients with higher serum cholesterol have lower mortality rates. Actual treatment patterns of hyperlipidemia are not well studied. METHODS: We assessed the prevalence, treatment and control of hyperlipidemia in this high-risk patient population from 1995 - 1998. We measured low-density lipoprotein cholesterol, treatment with a lipid-lowering agent, and prevalence of hyperlipidemia as defined by the National Cholesterol Education Program (NCEP), Adult Treatment Panel (ATP) II guidelines in 812 incident hemodialysis (HD), and peritoneal dialysis (PD) patients from dialysis clinics in 19 states throughout the United States. RESULTS: Hyperlipidemia was present in 40% of HD and 62% of PD patients. Among subjects with hyperlipidemia, 67% of HD and 63% of PD patients were untreated and only 22% of HD and 14% of PD patients were treated and controlled. Those who entered the study in 1997 or 1998, those with diabetes, males and Caucasians were more likely to be treated and controlled, whereas subjects on PD and those with ASCVD were less likely to be treated and controlled. CONCLUSION: These data suggest that high rates of undertreatment exist in the United States ESRD dialysis population. Whether improved rates of treatment will result in decreased cardiovascular disease events needs to be tested in randomized clinical trials.

Is a low leptin concentration, a low resting metabolic rate, or both the expression of the "thrifty genotype"? Results from Mexican Pima Indians.

BACKGROUND: The high prevalence of obesity and type 2 diabetes in some populations is believed to be the expression of a "thrifty genotype," which conferred survival advantages during periods of harsh environmental conditions, but has become a liability in industrialized environments of abundance. Low plasma leptin concentrations and a low metabolic rate may be the phenotypic expression of this genotype. OBJECTIVE: We hypothesized that plasma leptin concentrations and resting metabolic rate would be lower in Mexican Pima Indians not yet exposed to an affluent lifestyle than in non-Pima Mexicans living in the same environment. DESIGN: We studied 208 nondiabetic Pima Indians (105 women and 103 men) living a traditional lifestyle in a remote, mountainous area of northwest Mexico and 183 nondiabetic non-Pima Mexicans (90 women and 93 men) living in the same environment. A subset of 40 (17 women and 23 men) Pima Indians and 40 (19 women and 21 men) non-Pima Mexicans was selected for studies of energy metabolism with a ventilated-hood system. RESULTS: Leptin concentrations were strongly correlated with percentage body fat in both groups (r = 0.83, P < 0.0001). There was no significant difference in plasma leptin concentration between groups in absolute value (P = 0.90) or after adjustment for percentage body fat, waist circumference, age, and sex (P = 0.40). Similarly, there was no significant difference in resting metabolic rate between groups in absolute value (P = 0.27) or after adjustment for fat-free mass (P = 0.32). CONCLUSIONS: These results do not support the hypothesis that hypoleptinemia, a relatively low resting metabolic rate, or both are expressions of the thrifty genotype.

A unique haplotype of the apolipoprotein B-100 allele associated with familial defective apolipoprotein B-100 in a Chinese man discovered during a study of the prevalence of this disorder.

The prevalence of familial defective apolipoprotein (apo) B-100 (FDB) was determined by sampling 5,160 volunteer subjects from among 14,058 eligible employees of a bank in California. The sample was ethnically diverse (44.6% of the population was non-Caucasian). The prevalence of FDB in the study population was 0.08% with a 90% confidence interval of 0.01-0.14%. Four subjects were found to have the apoB 3500 codon mutation by mutagenic polymerase chain reaction, which creates an MspI site at the 3500 codon of normal alleles but not alleles coding for the Arg-->Gln mutation of FDB. Three of these were Caucasian and born in North America. The fourth was a native of China. Haplotype analysis of the affected allele of the Chinese subject using 10 markers described by Ludwig and McCarthy (1990. Am. J. Hum. Genet. 47: 712-720) revealed a unique haplotype that differed from the haplotype of all other subjects with FDB. This unique allele had 30 repeats of a 3' hypervariable element instead of 48 as was found in the allele associated with FDB in other subjects, and in the 3' region there was an EcoRI site that was also not present in the allele most commonly found in association with FDB. We conclude that the prevalence of FDB in our ethnically diverse population is lower than that reported in previous studies of predominantly Caucasian populations and that the Chinese subject represents either an independent mutation or possibly recombination at the 3' end of the apoB gene, an event not previously described.

Hormone therapy to prevent disease and prolong life in postmenopausal women.

PURPOSE: To critically review the risks and benefits of hormone therapy for asymptomatic postmenopausal women who are considering long-term hormone therapy to prevent disease or to prolong life. DATA SOURCES: Review of the English-language literature since 1970 on the effect of estrogen therapy and estrogen plus progestin therapy on endometrial cancer, breast cancer, coronary heart disease, osteoporosis, and stroke. We used standard meta-analytic statistical methods to pool estimates from studies to determine summary relative risks for these diseases in hormone users and modified lifetable methods to estimate changes in lifetime probability and life expectancy due to use of hormone regimens. RESULTS: There is evidence that estrogen therapy decreases risk for coronary heart disease and for hip fracture, but long-term estrogen therapy increases risk for endometrial cancer and may be associated with a small increase in risk for breast cancer. The increase in endometrial cancer risk can probably be avoided by adding a progestin to the estrogen regimen for women who have a uterus, but the effects of combination hormones on risk for other diseases has not been adequately studied. We present estimates for changes in lifetime probabilities of disease and life expectancy due to hormone therapy in women who have had a hysterectomy; with coronary heart disease; and at increased risk for coronary heart disease, hip fracture, and breast cancer. CONCLUSIONS: Hormone therapy should probably be recommended for women who have had a hysterectomy and for those with coronary heart disease or at high risk for coronary heart disease. For other women, the best course of action is unclear.