Cardiovascular disease (CVD) is the leading cause of death and disability worldwide. Raised blood pressure (BP), cholesterol and smoking, are the major risk factors. Among these, raised BP is the most important cause, accounting for 62% of strokes and 49% of coronary heart disease. Importantly, the risk is throughout the range of BP, starting at systolic 115 mm Hg. There is strong evidence that our current consumption of salt is the major factor increasing BP and thereby CVD. Furthermore, a high salt diet may have direct harmful effects independent of its effect on BP, for example, increasing the risk of stroke, left ventricular hypertrophy and renal disease. Increasing evidence also suggests that salt intake is related to obesity through soft drink consumption, associated with renal stones and osteoporosis and is probably a major cause of stomach cancer. In most developed countries, a reduction in salt intake can be achieved by a gradual and sustained reduction in the amount of salt added to food by the food industry. In other countries where most of the salt consumed comes from salt added during cooking or from sauces, a public health campaign is needed to encourage consumers to use less salt. Several countries have already reduced salt intake, for example, Japan (1960-1970), Finland (1975 onwards) and now the United Kingdom. The challenge is to spread this out to all other countries. A modest reduction in population salt intake worldwide will result in a major improvement in public health.

The mammalian proprotein convertases constitute a family of nine secretory serine proteases that are related to bacterial subtilisin and yeast kexin. Seven of these (proprotein convertase 1 (PC1), PC2, furin, PC4, PC5, paired basic amino acid cleaving enzyme 4 (PACE4) and PC7) activate cellular and pathogenic precursor proteins by cleavage at single or paired basic residues, whereas subtilisin kexin isozyme 1 (SKI-1) and proprotein convertase subtilisin kexin 9 (PCSK9) regulate cholesterol and/or lipid homeostasis via cleavage at non-basic residues or through induced degradation of receptors. Proprotein convertases are now considered to be attractive targets for the development of powerful novel therapeutics. In this Review, we summarize the physiological functions and pathological implications of the proprotein convertases, and discuss proposed strategies to control some of their activities, including their therapeutic application and validation in selected disease states.

Novel synthetic lipid derivatives of poly(ethylene glycol) (PEG) have been synthesized and tested for their ability to decrease uptake of liposomes into the mononuclear phagocyte system (MPS, reticuloendothelial system) in mice and to prolong circulation half-lives of liposomes. A carbamate derivative of PEG-1900 with distearoylphosphatidylethanolamine (PEG-DSPE) had the greatest ability to decrease MPS uptake of liposomes, at optimum concentrations of 5-7 mol% in liposomes composed of sphingomyelin/egg phosphatidylcholine/cholesterol (SM/PC/Chol, 1:1:1, molar ratio). Results obtained with this compound were equivalent to results previously obtained with 10 mol% monosialoganglioside GM1 in liposomes of similar compositions (Allen, T.M. and Chonn, A. (1987) FEBS Lett. 223, 42-46). Non-derivatized methyl PEG or PEG-stearic acid (PEG-SA) were incapable of decreasing MPS uptake of liposomes. PEG-Chol and PEG-dipalmitoylglycerol (PEG-DPG) were intermediate in their effects on MPS uptake. Altering liposome size for liposomes containing PEG-DSPE resulted in only minor changes in blood levels of liposomes. Half-lives of 0.1 microns liposomes of SM/PC/Chol/PEG-DSPE (1:1:1:0.2, molar ratio) in circulation was in excess of 20 h following either i.v. or i.p. injection. Liver plus spleen liposome levels for these liposomes was below 15% of injected label at 48 h following i.v. liposome injection and below 10% following i.p. injection. The major site of liposome uptake was in carcass tissues, with over 50% of label remaining in vivo at 48 h post-injections, either i.v. or i.p., in the carcass.

Biochemical, epidemiological, and genetic findings demonstrate a link between cholesterol levels, processing of the amyloid precursor protein (APP), and Alzheimer's disease. In the present report, we identify the alpha-secretase ADAM 10 (a disintegrin and metalloprotease) as a major target of the cholesterol effects on APP metabolism. Treatment of various peripheral and neural cell lines with either the cholesterol-extracting agent methyl-beta-cyclodextrin or the hydroxymethyl glutaryl-CoA reductase inhibitor lovastatin resulted in a drastic increase of secreted alpha-secretase cleaved soluble APP. This strong stimulatory effect was in the range obtained with phorbol esters and was further increased in cells overexpressing ADAM 10. In cells overexpressing APP, the increase of alpha-secretase activity resulted in a decreased secretion of Abeta peptides. Several mechanisms were elucidated as being the basis of enhanced alpha-secretase activity: increased membrane fluidity and impaired internalization of APP were responsible for the effect observed with methyl-beta-cyclodextrin; treatment with lovastatin resulted in higher expression of the alpha-secretase ADAM 10. Our results demonstrate that cholesterol reduction promotes the nonamyloidogenic alpha-secretase pathway and the formation of neuroprotective alpha-secretase cleaved soluble APP by several mechanisms and suggest approaches to prevention of or therapy for Alzheimer's disease.

The gut microbiota is considered a metabolic "organ" that not only facilitates harvesting of nutrients and energy from the ingested food but also produces numerous metabolites that signal through their cognate receptors to regulate host metabolism. One such class of metabolites, bile acids, is produced in the liver from cholesterol and metabolized in the intestine by the gut microbiota. These bioconversions modulate the signaling properties of bile acids via the nuclear farnesoid X receptor and the G protein-coupled membrane receptor 5, which regulate numerous metabolic pathways in the host. Conversely, bile acids can modulate gut microbial composition both directly and indirectly through activation of innate immune genes in the small intestine. Thus, host metabolism can be affected through microbial modifications of bile acids, which lead to altered signaling via bile acid receptors, but also by altered microbiota composition.

OBJECTIVE

To assess the relation between forced expiratory volume in one second (FEV1) and subsequent mortality.

METHODS

Prospective general population study.

METHODS

Renfrew and Paisley, Scotland.

METHODS

7058 men and 8353 women aged 45-64 years at baseline screening in 1972-6.

METHODS

Mortality from all causes, ischaemic heart disease, cancer, hung and other cancers, stroke, respiratory disease, and other causes of death after 15 years of follow up.

RESULTS

2545 men and 1894 women died during the follow up period. Significant trends of increasing risk with diminishing FEV1 are apparent for both sexes for all the causes of death examined after adjustment for age, cigarette smoking, diastolic blood pressure, cholesterol concentration, body mass index, and social class. The relative hazard ratios for all cause mortality for subjects in the lowest fifth of the FEV1 distribution were 1.92 (95% confidence interval 1.68 to 2.20) for men and 1.89 (1.63 to 2.20) for women. Corresponding relative hazard ratios were 1.56 (1.26 to 1.92) and 1.88 (1.44 to 2.47) for ischaemic heart disease, 2.53 (1.69 to 3.79) and 4.37 (1.84 to 10.42) for lung cancer, and 1.66 (1.07 to 2.59) and 1.65 (1.09 to 2.49) for stroke. Reduced FEV1 was also associated with an increased risk for each cause of death examined except cancer for lifelong nonsmokers.

CONCLUSIONS

Impaired lung function is a major clinical indicator of mortality risk in men and women for a wide range of diseases. The use of FEV1 as part of any health assessment of middle aged patients should be considered. Smokers with reduced FEV1 should form a priority group for targeted advice to stop smoking.

BACKGROUND

Coronary heart disease patients with low high-density lipoprotein cholesterol (HDL-C) levels, high triglyceride levels, or both are at an increased risk of cardiovascular events, but the clinical impact of raising HDL-C or decreasing triglycerides remains to be confirmed.

RESULTS

In a double-blind trial, 3090 patients with a previous myocardial infarction or stable angina, total cholesterol of 180 to 250 mg/dL, HDL-C < or =45 mg/dL, triglycerides < or =300 mg/dL, and low-density lipoprotein cholesterol < or =180 mg/dL were randomized to receive either 400 mg of bezafibrate per day or a placebo; they were followed for a mean of 6.2 years. The primary end point was fatal or nonfatal myocardial infarction or sudden death. Bezafibrate increased HDL-C by 18% and reduced triglycerides by 21%. The frequency of the primary end point was 13. 6% on bezafibrate versus 15.0% on placebo (P=0.26). After 6.2 years, the reduction in the cumulative probability of the primary end point was 7.3%, (P=0.24). In a post hoc analysis in the subgroup with high baseline triglycerides >> or =200 mg/dL), the reduction in the cumulative probability of the primary end point by bezafibrate was 39.5% (P=0.02). Total and noncardiac mortality rates were similar, and adverse events and cancer were equally distributed.

CONCLUSIONS

Bezafibrate was safe and effective in elevating HDL-C levels and lowering triglycerides. An overall trend in a reduction of the incidence of primary end points was observed. The reduction in the primary end point in patients with high baseline triglycerides >> or =200 mg/dL) requires further confirmation.

Two treatments, fasting/refeeding and administration of liver X receptor (LXR) agonists, elevate the mRNA for sterol regulatory element-binding protein-1c (SREBP-1c) and enhance lipid synthesis in liver. These treatments do not affect the mRNA for SREBP-1a, an alternative transcript from the same gene. Through homologous recombination, we eliminated the exon encoding SREBP-1c from the mouse genome, leaving the SREBP-1a transcript intact. On a normal diet, livers of SREBP-1c(-/-) mice manifested reductions in multiple mRNAs encoding enzymes of fatty acid and triglyceride synthesis, including acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). In contrast, SREBP-1c(-/-) livers showed a compensatory increase in hepatic SREBP-2 mRNA, accompanied by increased mRNA levels for cholesterol biosynthetic enzymes. In fasted/refed animals, ACC and FAS mRNAs rose, but not to the same extent as in wild-type livers. The refeeding-induced increase in SREBP-1c(-/-) mice was greater than in mice lacking SREBP cleavage-activating protein (SCAP), in which all nuclear SREBPs are absent. Thus, SREBP-2 and/or SREBP-1a can substitute partially for SREBP-1c in permitting an insulin-mediated increase in ACC and FAS mRNAs. In contrast, mRNAs for several other lipogenic enzymes (glucose-6-phosphate dehydrogenase, malic enzyme, glycerol-3-phosphate acyltransferase, and stearoyl-CoA desaturase-1) showed a complete failure of the normal inductive response to refeeding, indicating specific reliance on SREBP-1c. Moreover, these mRNAs, as well as multiple other lipogenic mRNAs, showed a markedly blunted response to the LXR agonist T090137, indicating an essential role of SREBP-1c in the LXR response.

The endoplasmic reticulum (ER) is an intracellular organelle consisting of a membranous labyrinth network that extends throughout the cytoplasm of the cell and is contiguous with the nuclear envelope. In all eukaryotic cells, the ER is the site where folding and assembly occurs for proteins destined to the extracellular space, plasma membrane, and the exo/endocytic compartments. The ER is exquisitely sensitive to alterations in homeostasis, and provides stringent quality control systems to ensure that only correctly folded proteins transit to the Golgi and unfolded or misfolded proteins are retained and ultimately degraded. A number of biochemical and physiologic stimuli, such as perturbation in calcium homeostasis or redox status, elevated secretory protein synthesis, expression of misfolded proteins, sugar/glucose deprivation, altered glycosylation, and overloading of cholesterol can disrupt ER homeostasis, impose stress to the ER, and subsequently lead to accumulation of unfolded or misfolded proteins in the ER lumen. The ER has evolved highly specific signaling pathways called the unfolded protein response (UPR) to cope with the accumulation of unfolded or misfolded proteins. Recent discoveries of the mechanisms of ER stress signaling have led to major new insights into the diverse cellular and physiologic processes that are regulated by the UPR. This review summarizes the complex regulation of UPR signaling and its relevance to human physiology and disease.

The translocator protein (18 kDa) (TSPO) is localized primarily in the outer mitochondrial membrane of steroid-synthesizing cells, including those in the central and peripheral nervous system. One of its main functions is the transport of the substrate cholesterol into mitochondria, a prerequisite for steroid synthesis. TSPO expression may constitute a biomarker of brain inflammation and reactive gliosis that could be monitored by using TSPO ligands as neuroimaging agents. Moreover, initial clinical trials have indicated that TSPO ligands might be valuable in the treatment of neurological and psychiatric disorders. This Review focuses on the biology and pathophysiology of TSPO and the potential of currently available TSPO ligands for the diagnosis and treatment of neurological and psychiatric disorders.

BACKGROUND

Tracking national progress in diabetes care may aid in the evaluation of past efforts and identify residual gaps in care.

METHODS

We analyzed data for adults with self-reported diabetes from the National Health and Nutrition Examination Survey and the Behavioral Risk Factor Surveillance System to examine risk-factor control, preventive practices, and risk scores for coronary heart disease over the 1999-2010 period.

RESULTS

From 1999 through 2010, the weighted proportion of survey participants who met recommended goals for diabetes care increased, by 7.9 percentage points (95% confidence interval [CI], 0.8 to 15.0) for glycemic control (glycated hemoglobin level <7.0%), 9.4 percentage points (95% CI, 3.0 to 15.8) for individualized glycemic targets, 11.7 percentage points (95% CI, 5.7 to 17.7) for blood pressure (target, <130/80 mm Hg), and 20.8 percentage points (95% CI, 11.6 to 30.0) for lipid levels (target level of low-density lipoprotein [LDL] cholesterol, <100 mg per deciliter [2.6 mmol per liter]). Tobacco use did not change significantly, but the 10-year probability of coronary heart disease decreased by 2.8 to 3.7 percentage points. However, 33.4 to 48.7% of persons with diabetes still did not meet the targets for glycemic control, blood pressure, or LDL cholesterol level. Only 14.3% met the targets for all three of these measures and for tobacco use. Adherence to the recommendations for annual eye and dental examinations was unchanged, but annual lipid-level measurement and foot examination increased by 5.5 percentage points (95% CI, 1.6 to 9.4) and 6.8 percentage points (95% CI, 4.8 to 8.8), respectively. Annual vaccination for influenza and receipt of pneumococcal vaccination for participants 65 years of age or older rose by 4.5 percentage points (95% CI, 0.8 to 8.2) and 6.9 percentage points (95% CI, 3.4 to 10.4), respectively, and daily glucose monitoring increased by 12.7 percentage points (95% CI, 10.3 to 15.1).

CONCLUSIONS

Although there were improvements in risk-factor control and adherence to preventive practices from 1999 to 2010, tobacco use remained high, and almost half of U.S. adults with diabetes did not meet the recommended goals for diabetes care.

Sterol regulatory element binding proteins (SREBPs) enhance transcription of genes encoding enzymes of cholesterol and fatty acid biosynthesis and uptake. In the current experiments, we observed a decline in the mRNA encoding one SREBP isoform, SREBP-1c, in the livers of rats that were rendered diabetic by treatment with streptozotocin. There was no change in the mRNA encoding SREBP-1a, which is derived from the same gene as SREBP-1c but uses a different promoter. The ratio of SREBP-1c:1a transcripts fell 25-fold from 5:1 in control rats to 0.2:1 in the diabetic animals. The SREBP-1c mRNA rose nearly to normal, and the 1c:1a ratio increased 17-fold when the diabetic rats were treated for 6 h with insulin. These treatments produced no change in the mRNA for SREBP-2, which is encoded by a separate gene. The SREBP-1c mRNA also fell selectively in freshly isolated rat hepatocytes and rose when the cells were treated with insulin. Considered together with recent data on hepatocytes [Foretz, M., Pacot, C., Dugal, I., et al. (1999) Mol. Cell. Biol. 19, 3760-3768], the current in vivo studies suggest that insulin may stimulate lipid synthesis in the liver by selectively inducing transcription of the SREBP-1c gene.

BACKGROUND

Elevated levels of C-reactive protein (CRP) are associated with increased risks of ischemic heart disease and ischemic cerebrovascular disease. We tested whether this is a causal association.

METHODS

We studied 10,276 persons from a general population cohort, including 1786 in whom ischemic heart disease developed and 741 in whom ischemic cerebrovascular disease developed. We examined another 31,992 persons from a cross-sectional general population study, of whom 2521 had ischemic heart disease and 1483 had ischemic cerebrovascular disease. Finally, we compared 2238 patients with ischemic heart disease with 4474 control subjects and 612 patients with ischemic cerebrovascular disease with 1224 control subjects. We measured levels of high-sensitivity CRP and conducted genotyping for four CRP polymorphisms and two apolipoprotein E polymorphisms.

RESULTS

The risk of ischemic heart disease and ischemic cerebrovascular disease was increased by a factor of 1.6 and 1.3, respectively, in persons who had CRP levels above 3 mg per liter, as compared with persons who had CRP levels below 1 mg per liter. Genotype combinations of the four CRP polymorphisms were associated with an increase in CRP levels of up to 64%, resulting in a theoretically predicted increased risk of up to 32% for ischemic heart disease and up to 25% for ischemic cerebrovascular disease. However, these genotype combinations were not associated with an increased risk of ischemic vascular disease. In contrast, apolipoprotein E genotypes were associated with both elevated cholesterol levels and an increased risk of ischemic heart disease.

CONCLUSIONS

Polymorphisms in the CRP gene are associated with marked increases in CRP levels and thus with a theoretically predicted increase in the risk of ischemic vascular disease. However, these polymorphisms are not in themselves associated with an increased risk of ischemic vascular disease.

Recent research suggests that several of the major diseases of later life, including coronary heart disease, hypertension, and type 2 diabetes, originate in impaired intrauterine growth and development. These diseases may be consequences of "programming," whereby a stimulus or insult at a critical, sensitive period of early life has permanent effects on structure, physiology, and metabolism. Evidence that coronary heart disease, hypertension, and diabetes are programmed came from longitudinal studies of 25,000 UK men and women in which size at birth was related to the occurrence of the disease in middle age. People who were small or disproportionate (thin or short) at birth had high rates of coronary heart disease, high blood pressure, high cholesterol concentrations, and abnormal glucose-insulin metabolism. These relations were independent of the length of gestation, suggesting that cardiovascular disease is linked to fetal growth restriction rather than to premature birth. Replication of the UK findings has led to wide acceptance that low rates of fetal growth are associated with cardiovascular disease in later life. Impaired growth and development in utero seem to be widespread in the population, affecting many babies whose birth weights are within the normal range. Although the influences that impair fetal development and program adult cardiovascular disease remain to be defined, there are strong pointers to the importance of the fetal adaptations invoked when the maternoplacental nutrient supply fails to match the fetal nutrient demand.

BACKGROUND

Despite consensus on the need for blood cholesterol reductions to prevent coronary heart disease (CHD), available evidence on optimal cholesterol levels or the added predictive value of additional lipids is sparse.

RESULTS

After 10 years follow-up of 12 339 middle-aged participants free of CHD in the Atherosclerosis Risk in Communities Study (ARIC), 725 CHD events occurred. The lowest incidence was observed in those at the lowest LDL cholesterol (LDL-C) quintile, with medians of 88 mg/dL in women and 95 mg/dL in men, and risk accelerated at higher levels, with relative risks (RRs) for the highest quintile of 2.7 in women and 2.5 in men. LDL-C, HDL-C, lipoprotein(a) [Lp(a)], and in women but not men, triglycerides (TG) were all independent CHD predictors, providing an RR, together with blood pressure, smoking, and diabetes, of 13.5 in women and 4.9 in men. Lp(a) was less significant in blacks than whites. Prediction was not enhanced by HDL-C density subfractions or apolipoproteins (apo) A-I or B. Despite strong univariate associations, apoB did not contribute to risk prediction in subgroups with elevated TG, with lower LDL-C, or with high apoB relative to LDL-C.

CONCLUSIONS

Optimal LDL-C values are <100 mg/dL in both women and men. LDL-C, HDL-C, TG, and Lp(a), without additional apolipoproteins or lipid subfractions, provide substantial CHD prediction, with much higher RR in women than men.

Although an immense knowledge has accumulated concerning regulation of cholesterol homeostasis in the body, this does not include the brain, where details are just emerging. Approximately 25% of the total amount of the cholesterol present in humans is localized to this organ, most of it present in myelin. Almost all brain cholesterol is a product of local synthesis, with the blood-brain barrier efficiently protecting it from exchange with lipoprotein cholesterol in the circulation. Thus, there is a highly efficient apolipoprotein-dependent recycling of cholesterol in the brain, with minimal losses to the circulation. Under steady-state conditions, most of the de novo synthesis of cholesterol in the brain appears to be balanced by excretion of the cytochrome P-450-generated oxysterol 24S-hydroxycholesterol. This oxysterol is capable of escaping the recycling mechanism and traversing the blood-brain barrier. Cholesterol levels and cholesterol turnover are affected in neurodegenerating disorders, and the capacity for cholesterol transport and recycling in the brain seems to be of importance for the development of such diseases. The possibility has been discussed that administration of inhibitors of cholesterol synthesis may reduce the prevalence of Alzheimer disease. No firm conclusions can, however, be drawn from the studies presented thus far. In the present review, the most recent advances in our understanding of cholesterol turnover in the brain is discussed.

The underlying pathophysiology of the metabolic syndrome is the subject of debate, with both insulin resistance and obesity considered as important factors. We evaluated the differential effects of insulin resistance and central body fat distribution in determining the metabolic syndrome as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III. In addition, we determined which NCEP criteria were associated with insulin resistance and central adiposity. The subjects, 218 healthy men (n = 89) and women (n = 129) with a broad range of age (26-75 years) and BMI (18.4-46.8 kg/m2), underwent quantification of the insulin sensitivity index (Si) and intra-abdominal fat (IAF) and subcutaneous fat (SCF) areas. The metabolic syndrome was present in 34 (15.6%) of subjects who had a lower Si [median: 3.13 vs. 6.09 x 10(-5) min(-1)/(pmol/l)] and higher IAF (166.3 vs. 79.1 cm2) and SCF (285.1 vs. 179.8 cm2) areas compared with subjects without the syndrome (P < 0.001). Multivariate models including Si, IAF, and SCF demonstrated that each parameter was associated with the syndrome. However, IAF was independently associated with all five of the metabolic syndrome criteria. In multivariable models containing the criteria as covariates, waist circumference and triglyceride levels were independently associated with Si and IAF and SCF areas (P < 0.001). Although insulin resistance and central body fat are both associated with the metabolic syndrome, IAF is independently associated with all of the criteria, suggesting that it may have a pathophysiological role. Of the NCEP criteria, waist circumference and triglycerides may best identify insulin resistance and visceral adiposity in individuals with a fasting plasma glucose <6.4 mmol/l.

OBJECTIVE

MRI provides accurate and high-resolution measurements of cardiac anatomy and function. The purpose of this study was to describe the imaging protocol and normal values of left ventricular (LV) function and mass in the Multi-Ethnic Study of Atherosclerosis (MESA).

METHODS

Eight hundred participants (400 men, 400 women) in four age strata (45-54, 55-64, 65-74, 75-84 years) were chosen at random. Participants with the following known cardiovascular risk factors were excluded: current smoker, systolic blood pressure>> 140 mm Hg, diastolic blood pressure>> 90 mm Hg, fasting glucose>> 110 mg/dL, total cholesterol>> 240 mg/dL, and high-density lipoprotein (HDL) cholesterol < 40 mg/dL. Cardiac MR images were analyzed using MASS software (version 4.2). Mean values, SDs, and correlation coefficients in relationship to patient age were calculated.

RESULTS

There were significant differences in LV volumes and mass between men and women. LV volumes were inversely associated with age (p < 0.05) for both sexes except for the LV end-systolic volume index. For men, LV mass was inversely associated with age (slope = -0.72 g/year, p = 0.0021), but LV mass index was not associated with age (slope = -0.179 g/m2/year, p = 0.075). For women, LV mass (slope = -0.15 g/year, p = 0.30) and LV mass index (slope = 0.0044 g/m2/year, p = 0.95) were not associated with age. LV mass was the largest in the African-American group (men, 181.6 +/- 35.8 [SD] g; women, 128.8 +/- 28.1 g) and was smallest in the Asian-American group (men, 129.1 +/- 20.0 g; women, 89.4 +/- 13.3 g).

CONCLUSIONS

The normal LV differs in volume and mass between sexes and among certain ethnic groups. When indexed by body surface area, LV mass was independent of age for both sexes. Studies that assess cardiovascular risk factors in relationship to cardiac function and structure need to account for these normal variations in the population.

OBJECTIVE

The amount and quality of fat in the diet could be of importance for development of insulin resistance and related metabolic disorders. Our aim was to determine whether a change in dietary fat quality alone could alter insulin action in humans.

METHODS

The KANWU study included 162 healthy subjects chosen at random to receive a controlled, isoenergetic diet for 3 months containing either a high proportion of saturated (SAFA diet) or monounsaturated (MUFA diet) fatty acids. Within each group there was a second assignment at random to supplements with fish oil (3.6 g n-3 fatty acids/d) or placebo.

RESULTS

Insulin sensitivity was significantly impaired on the saturated fatty acid diet (-10%, p = 0.03) but did not change on the monounsaturated fatty acid diet (+2%, NS) (p = 0.05 for difference between diets). Insulin secretion was not affected. The addition of n-3 fatty acids influenced neither insulin sensitivity nor insulin secretion. The favourable effects of substituting a monounsaturated fatty acid diet for a saturated fatty acid diet on insulin sensitivity were only seen at a total fat intake below median (37E%). Here, insulin sensitivity was 12.5% lower and 8.8% higher on the saturated fatty acid diet and monounsaturated fatty acid diet respectively (p = 0.03). Low density lipoprotein cholesterol (LDL) increased on the saturated fatty acid diet (+4.1%, p < 0.01) but decreased on the monounsaturated fatty acid diet (MUFA) (-5.2, p < 0.001), whereas lipoprotein (a) [Lp(a)] increased on a monounsaturated fatty acid diet by 12% (p < 0.001).

CONCLUSIONS

A change of the proportions of dietary fatty acids, decreasing saturated fatty acid and increasing monounsaturated fatty acid, improves insulin sensitivity but has no effect on insulin secretion. A beneficial impact of the fat quality on insulin sensitivity is not seen in individuals with a high fat intake >> 37E%).

This review examines the association between the apolipoprotein (apo) var epsilon gene polymorphism (or its protein product (apo E)), metabolic regulation of cholesterol, and cardiovascular disease. The apo var epsilon gene is located at chromosome 19q13.2. Among the variants of this gene, alleles (*) epsilon2, (*) epsilon3, and (*) epsilon4 constitute the common polymorphism found in most populations. Of these variants, apo (*) epsilon3 is the most frequent (>60%) in all populations studied. The polymorphism has functional effects on lipoprotein metabolism mediated through the hepatic binding, uptake, and catabolism of chylomicrons, chylomicron remnants, very low density lipoprotein (VLDL), and high density lipoprotein subspecies. Apo E is the primary ligand for two receptors, the low density lipoprotein (LDL) receptor (also known as the B/E receptor) found on the liver and other tissues and an apo E-specific receptor found on the liver. The coordinate interaction of these lipoprotein complexes with their receptors forms the basis for the metabolic regulation of cholesterol. Allelic variation in apo var epsilon is consistently associated with plasma concentrations of total cholesterol, LDL cholesterol, and apo B (the major protein of LDL, VLDL, and chylomicrons). Apo var epsilon has been studied in disorders associated with elevated cholesterol levels or lipid derangements (i.e., hyperlipoproteinemia type III, coronary heart disease, strokes, peripheral artery disease, and diabetes mellitus). The apo var epsilon genotype yields poor predictive values when screening for clinically defined atherosclerosis despite positive, but modest associations with plaque and coronary heart disease outcomes. In addition to genotype-phenotype associations with vascular disease, the alleles and isoforms of apo var epsilon have been related to dementias, most commonly Alzheimer's disease.

The relation between coronary heart disease (CHD) prevalence and fasting lipid levels was assessed by a case-control study in five populations with a total of 6859 men and women of black, Japanese and white ancestry drawn from subjects aged 40 years and older from populations in Albany, Framingham, Evans County, Honolulu and San Francisco. In each major study group mean levels of high density lipoprotein (HDL) cholesterol were lower in persons with CHD than in those without the disease. The average difference was small -- typically 3-4 mg/dl -- but statistically significant. It was found in most age-race-sex specific groups. The inverse HDL cholesterol-CHD association was not appreciably diminished when adjusted for levels of low density lipoprotein (LDL) cholesterol and triglyceride. LDL, totoal cholesterol and triglycerides were directly related to CHD prevalence; surprisingly, these findings were less uniformly present in the various study groups than the inverse HDL cholesterol-CHD association.

The Cholesterol-Lowering Atherosclerosis Study (CLAS) was a randomized, placebo-controlled, angiographic trial testing combined colestipol hydrochloride and niacin therapy in 162 nonsmoking men aged 40 to 59 years with previous coronary bypass surgery. During two years of treatment there was a 26% reduction in total plasma cholesterol, a 43% reduction in low-density lipoprotein cholesterol, plus a simultaneous 37% elevation of high-density lipoprotein cholesterol. This resulted in a significant reduction in the average number of lesions per subject that progressed (P less than .03) and the percentage of subjects with new atheroma formation (P less than .03) in native coronary arteries. Also, the percentage of subjects with new lesions (P less than .04) or any adverse change in bypass grafts (P less than .03) was significantly reduced. Deterioration in overall coronary status was significantly less in drug-treated subjects than placebo-treated subjects (P less than .001). Atherosclerosis regression, as indicated by perceptible improvement in overall coronary status, occurred in 16.2% of colestipol-niacin treated vs 2.4% placebo treated (P = .002).

Triacylglycerol (TAG) is known to be synthesized in a reaction that uses acyl-CoA as acyl donor and diacylglycerol (DAG) as acceptor, and which is catalyzed by the enzyme acyl-CoA:diacylglycerol acyltransferase. We have found that some plants and yeast also have an acyl-CoA-independent mechanism for TAG synthesis, which uses phospholipids as acyl donors and DAG as acceptor. This reaction is catalyzed by an enzyme that we call phospholipid:diacylglycerol acyltransferase, or PDAT. PDAT was characterized in microsomal preparations from three different oil seeds: sunflower, castor bean, and Crepis palaestina. We found that the specificity of the enzyme for the acyl group in the phospholipid varies between these species. Thus, C. palaestina PDAT preferentially incorporates vernoloyl groups into TAG, whereas PDAT from castor bean incorporates both ricinoleoyl and vernoloyl groups. We further found that PDAT activity also is present in yeast microsomes. The substrate specificity of this PDAT depends on the head group of the acyl donor, the acyl group transferred, and the acyl chains of the acceptor DAG. The gene encoding the enzyme was identified. The encoded PDAT protein is related to lecithin:cholesterol acyltransferase, which catalyzes the acyl-CoA-independent synthesis of cholesterol esters. However, budding yeast PDAT and its relatives in fission yeast and Arabidopsis form a distinct branch within this protein superfamily, indicating that a separate PDAT enzyme arose at an early point in evolution.

OBJECTIVE

The Diabetes Control and Complications Trial (DCCT) demonstrated the powerful impact of glycemic control on the early manifestations of microvascular complications. Contemporary prospective data on the evolution of macrovascular and late microvascular complications of type 1 diabetes are limited. The Epidemiology of Diabetes Interventions and Complications (EDIC) study is a multicenter, longitudinal, observational study designed to use the well-characterized DCCT cohort of>> 1,400 patients to determine the long-term effects of prior separation of glycemic levels on micro- and macrovascular outcomes.

METHODS

Using a standardized annual history and physical examination, 28 EDIC clinical centers that were DCCT clinics will follow the EDIC cohort for 10 years. Annual evaluation also includes resting electrocardiogram. Doppler ultrasound measurements of ankle/arm blood pressure, and screening for nephropathy. At regular intervals, a timed 4-h urine is collected, lipid profiles are obtained, and stereoscopic fundus photographs are taken. In addition, dual B-mode Doppler ultrasound scans of the common and internal carotid arteries will be performed at years 1 and 6 and at study end.

RESULTS

Written informed consent was obtained from 96% of the DCCT subjects. The participants, compared with nonparticipants, tended to have better glycemic control at the completion of the DCCT and were more likely to have their diabetes care provided by DCCT personnel. The EDIC baseline measurement stratified by sex delineates multiple cardiovascular disease risk factor differences such as age (older in men), waist-to-hip ratio (higher in men). HDL cholesterol (lower in men), hypertension (more prevalent in men), and maximum intimal-medial thickness of common and internal carotid arteries (thicker in men). Of the original conventional treatment group, 69% have changed to continuous subcutaneous insulin infusion or multiple daily injections. Although the mean HbA1c difference between the intensive and conventional treatment groups narrowed at EDIC years 1 and 2, HbA1c remained significantly lower in the intensive group. Of all expected clinic visits, 95% were completed, and the quality of EDIC data is very similar to that observed in the DCCT.

CONCLUSIONS

Although obvious problems exist in extended follow-up studies of completed clinical trials, these are balanced by the value of continued systematic observation of the DCCT cohort. In contrast to other epidemiologic studies, EDIC will provide 1) definitive data on type 1 as distinct from type 2 diabetes; 2) reliance on prospective rather than on cross-sectional analysis; 3) long-term follow-up in a large population; 4) consistent use of objective, reliable measures of outcomes and glycemia; and 5) observation of patients from before the onset of complications.