Membrane lipids are essential for biological functions ranging from membrane trafficking to signal transduction. The composition of lipid membranes influences their organization and properties, so it is not surprising that disorders in lipid metabolism and transport have a role in human disease. Significant recent progress has enhanced our understanding of the molecular and cellular basis of lipid-associated disorders such as Tangier disease, Niemann-Pick disease type C and atherosclerosis. These insights have also led to improved understanding of normal physiology.

OBJECTIVE

To develop and validate version two of the QRISK cardiovascular disease risk algorithm (QRISK2) to provide accurate estimates of cardiovascular risk in patients from different ethnic groups in England and Wales and to compare its performance with the modified version of Framingham score recommended by the National Institute for Health and Clinical Excellence (NICE).

METHODS

Prospective open cohort study with routinely collected data from general practice, 1 January 1993 to 31 March 2008.

METHODS

531 practices in England and Wales contributing to the national QRESEARCH database.

METHODS

2.3 million patients aged 35-74 (over 16 million person years) with 140,000 cardiovascular events. Overall population (derivation and validation cohorts) comprised 2.22 million people who were white or whose ethnic group was not recorded, 22,013 south Asian, 11,595 black African, 10,402 black Caribbean, and 19,792 from Chinese or other Asian or other ethnic groups.

METHODS

First (incident) diagnosis of cardiovascular disease (coronary heart disease, stroke, and transient ischaemic attack) recorded in general practice records or linked Office for National Statistics death certificates. Risk factors included self assigned ethnicity, age, sex, smoking status, systolic blood pressure, ratio of total serum cholesterol:high density lipoprotein cholesterol, body mass index, family history of coronary heart disease in first degree relative under 60 years, Townsend deprivation score, treated hypertension, type 2 diabetes, renal disease, atrial fibrillation, and rheumatoid arthritis.

RESULTS

The validation statistics indicated that QRISK2 had improved discrimination and calibration compared with the modified Framingham score. The QRISK2 algorithm explained 43% of the variation in women and 38% in men compared with 39% and 35%, respectively, by the modified Framingham score. Of the 112,156 patients classified as high risk (that is,>>or=20% risk over 10 years) by the modified Framingham score, 46,094 (41.1%) would be reclassified at low risk with QRISK2. The 10 year observed risk among these reclassified patients was 16.6% (95% confidence interval 16.1% to 17.0%)-that is, below the 20% treatment threshold. Of the 78 024 patients classified at high risk on QRISK2, 11,962 (15.3%) would be reclassified at low risk by the modified Framingham score. The 10 year observed risk among these patients was 23.3% (22.2% to 24.4%)-that is, above the 20% threshold. In the validation cohort, the annual incidence rate of cardiovascular events among those with a QRISK2 score of>>or=20% was 30.6 per 1000 person years (29.8 to 31.5) for women and 32.5 per 1000 person years (31.9 to 33.1) for men. The corresponding figures for the modified Framingham equation were 25.7 per 1000 person years (25.0 to 26.3) for women and 26.4 (26.0 to 26.8) for men). At the 20% threshold, the population identified by QRISK2 was at higher risk of a CV event than the population identified by the Framingham score.

CONCLUSIONS

Incorporating ethnicity, deprivation, and other clinical conditions into the QRISK2 algorithm for risk of cardiovascular disease improves the accuracy of identification of those at high risk in a nationally representative population. At the 20% threshold, QRISK2 is likely to be a more efficient and equitable tool for treatment decisions for the primary prevention of cardiovascular disease. As the validation was performed in a similar population to the population from which the algorithm was derived, it potentially has a "home advantage." Further validation in other populations is therefore advised.

Arterial stiffness may predict coronary heart disease beyond classic risk factors. In a longitudinal study, we assessed the predictive value of arterial stiffness on coronary heart disease in patients with essential hypertension and without known clinical cardiovascular disease. Aortic stiffness was determined from carotid-femoral pulse wave velocity at baseline in 1045 hypertensives. The risk assessment of coronary heart disease was made by calculating the Framingham risk score according to the categories of gender, age, blood pressure, cholesterol, diabetes, and smoking. Mean age at entry was 51 years, and mean follow-up was 5.7 years. Coronary events (fatal and nonfatal myocardial infarction, coronary revascularization, and angina pectoris) and all cardiovascular events served as outcome variables in Cox proportional-hazard regression models. Fifty-three coronary events and 97 total cardiovascular events occurred. In univariate analysis, the relative risk of follow-up coronary event or any cardiovascular event increased with increasing level of pulse wave velocity; for 1 SD, ie, 3.5 m/s, relatives risks were 1.42 (95% confidence interval [CI], 1.10 to 1.82; P<0.01) and 1.41 (95% CI, 1.17 to 1.70; P<0.001), respectively. Framingham score significantly predicted the occurrence of coronary and all cardiovascular events in this population (P<0.01 and P<0.0001, respectively). In multivariate analysis, pulse wave velocity remained significantly associated with the occurrence of coronary event after adjustment either of Framingham score (for 3.5 m/s: relative risk, 1.34; 95% CI, 1.01 to 1.79; P=0.039) or classic risk factors (for 3.5 m/s: relative risk, 1.39; 95% CI, 1.08 to 1.79; P=0.01). Parallel results were observed for all cardiovascular events. This study provides the first direct evidence in a longitudinal study that aortic stiffness is an independent predictor of primary coronary events in patients with essential hypertension.

The vast majority of Alzheimer's disease (AD) cases are late-onset and their development is probably influenced by both genetic and environmental risk factors. A strong genetic risk factor for late-onset AD is the presence of the epsilon4 allele of the apolipoprotein E (APOE) gene, which encodes a protein with crucial roles in cholesterol metabolism. There is mounting evidence that APOE4 contributes to AD pathogenesis by modulating the metabolism and aggregation of amyloid-beta peptide and by directly regulating brain lipid metabolism and synaptic functions through APOE receptors. Emerging knowledge of the contribution of APOE to the pathophysiology of AD presents new opportunities for AD therapy.

BACKGROUND

Obesity is an independent risk factor for cardiovascular disease, which may be mediated by increased secretion of proinflammatory cytokines by adipose tissue.

OBJECTIVE

To determine the effect of a program of changes in lifestyle designed to obtain a sustained reduction of body weight on markers of systemic vascular inflammation and insulin resistance.

METHODS

Randomized single-blind trial conducted from February 1999 to February 2002 at a university hospital in Italy.

METHODS

One hundred twenty premenopausal obese women (body mass index>> or =30) aged 20 to 46 years without diabetes, hypertension, or hyperlipidemia.

METHODS

The 60 women randomly assigned to the intervention group received detailed advice about how to achieve a reduction of weight of 10% or more through a low-energy Mediterranean-style diet and increased physical activity. The control group (n = 60) was given general information about healthy food choices and exercise.

METHODS

Lipid and glucose intake; blood pressure; homeostatic model assessment of insulin sensitivity; and circulating levels of interleukin 6 (IL-6), interleukin 18 (IL-18), C-reactive protein (CRP), and adiponectin.

RESULTS

After 2 years, women in the intervention group consumed more foods rich in complex carbohydrates (9% corrected difference; P<.001), monounsaturated fat (2%; P =.009), and fiber (7 g/d; P<.001); had a lower ratio of omega-6 to omega-3 fatty acids (-5; P<.001); and had lower energy (-310 kcal/d; P<.001), saturated fat (-3.5%; P =.007), and cholesterol intake (-92 mg/d; P<.001) than controls. Body mass index decreased more in the intervention group than in controls (-4.2; P<.001), as did serum concentrations of IL-6 (-1.1 pg/mL; P =.009), IL-18 (-57 pg/mL; P =.02), and CRP (-1.6 mg/L; P =.008), while adiponectin levels increased significantly (2.2 microg/mL; P =.01). In multivariate analyses, changes in free fatty acids (P =.008), IL-6 (P =.02), and adiponectin (P =.007) levels were independently associated with changes in insulin sensitivity.

CONCLUSIONS

In this study, a multidisciplinary program aimed to reduce body weight in obese women through lifestyle changes was associated with a reduction in markers of vascular inflammation and insulin resistance.

During the past decade, our understanding of the pathophysiology of coronary artery disease (CAD) has undergone a remarkable evolution. We review here how these advances have altered our concepts of and clinical approaches to both the chronic and acute phases of CAD. Previously considered a cholesterol storage disease, we currently view atherosclerosis as an inflammatory disorder. The appreciation of arterial remodeling (compensatory enlargement) has expanded attention beyond stenoses evident by angiography to encompass the biology of nonstenotic plaques. Revascularization effectively relieves ischemia, but we now recognize the need to attend to nonobstructive lesions as well. Aggressive management of modifiable risk factors reduces cardiovascular events and should accompany appropriate revascularization. We now recognize that disruption of plaques that may not produce critical stenoses causes many acute coronary syndromes (ACS). The disrupted plaque represents a "solid-state" stimulus to thrombosis. Alterations in circulating prothrombotic or antifibrinolytic mediators in the "fluid phase" of the blood can also predispose toward ACS. Recent results have established the multiplicity of "high-risk" plaques and the widespread nature of inflammation in patients prone to develop ACS. These findings challenge our traditional view of coronary atherosclerosis as a segmental or localized disease. Thus, treatment of ACS should involve 2 overlapping phases: first, addressing the culprit lesion, and second, aiming at rapid "stabilization" of other plaques that may produce recurrent events. The concept of "interventional cardiology" must expand beyond mechanical revascularization to embrace preventive interventions that forestall future events.

OBJECTIVE

Overweight and obese individuals are encouraged to lose 5-10% of their body weight to improve cardiovascular disease (CVD) risk, but data supporting this recommendation are limited, particularly for individuals with type 2 diabetes.

METHODS

We conducted an observational analysis of participants in the Look AHEAD (Action For Health in Diabetes) study (n=5,145, 40.5% male, 37% from ethnic/racial minorities) and examined the association between the magnitude of weight loss and changes in CVD risk factors at 1 year and the odds of meeting predefined criteria for clinically significant improvements in risk factors in individuals with type 2 diabetes.

RESULTS

The magnitude of weight loss at 1 year was strongly (P<0.0001) associated with improvements in glycemia, blood pressure, triglycerides, and HDL cholesterol but not with LDL cholesterol (P=0.79). Compared with weight-stable participants, those who lost 5 to <10% ([means±SD] 7.25±2.1 kg) of their body weight had increased odds of achieving a 0.5% point reduction in HbA1c (odds ratio 3.52 [95% CI 2.81-4.40]), a 5-mmHg decrease in diastolic blood pressure (1.48 [1.20-1.82]), a 5-mmHg decrease in systolic blood pressure (1.56 [1.27-1.91]), a 5 mg/dL increase in HDL cholesterol (1.69 [1.37-2.07]), and a 40 mg/dL decrease in triglycerides (2.20 [1.71-2.83]). The odds of clinically significant improvements in most risk factors were even greater in those who lost 10-15% of their body weight.

CONCLUSIONS

Modest weight losses of 5 to <10% were associated with significant improvements in CVD risk factors at 1 year, but larger weight losses had greater benefits.

BACKGROUND

Multiple genetic loci have been convincingly associated with the risk of type 2 diabetes mellitus. We tested the hypothesis that knowledge of these loci allows better prediction of risk than knowledge of common phenotypic risk factors alone.

METHODS

We genotyped single-nucleotide polymorphisms (SNPs) at 18 loci associated with diabetes in 2377 participants of the Framingham Offspring Study. We created a genotype score from the number of risk alleles and used logistic regression to generate C statistics indicating the extent to which the genotype score can discriminate the risk of diabetes when used alone and in addition to clinical risk factors.

RESULTS

There were 255 new cases of diabetes during 28 years of follow-up. The mean (+/-SD) genotype score was 17.7+/-2.7 among subjects in whom diabetes developed and 17.1+/-2.6 among those in whom diabetes did not develop (P<0.001). The sex-adjusted odds ratio for diabetes was 1.12 per risk allele (95% confidence interval, 1.07 to 1.17). The C statistic was 0.534 without the genotype score and 0.581 with the score (P=0.01). In a model adjusted for sex and self-reported family history of diabetes, the C statistic was 0.595 without the genotype score and 0.615 with the score (P=0.11). In a model adjusted for age, sex, family history, body-mass index, fasting glucose level, systolic blood pressure, high-density lipoprotein cholesterol level, and triglyceride level, the C statistic was 0.900 without the genotype score and 0.901 with the score (P=0.49). The genotype score resulted in the appropriate risk reclassification of, at most, 4% of the subjects.

CONCLUSIONS

A genotype score based on 18 risk alleles predicted new cases of diabetes in the community but provided only a slightly better prediction of risk than knowledge of common risk factors alone.

Bile acids are physiological detergents that generate bile flow and facilitate intestinal absorption and transport of lipids, nutrients, and vitamins. Bile acids also are signaling molecules and inflammatory agents that rapidly activate nuclear receptors and cell signaling pathways that regulate lipid, glucose, and energy metabolism. The enterohepatic circulation of bile acids exerts important physiological functions not only in feedback inhibition of bile acid synthesis but also in control of whole-body lipid homeostasis. In the liver, bile acids activate a nuclear receptor, farnesoid X receptor (FXR), that induces an atypical nuclear receptor small heterodimer partner, which subsequently inhibits nuclear receptors, liver-related homolog-1, and hepatocyte nuclear factor 4alpha and results in inhibiting transcription of the critical regulatory gene in bile acid synthesis, cholesterol 7alpha-hydroxylase (CYP7A1). In the intestine, FXR induces an intestinal hormone, fibroblast growth factor 15 (FGF15; or FGF19 in human), which activates hepatic FGF receptor 4 (FGFR4) signaling to inhibit bile acid synthesis. However, the mechanism by which FXR/FGF19/FGFR4 signaling inhibits CYP7A1 remains unknown. Bile acids are able to induce FGF19 in human hepatocytes, and the FGF19 autocrine pathway may exist in the human livers. Bile acids and bile acid receptors are therapeutic targets for development of drugs for treatment of cholestatic liver diseases, fatty liver diseases, diabetes, obesity, and metabolic syndrome.

The conversion of cholesterol into bile acids in the liver represents the major catabolic pathway for the removal of cholesterol from the body. In this complex biosynthetic pathway, at least 10 enzymes modify both the ring structure and side chain of cholesterol, resulting in the formation of the primary bile acids, cholic acid, and chenodeoxycholic acid. To gain insight into the details and regulation of this pathway, we have used protein sequencing and molecular cloning techniques to isolate and characterize a cDNA encoding the rabbit mitochondrial sterol 26-hydroxylase. This enzyme catalyzes the first step in the oxidation of the side chain of sterol intermediates in the biosynthesis of bile acids. The structure of the sterol 26-hydroxylase, as deduced by both DNA sequence analysis of the cDNA and protein sequence analysis, reveals it to be a mitochondrial cytochrome P-450. A signal sequence of 36 residues precedes a coding region of 499 amino acids, predicting a molecular weight of 56,657 for the mature protein. The identity of the 26-hydroxylase cDNA was further confirmed by expression in monkey COS cells employing a versatile eukaryotic expression vector. Blotting experiments revealed that the mRNA for this enzyme is expressed in many tissues and that it is encoded by a low copy number gene in the rabbit genome.

There is mounting evidence that inflammation plays a role in the development of coronary heart disease (CHD). Observations have been made linking the presence of infections in the vessel wall with atherosclerosis, and epidemiological data also implicate infection in remote sites in the aetiology of CHD. In this article we propose a key role for the proinflammatory cytokine interleukin-6 (IL-6) in several mechanisms that contribute to the development of CHD. IL-6 is a powerful inducer of the hepatic acute phase response. Elevated concentrations of acute phase reactants, such as C-reactive protein (CRP), are found in patients with acute coronary syndromes, and predict future risk in apparently healthy subjects. The acute phase reaction is associated with elevated levels of fibrinogen, a strong risk factor for CHD, with autocrine and paracrine activation of monocytes by IL-6 in the vessel wall contributing to the deposition of fibrinogen. The acute phase response is associated with increased blood viscosity, platelet number and activity. Furthermore, raised serum amyloid A lowers HDL-cholesterol levels. IL-6 decreases lipoprotein lipase (LPL) activity and monomeric LPL levels in plasma, which increases macrophage uptake of lipids. In fatty streaks and in the atheromatous 'cap' and 'shoulder' regions, macrophage foam cells and smooth muscle cells (SMC) express IL-6, suggesting a role for this cytokine along with interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha), in the progression of atherosclerosis. Both these cytokines induce the release of IL-6 from several cell types, including SMC. During vascular injury SMC are exposed to platelets or their products, and cytokine production by SMC further contributes to vascular damage. Furthermore, circulating IL-6 stimulates the hypothalamic-pituitary-adrenal (HPA) axis, activation of which is associated with central obesity, hypertension and insulin resistance. Thus we propose a role for IL-6 in the pathogenesis of CHD through a combination of autocrine, paracrine and endocrine mechanisms. This hypothesis lends itself to testing using interventions to influence IL-6 secretion and actions.

BACKGROUND

Despite the popularity of the low-carbohydrate, high-protein, high-fat (Atkins) diet, no randomized, controlled trials have evaluated its efficacy.

METHODS

We conducted a one-year, multicenter, controlled trial involving 63 obese men and women who were randomly assigned to either a low-carbohydrate, high-protein, high-fat diet or a low-calorie, high-carbohydrate, low-fat (conventional) diet. Professional contact was minimal to replicate the approach used by most dieters.

RESULTS

Subjects on the low-carbohydrate diet had lost more weight than subjects on the conventional diet at 3 months (mean [+/-SD], -6.8+/-5.0 vs. -2.7+/-3.7 percent of body weight; P=0.001) and 6 months (-7.0+/-6.5 vs. -3.2+/-5.6 percent of body weight, P=0.02), but the difference at 12 months was not significant (-4.4+/-6.7 vs. -2.5+/-6.3 percent of body weight, P=0.26). After three months, no significant differences were found between the groups in total or low-density lipoprotein cholesterol concentrations. The increase in high-density lipoprotein cholesterol concentrations and the decrease in triglyceride concentrations were greater among subjects on the low-carbohydrate diet than among those on the conventional diet throughout most of the study. Both diets significantly decreased diastolic blood pressure and the insulin response to an oral glucose load.

CONCLUSIONS

The low-carbohydrate diet produced a greater weight loss (absolute difference, approximately 4 percent) than did the conventional diet for the first six months, but the differences were not significant at one year. The low-carbohydrate diet was associated with a greater improvement in some risk factors for coronary heart disease. Adherence was poor and attrition was high in both groups. Longer and larger studies are required to determine the long-term safety and efficacy of low-carbohydrate, high-protein, high-fat diets.

Tangier disease (TD) is an autosomal recessive disorder of lipid metabolism. It is characterized by absence of plasma high-density lipoprotein (HDL) and deposition of cholesteryl esters in the reticulo-endothelial system with splenomegaly and enlargement of tonsils and lymph nodes. Although low HDL cholesterol is associated with an increased risk for coronary artery disease, this condition is not consistently found in TD pedigrees. Metabolic studies in TD patients have revealed a rapid catabolism of HDL and its precursors. In contrast to normal mononuclear phagocytes (MNP), MNP from TD individuals degrade internalized HDL in unusual lysosomes, indicating a defect in cellular lipid metabolism. HDL-mediated cholesterol efflux and intracellular lipid trafficking and turnover are abnormal in TD fibroblasts, which have a reduced in vitro growth rate. The TD locus has been mapped to chromosome 9q31. Here we present evidence that TD is caused by mutations in ABC1, encoding a member of the ATP-binding cassette (ABC) transporter family, located on chromosome 9q22-31. We have analysed five kindreds with TD and identified seven different mutations, including three that are expected to impair the function of the gene product. The identification of ABC1 as the TD locus has implications for the understanding of cellular HDL metabolism and reverse cholesterol transport, and its association with premature cardiovascular disease.

Lateral heterogeneities in the classical fluid-mosaic model of cell membranes are now envisaged as domains or 'rafts' that are enriched in (glyco)sphingolipids, cholesterol, specific membrane proteins and glycosylphosphatidylinositol (GPI)-anchored proteins. These rafts dictate the sorting of associated proteins and/or provide sites for assembling cytoplasmic signalling molecules. However, there is no direct evidence that rafts exist in living cells. We have now measured the extent of energy transfer between isoforms of the folate receptor bound to a fluorescent analogue of folic acid, in terms of the dependence of fluorescence polarization on fluorophore densities in membranes. We find that the extent of energy transfer for the GPI-anchored folate-receptor isoform is density-independent, which is characteristic of organization in sub-pixel-sized domains at the surface of living cells; however, the extent of energy transfer for the transmembrane-anchored folate-receptor isoform was density-dependent, which is consistent with a random distribution. These domains are likely to be less than 70 nm in diameter and are disrupted by removal of cellular cholesterol. These results indicate that lipid-linked proteins are organized in cholesterol-dependent submicron-sized domains. Our methodology offers a new way of monitoring nanometre-scale association between molecules in living cells.

OBJECTIVE

The purpose of this study was to examine the prevalence of individual risk factors for metabolic syndrome as well as the prevalence of metabolic syndrome in the National Health and Nutrition Examination Survey (NHANES) 2003-2006.

METHODS

The analytic sample consisted of 3,423 adults, 20 years of age and over, from NHANES 2003-2006. The National Cholesterol Education Program's Adult Treatment Panel III (NCEP/ATP III) guidelines were used to identify adults who met their criteria for metabolic syndrome. Prevalence estimates were calculated for each risk factor for metabolic syndrome in addition to the prevalence of metabolic syndrome. Prevalence estimates and odds ratios were analyzed by sex and by age group, race and ethnicity, and body mass index (BMI) stratified by sex.

RESULTS

Approximately 34% of adults met the criteria for metabolic syndrome. Males and females 40-59 years of age were about three times as likely as those 20-39 years of age to meet the criteria for metabolic syndrome. Males 60 years of age and over were more than four times as likely and females 60 years of age and over were more than six times as likely as the youngest age group to meet the criteria. Non-Hispanic black males were about one-half as likely as non-Hispanic white males to meet the criteria for metabolic syndrome, while non-Hispanic black and Mexican-American females were about 1.5 times as likely as non-Hispanic white females to meet the criteria. Overweight males were about six times as likely and obese males were about 32 times as likely as normal weight males to meet the criteria. Overweight females were more than five times as likely and obese females were more than 17 times as likely as normal weight females to meet the criteria.

CONCLUSIONS

These results demonstrate that metabolic syndrome is prevalent and that it increases with age and with BMI. The prevalence varied by race and ethnicity but the pattern was different for males and females.

The VFA, also known as short-chain fatty acids, are produced in the gastrointestinal tract by microbial fermentation of carbohydrates and endogenous substrates, such as mucus. This can be of great advantage to the animal, since no digestive enzymes exist for breaking down cellulose or other complex carbohydrates. The VFA are produced in the largest amounts in herbivorous animal species and especially in the forestomach of ruminants. The VFA, however, also are produced in the lower digestive tract of humans and all animal species, and intestinal fermentation resembles that occurring in the rumen. The principal VFA in either the rumen or large intestine are acetate, propionate, and butyrate and are produced in a ratio varying from approximately 75:15:10 to 40:40:20. Absorption of VFA at their site of production is rapid, and large quantities are metabolized by the ruminal or large intestinal epithelium before reaching the portal blood. Most of the butyrate is converted to ketone bodies or CO2 by the epithelial cells, and nearly all of the remainder is removed by the liver. Propionate is similarly removed by the liver but is largely converted to glucose. Although species differences exist, acetate is used principally by peripheral tissues, especially fat and muscle. Considerable energy is obtained from VFA in herbivorous species, and far more research has been conducted on ruminants than on other species. Significant VFA, however, are now known to be produced in omnivorous species, such as pigs and humans. Current estimates are that VFA contribute approximately 70% to the caloric requirements of ruminants, such as sheep and cattle, approximately 10% for humans, and approximately 20-30% for several other omnivorous or herbivorous animals. The amount of fiber in the diet undoubtedly affects the amount of VFA produced, and thus the contribution of VFA to the energy needs of the body could become considerably greater as the dietary fiber increases. Pigs and some species of monkey most closely resemble humans, and current research should be directed toward examining the fermentation processes and VFA metabolism in those species. In addition to the energetic or nutritional contributions of VFA to the body, the VFA may indirectly influence cholesterol synthesis and even help regulate insulin or glucagon secretion. In addition, VFA production and absorption have a very significant effect on epithelial cell growth, blood flow, and the normal secretory and absorptive functions of the large intestine, cecum, and rumen. The absorption of VFA and sodium, for example, seem to be interdependent, and release of bicarbonate usually occurs during VFA absorption.(ABSTRACT TRUNCATED AT 400 WORDS)

The objective of the present study was to develop a rat model that replicates the natural history and metabolic characteristics of human type 2 diabetes and is also suitable for pharmacological screening. Male Sprague-Dawley rats (160-180 g) were divided into two groups and fed with commercially available normal pellet diet (NPD) (12% calories as fat) or in-house prepared high-fat diet (HFD) (58% calories as fat), respectively, for a period of 2 weeks. The HFD-fed rats exhibited significant increase in body weight, basal plasma glucose (PGL), insulin (PI), triglycerides (PTG) and total cholesterol (PTC) levels as compared to NPD-fed control rats. Besides, the HFD rats showed significant reduction in glucose disappearance rate (K-value) on intravenous insulin glucose tolerance test (IVIGTT). Hyperinsulinemia together with reduced glucose disappearance rate (K-value) suggested that the feeding of HFD-induced insulin resistance in rats. After 2 weeks of dietary manipulation, a subset of the rats from both groups was injected intraperitoneally with low dose of streptozotocin (STZ) (35 mg kg(-1)). Insulin-resistant HFD-fed rats developed frank hyperglycemia upon STZ injection that, however, caused only mild elevation in PGL in NPD-fed rats. Though there was significant reduction in PI level after STZ injection in HFD rats, the reduction observed was only to a level that was comparable with NPD-fed control rats. In addition, the levels of PTG and PTC were further accentuated after STZ treatment in HFD-fed rats. In contrast, STZ (35 mg kg(-1), i.p.) failed to significantly alter PI, PTG and PTC levels in NPD-fed rats. Thus, these fat-fed/STZ-treated rats simulate natural disease progression and metabolic characteristics typical of individuals at increased risk of developing type 2 diabetes because of insulin resistance and obesity. Further, the fat-fed/STZ-treated rats were found to be sensitive for glucose lowering effects of insulin sensitizing (pioglitazone) as well as insulinotropic (glipizide) agents. Besides, the effect of pioglitazone and glipizide on the plasma lipid parameters (PTG and PTC) was shown in these diabetic rats. The present study represents that the combination of HFD-fed and low-dose STZ-treated rat serves as an alternative animal model for type 2 diabetes simulating the human syndrome that is also suitable for testing anti-diabetic agents for the treatment of type 2 diabetes.

BACKGROUND

Exposure to cardiovascular risk factors during childhood and adolescence may be associated with the development of atherosclerosis later in life.

OBJECTIVE

To study the relationship between cardiovascular risk factors measured in childhood and adolescence and common carotid artery intima-media thickness (IMT), a marker of preclinical atherosclerosis, measured in adulthood.

METHODS

Population-based, prospective cohort study conducted at 5 centers in Finland among 2229 white adults aged 24 to 39 years who were examined in childhood and adolescence at ages 3 to 18 years in 1980 and reexamined 21 years later, between September 2001 and January 2002.

METHODS

Association between cardiovascular risk variables (levels of low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides; LDL-C/HDL-C ratio; systolic and diastolic blood pressure; body mass index; smoking) measured in childhood and adulthood and common carotid artery IMT measured in adulthood.

RESULTS

In multivariable models adjusted for age and sex, IMT in adulthood was significantly associated with childhood LDL-C levels (P =.001), systolic blood pressure (P<.001), body mass index (P =.007), and smoking (P =.02), and with adult systolic blood pressure (P<.001), body mass index (P<.001), and smoking (P =.004). The number of risk factors measured in 12- to 18-year-old adolescents, including high levels (ie, extreme age- and sex-specific 80th percentile) of LDL-C, systolic blood pressure, body mass index, and cigarette smoking, were directly related to carotid IMT measured in young adults at ages 33 through 39 years (P<.001 for both men and women), and remained significant after adjustment for contemporaneous risk variables. The number of risk factors measured at ages 3 to 9 years demonstrated a weak direct relationship with carotid IMT at ages 24 to 30 years in men (P =.02) but not in women (P =.63).

CONCLUSIONS

Risk factor profile assessed in 12- to 18-year-old adolescents predicts adult common carotid artery IMT independently of contemporaneous risk factors. These findings suggest that exposure to cardiovascular risk factors early in life may induce changes in arteries that contribute to the development of atherosclerosis.

OBJECTIVE

We examined the associations of objectively measured sedentary time and physical activity with continuous indexes of metabolic risk in Australian adults without known diabetes.

METHODS

An accelerometer was used to derive the percentage of monitoring time spent sedentary and in light-intensity and moderate-to-vigorous-intensity activity, as well as mean activity intensity, in 169 Australian Diabetes, Obesity and Lifestyle Study (AusDiab) participants (mean age 53.4 years). Associations with waist circumference, triglycerides, HDL cholesterol, resting blood pressure, fasting plasma glucose, and a clustered metabolic risk score were examined.

RESULTS

Independent of time spent in moderate-to-vigorous-intensity activity, there were significant associations of sedentary time, light-intensity time, and mean activity intensity with waist circumference and clustered metabolic risk. Independent of waist circumference, moderate-to-vigorous-intensity activity time was significantly beneficially associated with triglycerides.

CONCLUSIONS

These findings highlight the importance of decreasing sedentary time, as well as increasing time spent in physical activity, for metabolic health.

BACKGROUND

The effect of childhood risk factors for cardiovascular disease on adult mortality is poorly understood.

METHODS

In a cohort of 4857 American Indian children without diabetes (mean age, 11.3 years; 12,659 examinations) who were born between 1945 and 1984, we assessed whether body-mass index (BMI), glucose tolerance, and blood pressure and cholesterol levels predicted premature death. Risk factors were standardized according to sex and age. Proportional-hazards models were used to assess whether each risk factor was associated with time to death occurring before 55 years of age. Models were adjusted for baseline age, sex, birth cohort, and Pima or Tohono O'odham Indian heritage.

RESULTS

There were 166 deaths from endogenous causes (3.4% of the cohort) during a median follow-up period of 23.9 years. Rates of death from endogenous causes among children in the highest quartile of BMI were more than double those among children in the lowest BMI quartile (incidence-rate ratio, 2.30; 95% confidence interval [CI], 1.46 to 3.62). Rates of death from endogenous causes among children in the highest quartile of glucose intolerance were 73% higher than those among children in the lowest quartile (incidence-rate ratio, 1.73; 95% CI, 1.09 to 2.74). No significant associations were seen between rates of death from endogenous or external causes and childhood cholesterol levels or systolic or diastolic blood-pressure levels on a continuous scale, although childhood hypertension was significantly associated with premature death from endogenous causes (incidence-rate ratio, 1.57; 95% CI, 1.10 to 2.24).

CONCLUSIONS

Obesity, glucose intolerance, and hypertension in childhood were strongly associated with increased rates of premature death from endogenous causes in this population. In contrast, childhood hypercholesterolemia was not a major predictor of premature death from endogenous causes.

BACKGROUND

The scarcity of data addressing the health effects of popular diets is an important public health concern, especially since patients and physicians are interested in using popular diets as individualized eating strategies for disease prevention.

OBJECTIVE

To assess adherence rates and the effectiveness of 4 popular diets (Atkins, Zone, Weight Watchers, and Ornish) for weight loss and cardiac risk factor reduction.

METHODS

A single-center randomized trial at an academic medical center in Boston, Mass, of overweight or obese (body mass index: mean, 35; range, 27-42) adults aged 22 to 72 years with known hypertension, dyslipidemia, or fasting hyperglycemia. Participants were enrolled starting July 18, 2000, and randomized to 4 popular diet groups until January 24, 2002.

METHODS

A total of 160 participants were randomly assigned to either Atkins (carbohydrate restriction, n=40), Zone (macronutrient balance, n=40), Weight Watchers (calorie restriction, n=40), or Ornish (fat restriction, n=40) diet groups. After 2 months of maximum effort, participants selected their own levels of dietary adherence.

METHODS

One-year changes in baseline weight and cardiac risk factors, and self-selected dietary adherence rates per self-report.

RESULTS

Assuming no change from baseline for participants who discontinued the study, mean (SD) weight loss at 1 year was 2.1 (4.8) kg for Atkins (21 [53%] of 40 participants completed, P = .009), 3.2 (6.0) kg for Zone (26 [65%] of 40 completed, P = .002), 3.0 (4.9) kg for Weight Watchers (26 [65%] of 40 completed, P < .001), and 3.3 (7.3) kg for Ornish (20 [50%] of 40 completed, P = .007). Greater effects were observed in study completers. Each diet significantly reduced the low-density lipoprotein/high-density lipoprotein (HDL) cholesterol ratio by approximately 10% (all P<.05), with no significant effects on blood pressure or glucose at 1 year. Amount of weight loss was associated with self-reported dietary adherence level (r = 0.60; P<.001) but not with diet type (r = 0.07; P = .40). For each diet, decreasing levels of total/HDL cholesterol, C-reactive protein, and insulin were significantly associated with weight loss (mean r = 0.36, 0.37, and 0.39, respectively) with no significant difference between diets (P = .48, P = .57, P = .31, respectively).

CONCLUSIONS

Each popular diet modestly reduced body weight and several cardiac risk factors at 1 year. Overall dietary adherence rates were low, although increased adherence was associated with greater weight loss and cardiac risk factor reductions for each diet group.

A hallmark of tuberculosis is the ability of the causative agent, Mycobacterium tuberculosis, to persist for decades despite a vigorous host immune response. Previously, we identified a mycobacterial gene cluster, mce4, that was specifically required for bacterial survival during this prolonged infection. We now show that mce4 encodes a cholesterol import system that enables M. tuberculosis to derive both carbon and energy from this ubiquitous component of host membranes. Cholesterol import is not required for establishing infection in mice or for growth in resting macrophages. However, this function is essential for persistence in the lungs of chronically infected animals and for growth within the IFN-gamma-activated macrophages that predominate at this stage of infection. This finding indicates that a major effect of IFN-gamma stimulation may be to sequester potential pathogens in a compartment devoid of more commonly used nutrients. The unusual capacity to catabolize sterols allows M. tuberculosis to circumvent this defense and thereby sustain a persistent infection.

Formation of senile plaques containing the beta-amyloid peptide (A beta) derived from the amyloid precursor protein (APP) is an invariant feature of Alzheimer's disease (AD). APP is cleaved either by beta-secretase or by alpha-secretase to initiate amyloidogenic (release of A beta) or nonamyloidogenic processing of APP, respectively. A key to understanding AD is to unravel how access of these enzymes to APP is regulated. Here, we demonstrate that lipid rafts are critically involved in regulating A beta generation. Reducing cholesterol levels in N2a cells decreased A beta production. APP and the beta-site APP cleavage enzyme (BACE1) could be induced to copatch at the plasma membrane upon cross-linking with antibodies and to segregate away from nonraft markers. Antibody cross-linking dramatically increased production of A beta in a cholesterol-dependent manner. A beta generation was dependent on endocytosis and was reduced after expression of the dynamin mutant K44A and the Rab5 GTPase-activating protein, RN-tre. This inhibition could be overcome by antibody cross-linking. These observations suggest the existence of two APP pools. Although APP inside raft clusters seems to be cleaved by beta-secretase, APP outside rafts undergoes cleavage by alpha-secretase. Thus, access of alpha- and beta-secretase to APP, and therefore A beta generation, may be determined by dynamic interactions of APP with lipid rafts.