Effect of a High-Fructose Weight-Maintaining Diet on Lipogenesis and Liver Fat.

CONTEXT: Consumption of high-fructose diets promotes hepatic fatty acid synthesis (de novo lipogenesis [DNL]) and an atherogenic lipid profile. It is unclear whether these effects occur independent of positive energy balance and weight gain. OBJECTIVES: We compared the effects of a high-fructose, (25% of energy content) weight-maintaining diet to those of an isocaloric diet with the same macronutrient distribution but in which complex carbohydrate (CCHO) was substituted for fructose. DESIGN, SETTING, AND PARTICIPANTS: Eight healthy men were studied as inpatients for consecutive 9-day periods. Stable isotope tracers were used to measure fractional hepatic DNL and endogenous glucose production (EGP) and its suppression during a euglycemic-hyperinsulinemic clamp. Liver fat was measured by magnetic resonance spectroscopy. RESULTS: Weight remained stable. Regardless of the order in which the diets were fed, the high-fructose diet was associated with both higher DNL (average, 18.6 ± 1.4% vs 11.0 ± 1.4% for CCHO; P = .001) and higher liver fat (median, +137% of CCHO; P = .016) in all participants. Fasting EGP and insulin-mediated glucose disposal did not differ significantly, but EGP during hyperinsulinemia was greater (0.60 ± 0.07 vs 0.46 ± 0.06 mg/kg/min; P = .013) with the high-fructose diet, suggesting blunted suppression of EGP. CONCLUSION: Short-term high-fructose intake was associated with increased DNL and liver fat in healthy men fed weight-maintaining diets.

Optimal waist:height ratio cut-off point for cardiometabolic risk factors in Turkish adults.

OBJECTIVE: To identify the optimal waist:height ratio (WHtR) cut-off point that discriminates cardiometabolic risk factors in Turkish adults. DESIGN: Cross-sectional study. Hypertension, dyslipidaemia, diabetes, metabolic syndrome score >or=2 (presence of two or more metabolic syndrome components except for waist circumference) and at least one risk factor (diabetes, hypertension or dyslipidaemia) were categorical outcome variables. Receiver-operating characteristic (ROC) curves were prepared by plotting 1 - specificity on the x-axis and sensitivity on the y-axis. The WHtR value that had the highest Youden index was selected as the optimal cut-off point for each cardiometabolic risk factor (Youden index = sensitivity + specificity - 1). SETTING: Turkey, 2003. SUBJECTS: Adults (1121 women and 571 men) aged 18 years and over were examined. RESULTS: Analysis of ROC coordinate tables showed that the optimal cut-off value ranged between 0.55 and 0.60 and was almost equal between men and women. The sensitivities of the identified cut-offs were between 0.63 and 0.81, the specificities were between 0.42 and 0.71 and the accuracies were between 0.65 and 0.73, for men and women. The cut-off point of 0.59 was the most frequently identified value for discrimination of the studied cardiometabolic risk factors. Subjects classified as having WHtR >or= 0.59 had significantly higher age and sociodemographic multivariable-adjusted odds ratios for cardiometabolic risk factors than subjects with WHtR < 0.59, except for diabetes in men. CONCLUSIONS: We show that the optimal WHtR cut-off point to discriminate cardiometabolic risk factors is 0.59 in Turkish adults.

Comparison between Turkish Cardiovascular Risk Platform and United States National Cholesterol Education Program Adult Treatment Panel III definitions of the metabolic syndrome in Turkish adults.

The Turkish Cardiovascular Risk Platform (TCRP) calls for the diagnosis of the metabolic syndrome (MS) if insulin resistance, impaired fasting glucose, impaired glucose tolerance, or diabetes mellitus and >or=2 other established criteria are present. TCRP defines insulin resistance as a homeostasis model assessment >2.7. The aim of this cross-sectional study was to compare TCRP guidelines with the United States National Cholesterol Education Program Adult Treatment Panel III (NCEP) definition of MS in Turkish adults (N=1690). The age- and sex-adjusted prevalence of MS was 25% with the TCRP and 40% for the NCEP definition. Patients with MS identified by the NCEP definition but not by the TCRP definition had lower body mass index and less insulin resistance, but had a similarly adverse cardiovascular risk factor profile to those with TCRP-identified MS, with high blood pressure, waist circumference, triglycerides, and total cholesterol/high-density lipoprotein cholesterol ratio. Other national health organizations should avoid using homeostasis model assessment as a prerequisite for diagnosing MS. Modification of the NCEP definition would be more appropriate for ethnic groups with different body sizes.

Genome-wide linkage and association analyses to identify genes influencing adiponectin levels: the GEMS Study.

Adiponectin has a variety of metabolic effects on obesity, insulin sensitivity, and atherosclerosis. To identify genes influencing variation in plasma adiponectin levels, we performed genome-wide linkage and association scans of adiponectin in two cohorts of subjects recruited in the Genetic Epidemiology of Metabolic Syndrome Study. The genome-wide linkage scan was conducted in families of Turkish and southern European (TSE, n = 789) and Northern and Western European (NWE, N = 2,280) origin. A whole genome association (WGA) analysis (500K Affymetrix platform) was carried out in a set of unrelated NWE subjects consisting of approximately 1,000 subjects with dyslipidemia and 1,000 overweight subjects with normal lipids. Peak evidence for linkage occurred at chromosome 8p23 in NWE subjects (lod = 3.10) and at chromosome 3q28 near ADIPOQ, the adiponectin structural gene, in TSE subjects (lod = 1.70). In the WGA analysis, the single-nucleotide polymorphisms (SNPs) most strongly associated with adiponectin were rs3774261 and rs6773957 (P < 10(-7)). These two SNPs were in high linkage disequilibrium (r(2) = 0.98) and located within ADIPOQ. Interestingly, our fourth strongest region of association (P < 2 x 10(-5)) was to an SNP within CDH13, whose protein product is a newly identified receptor for high-molecular-weight species of adiponectin. Through WGA analysis, we confirmed previous studies showing SNPs within ADIPOQ to be strongly associated with variation in adiponectin levels and further observed these to have the strongest effects on adiponectin levels throughout the genome. We additionally identified a second gene (CDH13) possibly influencing variation in adiponectin levels. The impact of these SNPs on health and disease has yet to be determined.

Anthropometric indices and their relationship with cardiometabolic risk factors in a sample of Turkish adults.

OBJECTIVE: To identify the best anthropometric index that predicts cardiometabolic risk factors.Design and settingCross-sectional study in Turkey, in 2003. SUBJECTS: Turkish men and women aged 18 years and over (n 1692) were examined. Body weight, height, waist and hip circumferences, blood pressure, total cholesterol, HDL cholesterol, TAG, glucose and insulin were measured. Metabolic syndrome score was calculated as the sum of modified National Cholesterol Education Program Adult Treatment Panel III criteria, excluding waist circumference. Insulin resistance was estimated by homeostasis model assessment (HOMA-IR). RESULTS: BMI, waist:hip ratio (WHpR), waist:height ratio (WHtR), waist circumference (WC) and hip circumference (HC) were significantly correlated with each other. Partial correlation coefficients between systolic blood pressure, HDL cholesterol, TAG levels or HOMA-IR and BMI, WC or WHtR were similar and higher than correlation coefficients of WHpR and HC. The association of anthropometric indices with metabolic syndrome score and Framingham risk score was highest for WHtR. Areas under the receiver-operating characteristic curves showed that WHtR was the best anthropometric index that discriminated between the presence and absence of hypertension, diabetes and metabolic syndrome, whereas WHpR was better for dyslipidaemia. CONCLUSIONS: WHtR was the best anthropometric index for predicting most cardiometabolic risk factors. WC and BMI ranked second for their predictive capability of cardiometabolic risk, followed by WHpR and HC.

Analysis of agreement among definitions of metabolic syndrome in nondiabetic Turkish adults: a methodological study.

BACKGROUND: We aimed to explore the agreement among World Health Organization (WHO), European Group for the Study of Insulin Resistance (EGIR), National Cholesterol Education Program (NCEP), American College of Endocrinology (ACE), and International Diabetes Federation (IDF) definitions of the metabolic syndrome. METHODS: 1568 subjects (532 men, 1036 women, mean age 45 and standard deviation (SD) 13 years) were evaluated in this cross-sectional, methodological study. Cardiometabolic risk factors were determined. Insulin sensitivity was calculated by HOMA-IR. Agreement among definitions was determined by the kappa statistic. ANOVA and post hoc Tukey's test were used to compare multiple groups. RESULTS: The agreement between WHO and EGIR definitions was very good (kappa: 0.83). The agreement between NCEP, ACE, and IDF definitions was substantial to very good (kappa: 0.77-0.84). The agreement between NCEP or ACE or IDF and WHO or EGIR definitions was fair (kappa: 0.32-0.37). The age and sex adjusted prevalence of metabolic syndrome was 38% by NCEP, 42% by ACE and IDF, 20% by EGIR and 19% by WHO definition. The evaluated definitions were dichotomized after analysis of design, agreement and prevalence: insulin measurement requiring definitions (WHO and EGIR) and definitions not requiring insulin measurement (NCEP, ACE, IDF). One definition was selected from each set for comparison. WHO-defined subjects were more insulin resistant than subjects without the metabolic syndrome (mean and SD for log HOMA-IR, 0.53 +/- 0.14 vs. 0.07 +/- 0.23, respectively, p < 0.05) and had higher Framingham risk scores (mean and SD, 2.99 +/- 4.64% vs. 1.10 +/- 1.87%, respectively, p < 0.05). The additional subjects identified by IDF definition, but not by WHO definition also had more insulin resistance and higher Framingham risk scores than subjects without the metabolic syndrome (mean and SD, log HOMA-IR 0.18 +/- 0.18 vs. 0.07 +/- 0.23, p < 0.05 and Framingham risk score 2.93 +/- 4.54% vs. 1.10 +/- 1.87%, p < 0.05). The IDF-identified additional subjects had similar Framingham risk scores as WHO-identified subjects (p > 0.05), but lower log HOMA-IR values (p < 0.05). CONCLUSION: The metabolic syndrome definitions that do not require measurement of insulin levels (NCEP, ACE and IDF) identify twice more patients with insulin resistance and increased Framingham risk scores and are more useful than the definitions that require measurement of insulin levels (WHO and EGIR).

Multiple QTLs influencing triglyceride and HDL and total cholesterol levels identified in families with atherogenic dyslipidemia.

We conducted a genome-wide scan using variance components linkage analysis to localize quantitative-trait loci (QTLs) influencing triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol, and total cholesterol (TC) levels in 3,071 subjects from 459 families with atherogenic dyslipidemia. The most significant evidence for linkage to TG levels was found in a subset of Turkish families at 11q22 [logarithm of the odds ratio (LOD)=3.34] and at 17q12 (LOD=3.44). We performed sequential oligogenic linkage analysis to examine whether multiple QTLs jointly influence TG levels in the Turkish families. These analyses revealed loci at 20q13 that showed strong epistatic effects with 11q22 (conditional LOD=3.15) and at 7q36 that showed strong epistatic effects with 17q12 (conditional LOD=3.21). We also found linkage on the 8p21 region for TG in the entire group of families (LOD=3.08). For HDL-C levels, evidence of linkage was identified on chromosome 15 in the Turkish families (LOD=3.05) and on chromosome 5 in the entire group of families (LOD=2.83). Linkage to QTLs for TC was found at 8p23 in the entire group of families (LOD=4.05) and at 5q13 in a subset of Turkish and Mediterranean families (LOD=3.72). These QTLs provide important clues for the further investigation of genes responsible for these complex lipid phenotypes. These data also indicate that a large proportion of the variance of TG levels in the Turkish population is explained by the interaction of multiple genetic loci.

Modulation of high-density lipoproteins in a population in istanbul, Turkey, with low levels of high-density lipoproteins.

The extent to which high-density lipoprotein (HDL) cholesterol levels can be increased in patients with low HDL cholesterol is important because low HDL cholesterol levels increase the risk of coronary heart disease (CHD). During the past 14 years, we have assessed risk factors in Turks, a population in which extremely low HDL cholesterol levels (mean 36 mg/dl in men, 42 mg/dl in women) are a prime CHD risk factor. Although genetically determined to a significant extent, these low HDL cholesterol levels can be modulated by lifestyle factors, as in other populations. We measured the HDL cholesterol levels in men and women residing in Istanbul at 3 time points: 1990 to 1993, 1996 to 2000, and 2003. The mean HDL cholesterol levels increased from 45.3 +/- 9.5 mg/dl in 1990 to 1993 to 49.7 +/- 12 mg/dl in 2003 (p <0.0001) in women, but were virtually unchanged in men (38 +/- 8 vs 39 +/- 10 mg/dl). In contrast to previous years, the HDL cholesterol levels in women in 2003 were markedly affected by education level and socioeconomic status, averaging 56 +/- 9 mg/dl in those with a university education and 48 +/- 12 mg/dl in those with a primary school education. Part of this difference could be explained by less smoking and more exercise and lower body mass index (average 25.6 +/- 4.9 vs 29.7 +/- 5.1 kg/m(2)) of the highly educated women. It is important to note the increase in the prevalence of obesity between the 1990 to 1993 interval and 2003 in men and women, including a remarkable change from 9.4% to 45.2% among women with a primary school education. None of these factors affected the HDL cholesterol levels of men by >2 mg/dl at any of the 3 points. In conclusion, because CHD risk changes by as much as 2% to 4% per 1 mg/dl difference in HDL cholesterol level, the 8 mg/dl difference may reflect as much as a 20% to 30% reduction in CHD risk associated with the benefit of higher education in women. Why education failed to affect the HDL cholesterol levels in Turkish men remains unclear.

Relation between atherogenic dyslipidemia and the Adult Treatment Program-III definition of metabolic syndrome (Genetic Epidemiology of Metabolic Syndrome Project).

Genetic Epidemiology of Metabolic Syndrome is a multinational, family-based study to explore the genetic basis of the metabolic syndrome. Atherogenic dyslipidemia (defined as low plasma high-density lipoprotein cholesterol with elevated triglycerides (<25th and >75th percentile for age, gender, and country, respectively) identified affected subjects for the metabolic syndrome. This report examines the frequency at which atherogenic dyslipidemia predicts the metabolic syndrome of the National Cholesterol Education Program Adult Treatment Panel III (ATP-III). One thousand four hundred thirty-six (854 men/582 women) affected patients by our criteria were compared with 1,672 (737 men/935 women) unaffected persons. Affected patients had more hypertension, obesity, and hyperglycemia, and they met a higher number of ATP-III criteria (3.2 +/- 1.1 SD vs 1.3 +/- 1.1 SD, p <0.001). Overall, 76% of affected persons also qualified for the ATP-III definition (Cohen's kappa 0.61, 95% confidence interval 0.59 to 0.64), similar to a separate group of 464 sporadic, unrelated cases (75%). Concordance increased from 41% to 82% and 88% for ages < or =35, 36 to 55, and > or =55 years, respectively. Affected status was also independently associated with waist circumference (p <0.001) and fasting glucose (p <0.001) but not systolic blood pressure (p = 0.43). Thus, the lipid-based criteria used to define affection status in this study substantially parallels the ATP-III definition of metabolic syndrome in subjects aged >35 years. In subjects aged <35 years, atherogenic dyslipidemia frequently occurs in the absence of other metabolic syndrome risk factors.

Risk determination of dyslipidemia in populations characterized by low levels of high-density lipoprotein cholesterol.

BACKGROUND: Current guidelines for managing dyslipidemia qualify patients for treatment based on low-density lipoprotein cholesterol (LDL-C) levels and other risk factors for coronary heart disease (CHD). However, when LDL-C is the sole lipid criterion for initiating therapy, patients with levels below the treatment initiation threshold who are at high risk because of low levels (<40 mg/dL) of high-density lipoprotein cholesterol (HDL-C) might not be identified. Twenty percent of male patients with CHD in the United States fall into this category. The total cholesterol/HDL-C (TC/HDL-C) ratio predicts CHD risk regardless of the absolute LDL-C and HDL-C. METHODS: We compared guidelines based on TC/HDL-C and LDL-C with those recommended by the National Cholesterol Education Program Adult Treatment Panel III (ATP III). Both sets of guidelines were applied to 9837 adults (>20 years of age) in the Turkish Heart Study, which has shown that 75% of men and 50% of women in Turkey have HDL-C <40 mg/dL. RESULTS: ATP III guidelines identified 14% of Turkish adults, 20 years or older, as candidates for lifestyle treatment only and an additional 18% for drug treatment. In conjunction with ATP III LDL-C thresholds, the TC/HDL-C ratio (>3.5, patients with CHD; > or =6.0, 2+ risk factors, > or =7.0, 0 to 1 risk factor) assigned lifestyle therapy alone to 18% and drug treatment to an additional 36%. Among primary prevention subjects at high risk because of age (men > or =45 years; women > or =55 years), both sets of guidelines prescribed lifestyle therapy for only 5%; however, drug treatment was recommended for an additional 13% by ATP III guidelines and an additional 18% by TC/HDL-C and LDL-C. CONCLUSIONS: In populations at risk for CHD caused by low HDL-C, qualification of subjects for treatment based on either the TC/HDL-C ratio or LDL-C thresholds identifies more high-risk subjects for treatment than LDL-C threshold values alone, and use of the ratio, instead of risk tables, simplifies the approach for physicians.

Managing dyslipidemia in Turkey: suggested guidelines for a population characterized by low levels of high density lipoprotein cholesterol.

Based on data from the Turkish Society of Cardiology and others, it is established that Turks have a high prevalence of coronary heart disease (CHD). Several risk factors are prominent in Turks: dyslipidemia, cigarette smoking, and hypertension. The dyslipidemia is unique in that very low levels of HDL-C and typically "normal" LDL-C levels characterize the Turkish population. The low HDL-C levels appear to be genetic in origin and are largely independent of high triglyceride levels (73% of Turkish men and 94% of women with HDL-C <40 mg/dl have triglyceride levels <150 mg/dl; only 15% of men and 3% of women with HDL-C <40 mg/dl have triglyceride levels >200 mg/dl). HDL-C levels are 10-15% mg/dl lower in Turks than seen in the United States or western Europe. Low HDL-C is a major risk factor; CHD risk increases 2-4% for every 1 mg/dl decrease in HDL-C levels. Existing treatment guidelines focus on plasma LDL-C levels and fail to take into account the continuous increase in CHD risk that occurs as HDL-C levels decrease. However, several studies show that patients with CHD or free of CHD but with multiple risk factors, who have low HDL-C and near optimal LDL-C, benefit very significantly from lipid-lowering therapy. Many of these patients with low HDL-C levels do not qualify for drug therapy based on existing guidelines. Therefore, we believe that unique guidelines must be developed to guide the treatment of low HDL-C Turkish patients. We suggest that treatment based on both the LDL-C level and the total cholesterol/HDL-C (TC/HDL-C) ratio is the best way to address treatment of patients with low HDL-C levels. The most effective drug treatment available presently in Turkey relies on lowering LDL-C levels to optimize the TC/HDL-C ratio.

Sources of variability in genetic association studies: insights from the analysis of hepatic lipase (LIPC).

Genetic association studies have been widely used to identify loci that influence plasma lipoprotein concentrations, but few of the associations reported have proved consistently reproducible across different study populations. This lack of consistency is a widely recognized limitation of association studies, and is often ascribed to inadequate statistical power, population substructure, and population-specific linkage disequilibrium. However, few studies have assessed the causes of variability underlying a given genotype-phenotype association. We have examined two possible sources of variability in the association between the -514 polymorphism in hepatic lipase (LIPC) and plasma HDL-C concentrations. First, we compared the association between this polymorphism and hepatic lipase activity in four populations. A single copy of the -514C allele was associated with a 10 mmol.hr(-1).l(-1) increase in hepatic lipase activity in white American and Turkish men but only approximately 5 mmol.hr(-1).l(-1) in Chinese and African-American men. Second, we tested the effects of a stanozolol-induced increase in hepatic lipase activity on plasma HDL-C concentrations in men with normal (< 150mg/dl) or elevated (150-300mg/dl) levels of plasma triglyceride. The increase in hepatic lipase activity was similar in the two groups, but the resulting decline in HDL-C levels was significantly greater in normolipidemic men. These data suggest that the effect of a polymorphism on gene expression can vary among individuals, and that the resulting phenotype may be further modified by interactions with other factors. Three novel LIPC polymorphisms were identified in the study (-1596insC, -2740A>G, and -2880G>C).