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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Large-scale and systemic epidemiological, pathological and experimental studies emphasized and documented the childhood origin of atherosclerosis. There is increasing consensus that lipid levels in children to a large extent determine the rate of coronary artery disease (CAD) in the adult population. Minimal sudanophilic intimal deposits, and the presence of intracellular and extracellular lipid, and a slight increase in interstitial ground substance in 3 years of age or older patients are found. In the Bogalusa Hearth Study aortic fatty streaks were strongly related the antemortem levels of both total cholesterol and low-density lipoprotein cholesterol (LDL-C) independent of race, sex, and age, and were negatively correlated with the ratio of high-density lipoprotein (HDL-C) to low-density plus very-low-density lipoprotein cholesterol (LDL-C+VLDL-C). The potential for primary prevention is real and the strongest piece of evidence for its is the remarkable trend in CHD mortality rates in recent times, rapidly downward in many western countries. A number of factors influence plasma levels of lipid and lipoproteins in newborn, in infants, in children and adolescents and their relevance as possible predictors of adult coronary artery disease. They are certain inherited disorders of dyslipoproteinemia (familial hypercholesterolemia, familial combined hyperlipidemia, hyperapobetalipoproteinemia, and hypoalphalipoproteinemia) and secondary causes of hyperlipidemia (congenital biliary atresia, glycogen storage diseases, hypothyroidism, diabetes mellitus and nephrotic syndrome, etc).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Atherosclerosis and juvenile dyslipidemias]. 818 5

The failure of patients to adhere adequately to prescribed medication and behavioral regimens is an important medical problem. Poor adherence is most common when the treatment regimen is preventive rather than curative, when patients are asymptomatic, and when the duration of treatment is long. For these reasons, adherence with dietary therapy for hypercholesterolemia is well recognized to be a significant clinical and research challenge. Medication adherence has been acknowledged to be a problem for those treatments with significant side effects, such as flushing and pruritus or the low palatability of bile acid sequestering agents. The availability of drugs that lack these effects has long been viewed as an important contribution to improving overall patient compliance. However, the literature on patient adherence with life-long treatment regimens that are simple and palatable (e.g., antihypertensives) suggests that while these improved treatments can enhance adherence, the overall rates of patient compliance still average only 50%. The fact that patients with heterozygous familial hypercholesterolemia are at high risk for early coronary artery disease and death if they fail to adhere to therapy is not sufficient to assure high rates of appropriate therapy over long periods of time, as demonstrated by the poor or erratic adherence commonly reported to treatments for other life-threatening diseases, such as advanced renal disease, hemophilia, and type I diabetes. The measurement of patient adherence to hypercholesterolemia therapy is often neglected in clinical practice and inadequate in hypercholesterolemia research.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Measuring adherence with therapy for chronic diseases: implications for the treatment of heterozygous familial hypercholesterolemia. 821 1

The genetic and environmental determinants of hypertension, lipid abnormalities, and coronary artery disease (CAD) have been studied for 15 years in Utah in population-based multigenerational pedigrees (2500 subjects among 98 pedigrees), twin pairs (74 monozygous and 78 dizygous), hypertensive siblings (131 sibships), siblings with CAD before age 55 (45 sibships), and anecdotally ascertained pedigrees with type II diabetes (271 subjects among 16 pedigrees), lipoprotein lipase deficiency (106 subjects in a single pedigree), and familial hypercholesterolemia (502 heterozygotes among 50 pedigrees). Estimates of heritability ranged from 20 to 75% for blood pressures and blood lipids. A strong positive family history predicts a future occurrence of hypertension (relative risk [RR] = 3.8) and CAD (RR = 12.7). Segregating single-gene effects were found for several 'intermediate phenotypes' associated with hypertension (erythrocyte sodium-lithium countertransport, intraerythrocytic sodium, a relative fat pattern, total urinary kallikrein excretion, and fasting insulin levels). Strong single-gene effects in segregation analysis were also found for low-density lipoprotein (LDL) cholesterol, lipoprotein (a) (Lp[a]), low high-density lipoprotein (HDL) cholesterol, and high apolipoprotein (apo) B. Deoxyribonucleic acid (DNA) markers of lipid abnormalities or hypertension have included LDL-receptor defects, lipoprotein lipase deficiency, high Lp(a), familial defective apo B, decreased quantitative levels of apo B, apo E phenotype, angiotensinogen, and 'glucocorticoid remediable aldosteronism (GRA) hypertension.' Also tested in Utah studies, but not found to be DNA markers for hypertension, were the genetic loci for the structural genes for renin and angiotensin-converting enzyme, and the sodium antiport system. In addition, important gene-gene interactions (LDL receptor with apo E2) and gene-environment interactions (kallikrein with potassium intake) were found.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Genetic basis of familial dyslipidemia and hypertension: 15-year results from Utah. 829 39

Hyperlipidemias may play a role in the progression of various renal diseases, including diabetes mellitus. We therefore examined the characteristics of low-density lipoprotein (LDL) binding and uptake in cultured rat mesangial cells. Mesangial cells bound and took up LDL in a manner consistent with specific receptor mediation. Furthermore, exposure of mesangial cells to LDL enhanced intracellular cholesteryl esterification and decreased de novo cholesterol synthesis. Mesangial cells expressed mRNA for LDL receptor and their expression was downregulated after preloading of cells with LDL. These results are consistent with regulation of cholesterol uptake and metabolism by a specific LDL receptor mechanism. During diabetes the apolipoprotein B of LDL undergoes nonenzymatic glycation, which may alter its affinity for the LDL receptor. Glycation of LDL reduced its affinity for binding to the receptor sites and decreased its uptake by mesangial cells. Thus, during diabetes less LDL may be taken up and more remain extracellularly, where it can be trapped in the matrix. Oxidation of LDL bound to extracellular matrix is believed to be a major factor in the pathobiology of hyperlipidemias. Specific scavenger receptors for oxidized LDL have been described and cloned. We therefore examined whether rat mesangial cells bound and took up oxidized LDL. We demonstrated low-affinity but high-capacity binding sites for oxidized LDL on mesangial cells. In contrast to LDL, which supported mesangial cell proliferation, oxidized LDL was cytotoxic for the cells and resulted in stimulation of mesangial cell prostaglandin E2 production. Trapping of LDL in the extracellular matrix is considered an initial event in LDL-induced vascular pathology. We therefore evaluated binding of LDL and modified LDL to extracellular matrix produced by cultured mesangial cells. Mesangial matrix had a high capacity to bind LDL and modified LDL (glycated or oxidized) in a nonsaturable manner. These results obtained with cultured mesangial cells and their matrix allow the formulation of a working hypothesis. Under normal eulipemic conditions mesangial cells handle LDL in a regulated manner. During hyperlipidemia or expansion of extracellular matrix LDL accumulates in the matrix. There LDL would be subject to oxidative modifications, especially under conditions of mesangial cell stress, such as inflammatory, mechanical, or ischemic injury. Part of the oxidized LDL could be taken up by scavenger receptors on mesangial cells and monocyte-macrophages, resulting in foam cell formation. Excess oxidized LDL, and specifically the lipid peroxides and lysolipids of oxidized LDL, would act as cytotoxic agents on mesangial, epithelial, and endothelial cells, thereby contributing to a vicious cycle of cell damage and sclerosis.
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PMID:Cellular mechanisms of lipid injury in the glomerulus. 832 98

The familial lipoprotein disorder type III hyperlipoproteinemia (HPL) carries a marked increase in the risk of accelerated and premature atherosclerosis, but there is considerable variation among affected individuals in susceptibility to cardiovascular disease (CVD). We studied the influence of independent risk factors for atherosclerosis in 67 patients with clinically overt type III HPL and homozygosity for apolipoprotein (apo) E2. Among the different risk factors (lipid and lipoprotein levels, age, sex, body mass index, smoking status, hypertension, and diabetes mellitus) there was only a statistically significant difference in age between 25 patients with atherosclerosis and 42 patients without atherosclerosis. Serum lipoprotein (a), [Lp, (a)], levels were 30.6% higher in the atherosclerosis group, but this was not statistically significant. We conclude that (in contrast to familial hypercholesterolemia) elevated Lp (a) concentrations may not be regarded as a component of the clinical syndrome of type III HPL.
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PMID:Relation of cardiovascular risk factors to atherosclerosis in type III hyperlipoproteinemia. 837 May 76

Hyperlipidemia is first detected by an increase in the plasma concentrations of cholesterol and/or triglycerides, and implies an abnormality of plasma lipoprotein metabolism. Disorders of lipoprotein metabolism are often classified specifically according to the lipoprotein affected. The WHO classification of lipoprotein phenotypes is a useful means of showing which lipoproteins are present in excess in individual hyperlipidemic patients. Hyperlipoproteinemia can be secondary to other well-known diseases that affect plasma lipoprotein metabolism, for example, diabetes mellitus, hypothyroidism or nephrotic syndrome. When such diseases are excluded, the hyperlipoproteinemia is defined as primary hyperlipoproteinemia. Many primary hyperlipoproteinemias have a genetic basis and the underlying molecular defect has been clarified in some genetic disorders. Hyperlipoproteinemia is considered to be one of the major risk factors for atherosclerosis and the development of atherosclerosis depends on the type of hyperlipoproteinemia. In this sense, familial hypercholesterolemia is a clinically important primary hyperlipoproteinemia because of its high risk of ischemic heart disease and its high prevalence in a normal population (1/500). It is necessary to make an exact diagnosis of specific genetic disorder, if possible, to provide prognostic and therapeutic information.
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PMID:[Primary hyperlipoproteinemia]. 841 90

Insulin resistance is found in association with obesity, non-insulin-dependent diabetes mellitus, and essential hypertension, which are all risk factors for atherosclerotic cardiovascular disease. Furthermore, hyperinsulinemia has been reported in familial combined hyperlipoproteinemia and endogenous hypertriglyceridemia. Finally, relatively high serum triglyceride and low high-density lipoprotein (HDL) cholesterol concentrations invariably accompany hyperinsulinemia. Whether insulin sensitivity is affected by the isolated presence of high levels of serum low-density lipoprotein (LDL) cholesterol has not been clearly established. We studied 13 subjects with heterozygous familial hypercholesterolemia (FHC) and 15 normocholesterolemic subjects selected to be free of any other known cause of insulin resistance. Thus FHC patients and controls had normal body weight and fat distribution, glucose tolerance, blood pressure, and serum triglyceride and HDL cholesterol concentrations, but were completely separated on plasma LDL cholesterol concentrations (6.05 +/- 0.38 v 3.27 +/- 0.15 mmol/L, P < .0001). Fasting plasma levels of glucose, insulin, free fatty acids (FFA), and potassium and fasting rates of net carbohydrate and lipid oxidation were superimposable in the two study groups. During a 2-hour euglycemic (approximately 5 mmol/L) hyperinsulinemic (approximately 340 pmol/L) clamp, whole-body glucose disposal rates averaged 30.4 +/- 2.3 and 31.1 +/- 3.0 mumol.kg-1 x min-1 in FHC and control subjects, respectively (P = 0.88). The ability of exogenous hyperinsulinemia to stimulate carbohydrate oxidation and energy expenditure and suppress lipid oxidation and plasma FFA and potassium levels was equivalent in FHC and control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin sensitivity in familial hypercholesterolemia. 841 51

Reactions involving glycation and oxidation of proteins and lipids are believed to contribute to atherogenesis. Glycation, the nonenzymatic binding of glucose to protein molecules, can increase the atherogenic potential of certain plasma constituents, including low-density lipoprotein (LDL). Glycation of LDL is significantly increased in diabetic patients compared with normal subjects, even in the presence of good glycemic control. Metabolic abnormalities associated with glycation of LDL include diminished recognition of LDL by the classic LDL receptor; increased covalent binding of LDL in vessel walls; enhanced uptake of LDL by macrophages, thus stimulating foam cell formation; increased platelet aggregation; formation of LDL-immune complexes; and generation of oxygen free radicals, resulting in oxidative damage to both the lipid and protein components of LDL and to any nearby macromolecules. Oxidized lipoproteins are characterized by cytotoxicity, potent stimulation of foam cell formation by macrophages, and procoagulant effects. Combined glycation and oxidation, "glycoxidation," occurs when oxidative reactions affect the initial products of glycation, and results in irreversible structural alterations of proteins. Glycoxidation is of greatest significance in long-lived proteins such as collagen. In these proteins, glycoxidation products, believed to be atherogenic, accumulate with advancing age: in diabetes, their rate of accumulation is accelerated. Inhibition of glycation, oxidation, and glycoxidation may form the basis of future antiatherogenic strategies in both diabetic and nondiabetic individuals.
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PMID:Glycation and oxidation: a role in the pathogenesis of atherosclerosis. 843 58

Low density lipoproteins (LDLs) were isolated by ultracentrifugation and radiolabeled with 111In. The in vitro binding of these radiolabels onto platelets of normolipemic volunteers (n = 15) and patients (n = 36) with heterozygous familial hypercholesterolemia (FH) was investigated. Binding was saturable and indicated high-affinity binding sites capable of binding 1,757 +/- 289 ng protein of 111In-LDL per 10(9) platelets (dissociation constant [Kd], 6 +/- 3 micrograms protein/mL) in healthy volunteers and significantly (p < 0.001) lower amounts in the FH patients (mean, 633 +/- 341 ng protein/10(9) platelets; Kd, 10 +/- 5 micrograms protein/mL). The capacity of native LDL to displace bound 111In-LDL by half amounted to 10 +/- 4 micrograms protein/mL in volunteers and 22 +/- 8 micrograms protein/mL in FH patients (p < 0.001). Treatment with gemfibrozil alone or in combination with cholestyramine in 10 patients resulted in increased 111In-LDL binding by platelets (470 +/- 307 [mean +/- SD] ng protein/10(9) platelets before therapy, 948 +/- 650 ng protein/10(9) platelets after 2 months of therapy [p < 0.01], and 1,272 +/- 701 ng protein/10(9) platelets after 6 months of therapy [p < 0.01]). Significant correlations between 111In-LDL binding capacity and apolipoprotein B (r = -0.83, p < 0.001) and LDL cholesterol (r = -0.80, p < 0.000) concentrations were found. Patients with clinically manifested atherosclerosis (p < 0.01) and those with diabetes mellitus (p < 0.05) had significantly lower platelet LDL binding sites. The findings demonstrate 111In-lipoprotein-specific binding sites on human platelets.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Binding of 111In-labeled LDL to platelets of normolipemic volunteers and patients with heterozygous familial hypercholesterolemia. 846 89

Low density lipoprotein (LDL) subclass phenotype B, characterized by a predominance of small LDL as determined by gradient gel electrophoresis, has been associated with increased risk of coronary heart disease and an atherogenic lipoprotein profile. Previous studies employing complex segregation analysis have demonstrated a major, single gene effect on the inheritance of this phenotype in families. Recently, linkage between this phenotype and variation at the LDL receptor locus on chromosome 19 has been reported. However, variation in LDL subclass phenotypes has also been associated with age, gender, diabetes status, beta-blocker medication, and diet. The present study further evaluates the relative importance of genetic and nongenetic influences on LDL subclass phenotypes and on LDL peak particle diameter (as a reflection of the size of the major LDL subclass) in monozygotic and dizygotic women twin pairs. The analysis is based on 203 monozygotic and 145 dizygotic pairs of adult female twins who participated in the second examination of the Kaiser Permanente Women Twins Study. The average age was 51 years at this exam and 90% were white. Concordance analysis revealed that monozygotic cotwins shared LDL subclass phenotypes more frequently than dizygotic cotwins, and this was confirmed using logistic regression analysis after controlling for potential confounding factors. Heritability analyses suggested that approximately one third to one half of the variation in LDL peak particle diameter, a continuous variable reflecting LDL size, could be attributed to genetic influences. Commingling analysis of the frequency distribution of LDL peak particle diameter identified three distinct subgroups of subjects, one of which corresponded to those subjects with LDL subclass phenotype B.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Genetics of LDL subclass phenotypes in women twins. Concordance, heritability, and commingling analysis. 848 20


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