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

Glycation and/or oxidation of LDL may promote diabetic nephropathy. The mitogen-activated protein kinase (MAPK) cascade, which includes extracellular signal-regulated protein kinases (ERKs), modulates cell function. Therefore, we examined the effects of LDL on ERK phosphorylation in cultured rat mesangial cells. In cells exposed to 100 microg/ml native LDL or LDL modified by glycation, and/or mild or marked (copper-mediated) oxidation, ERK activation peaked at 5 min. Five minutes of exposure to 10-100 microg/ml native or modified LDL produced a concentration-dependent (up to sevenfold) increase in ERK activity. Also, 10 microg/ml native LDL and mildly modified LDL (glycated and/or mildly oxidized) produced significantly greater ERK activation than that induced by copper-oxidized LDL +/- glycation (P < 0.05). Pretreatment of cells with Src kinase and MAPK kinase inhibitors blocked ERK activation by 50-80% (P < 0.05). Native and mildly modified LDL, which are recognized by the native LDL receptor, induced a transient spike of intracellular calcium. Copper-oxidized (+/- glycation) LDL, recognized by the scavenger receptor, induced a sustained rise in intracellular calcium. The intracellular calcium chelator (EGTA/AM) further increased ERK activation by native and mildly modified LDL (P < 0.05). These findings demonstrate that native and modified LDL activate ERKs 1 and 2, an early mitogenic signal, in mesangial cells and provide evidence for a potential link between modified LDL and the development of glomerular injury in diabetes.
Diabetes 2000 Dec
PMID:Native and modified LDL activate extracellular signal-regulated kinases in mesangial cells. 1111 21

During the postprandial state, dietary lipid is transported from the intestine to peripheral tissues by plasma lipoproteins called chylomicrons. In the capillary beds of peripheral tissues, chylomicron triglycerides are lipolyzed by the enzyme, lipoprotein lipase, allowing the delivery of free fatty acids to the cells. As a result, this produces a new particle of smaller size and enriched with cholesteryl ester referred to as chylomicron remnants. These particles are rapidly removed from the blood primarily by the liver. The liver has a complex chylomicron remnant removal system which is comprised of a combination of different mechanisms that include the low-density-lipoprotein receptor (LDLR) and the LDLR-related-protein (LRP). Furthermore, it has been suggested that there is a sequestration component whereby chylomicron remnants bind to heparan sulfate proteoglycans (HSPG) and/or hepatic lipase; this is then followed by transport to one or both of the above receptors for hepatic uptake. Over the years, a major concern has arisen about the association of chylomicron remnants and coronary heart disease (CHD) in man. Slow removal of chylomicron remnants, as reflected by a prolonged postprandial state, is now commonly observed in patients with CHD and those that have abnormal lipid disorders such as hypertriglyceridemia, familial hypercholesterolemia, familial combined hyperlipidemia and non-insulin-dependent-diabetes-mellitus. The present review will focus on (a) the details of the metabolic pathway (exogenous pathway) that describes the two-step processing of postprandial lipoproteins, (b) the role of the liver, the receptors, and the importance of efficient removal of chylomicron remnants from the blood circulation, and (c) the potential atherogenic effects of chylomicron remnants on the arterial wall.
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PMID:Postprandial lipoproteins and atherosclerosis. 1122 85

Epidemiological evidence shows that among women, the incidence of all, including less severe, coronary events is still increasing. However, owing both to diminished lethality as well as the reduction in the rate of acute myocardial infarction, mortality has globally decreased. The strong association observed between mortality and major cardiovascular risk factors as well as between their temporal changes and the occurrence of coronary disease makes the undertaking of multifactorial prevention strategies, including the formulation of risk charts for asymptomatic women and men, necessary. The different "penetrance" of risk factors in women, together with their interaction with female hormones, plays an important role in the development of cardiovascular disease. The excess risk of cigarette smoking is 2-4 times higher in women than in men and the correlation with the number of cigarettes smoked daily is distinct. However, the risk starts to decrease immediately after stopping and after 3-5 years is similar to that of non-smokers. In women, the association between hypertension, coronary artery disease and early mortality is stronger than in men: there is no threshold below which the risk disappears. Diet and lifestyle strongly influence the development of hypertension. For this reason, the American Heart Association/American College of Cardiology guidelines recommend adherence to a set of dietary and lifestyle habits including body weight control and physical activity. In particular, diet may modify the "penetrance" of risk factors in women: hence excess intake of saturated fatty acids associated with decreased cereals, fruit and vegetables does not only alter the lipid profile but also increases the risk of coronary disease. An elevated total/HDL cholesterol ratio and the presence of lipoprotein(a) constitute significant risk factors for coronary events. On the other hand, high HDL cholesterol levels (> 45 mg/dl) are considered to be protective in women. However, data on the efficacy of strategies aimed at reducing blood LDL levels in hypercholesterolemic women are limited and controversial. Pharmacological therapy is recommended in women with primary familial hypercholesterolemia and during menopause when the patient presents with two or more risk factors. Besides, pharmacological therapy is also indicated for women with a history of coronary artery disease in whom benefits exceed those observed in male patients with a similar clinical picture. In diabetic women, the risk of coronary mortality is increased 3 to 7-fold compared to the 2 to 3-fold increase observed in diabetic men. Diabetes definitely increases the effects of the other risk factors and modifies the protective effect by estrogens. However, to date, there is no evidence that keeping glucose levels within normal limits reduces the risk of coronary artery disease nor has a glycemic threshold capable of predicting mortality risk in diabetic women been established. For this reason, guidelines for such patients are aimed at keeping the other risk factors under strict control in order to significantly reduce their effect. Obesity results in a series of metabolic alterations that increase the risk of cardiovascular disease in both sexes. Although most, if not all, data confirm that obesity alone is not of predictive value, central obesity constitutes a risk factor for cardiovascular disease. A body mass index < 24.9 kg/m2 and a waist circumference < 80 cm are recommended so as to decrease the likelihood of developing a menopausal insulin-resistance syndrome. It has been demonstrated that in men, a sedentary lifestyle is correlated with a higher cardiovascular and all-cause mortality; some recent observational studies suggest a 25-30% decrease in the mortality risk for women who perform physical exercise. Current guidelines recommend at least 30 min daily of dynamic moderately vigorous activity, including brisk walking. Rather than to the reduction in the serum levels of endogenous estrogens, the increase in the incidence of disease and of mortality following menopause should be attributed to the age-related modifications in risk factors which result in an increased risk of coronary artery disease. In spite of the proved detrimental effect of estrogen deficiency on LDL- and HDL-cholesterol, on arterial smooth muscle cell proliferation and on insulin secretion and in spite of the data of numerous observational studies and of the HERS trial (all, however, with methodological limitations), clinical evidence does not justify widespread estrogen prescription, not even for purposes of secondary prevention. Besides, the dosages and the route of administration are still subject of debate. (ABSTRACT TRUNCATED)
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PMID:[Cardiovascular risk factors and prevention in women: similarities and differences]. 1125 80

The nonenzymatic glycation of LDL is a naturally occurring chemical modification of apolipoprotein (apo)-B lysine residues by glucose. Once glycated, LDL is only poorly recognized by lipoprotein receptors including the LDL receptor (LDL-R), the LDL-R-related protein (LRP), and scavenger receptors. Glycated LDL (gLDL) is a preferred target for oxidative modifications. Additionally, its presence initiates different processes that can be considered "proatherogenic." Thus, LDL glycation might contribute to the increased atherosclerotic risk of patients with diabetes and familial hypercholesterolemia. Here we investigate whether lipoprotein lipase (LPL) can mediate the cellular uptake of gLDL. The addition of exogenous LPL to the culture medium of human skin fibroblasts, porcine aortic endothelial cells, and mouse peritoneal macrophages enhanced the binding, uptake, and degradation of gLDL markedly, and the relative effect of LPL on lipoprotein uptake increased with the degree of apoB glycation. The efficient uptake of gLDL by LDL-R-deficient fibroblasts and LRP-deficient Chinese hamster ovary cells in the presence of LPL suggested a mechanism that was independent of the LDL-R and LRP. In macrophages, the uptake of gLDL was also correlated with their ability to produce LPL endogenously. Mouse peritoneal macrophages from genetically modified mice, which lacked LPL, exhibited a 75% reduction of gLDL uptake compared with normal macrophages. The LPL-mediated effect required the association of the enzyme with cell surface glycosaminoglycans but was independent of its enzymatic activity. The uptake of gLDL in different cell types by an LPL-mediated process might have important implications for the cellular response after gLDL exposure as well as the removal of gLDL from the circulation.
Diabetes 2001 Jul
PMID:Lipoprotein lipase mediates the uptake of glycated LDL in fibroblasts, endothelial cells, and macrophages. 1142 87

The influence of opuntia robusta (prickly pear), a traditionally used dietary nutrient against diabetes mellitus among the American Indian population, was examined in 15 young patients suffering from familial heterozygous isolated hypercholesterolemia. Oxidation injury was determined via 8-epi-PGF(2 alpha)in plasma, serum and urine. Daily consumption of 250 g broiled edible pulp of prickly pear had no influence on body weight and body fat composition. Total cholesterol was lowered (P<0.01) as was LDL-cholesterol (P<0.04). No significant changes were observed either in triglycerides or in HDL. Prickly pear induced a significant decrease in plasma (27.9+/-3.3-->25.6+/-3.2;P<0.03), serum (302.0+/-11.4-->283.2+/-14.5;P<0.0003) and urinary (355.9+/-18.4-->323.9+/-16;P<0.00002) 8-epi-PGF(2alpha)values. The findings on a decrease of 8-epi-PGF(2alpha)were more pronounced in females than in males, the highest significance being found in urine, while, in contrast, the effects on total- and LDL-cholesterol were more pronounced in males. A prerunning 4 weeks period of dietary counseling had no significant effect on either of the parameters examined. These findings indicate that the regular ingestion of opuntia robusta is able to significantly reduce in-vivo oxidation injury in a group of patients suffering from familial hypercholesterolemia. This traditional food of the American Indians thus may have a significant cardiovascular benefit.
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PMID:Regular ingestion of opuntia robusta lowers oxidation injury. 1148 8

For the care of an expanding segment of the US population with multiple coronary risk factors, combination lipid-altering therapy is emerging as a treatment imperative. The most recent National Cholesterol Education Program's consensus guidelines emphasize long-term global coronary heart disease (CHD) risk status, designate patients with CHD risk equivalents (eg, diabetes, peripheral arterial disease, 20% or more 10-year absolute CHD risk) for aggressive lipid-altering therapy, and deem the metabolic syndrome (eg, obesity, insulin resistance, hypertension, elevated triglycerides, low levels of high-density lipoprotein cholesterol, small dense low-density lipoprotein particles) as a secondary target for intervention. With the advancing age of the US population and the high prevalence of diabetes, the metabolic syndrome, and CHD, increasing numbers of patients will require a more balanced metabolic attack attainable only through combination lipid-altering regimens. Many of these patients, as well as persons at heightened risk for cardiovascular disease because of a range of heritable conditions (eg, familial hypercholesterolemia, familial combined hyperlipidemia), will undoubtedly require binary or ternary regimens involving statins in concert with niacin, fibric-acid derivatives, or bile acid resins. Such approaches enable the clinician to exploit the complementary effects of these agents, allowing them to be administered at low, optimally tolerable doses that are consistent with superior efficacy and a lower risk of adverse events as compared with escalating doses of monotherapy.
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PMID:Combination lipid-altering therapy: an emerging treatment paradigm for the 21st century. 1148 48

Diabetes mellitus accelerating atherosclerosis was associated with the enhanced glycoxidative modification of lipoproteins. LOX-1, the endothelial oxidized LDL receptor might be involved in the pathogenesis of diabetic atherosclerosis. In this study, we examined the vascular expression of LOX-1 in streptozotocin-induced diabetic rats. We found that LOX-1 was significantly increased in diabetic rat aorta compared with nondiabetic control. Immunohistochemistry revealed that the most distinctive staining of LOX-1 was in the endothelial cells, especially in the bifurcations of artery branches from aorta. In cultured aortic endothelial cells, diabetic rat serum and advanced glycation endproducts-BSA induced LOX-1 expression, while control rat serum along with high glucose did not. Applying a competitive inhibition assay, we found that LOX-1 ligand activity was accumulated in the diabetic rat serum, mainly in VLDL/LDL fractions. In addition, VLDL/LDL prominently increased LOX-1 among all the lipoprotein fractions of diabetic rat serum. In conclusion, diabetes markedly upregulated LOX-1 expression in the aortic endothelial cells. The enhanced glycoxidative modification of lipoproteins may contribute to the underlying mechanisms.
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PMID:Diabetes enhances lectin-like oxidized LDL receptor-1 (LOX-1) expression in the vascular endothelium: possible role of LOX-1 ligand and AGE. 1157 59

The aim of this study was to determine whether phenotypes associated with type 2 diabetes are altered in dyslipidemic obese mice. C57BL/6 wild-type, low-density lipoprotein (LDL) receptor-deficient (LDLR-/-), and apolipoprotein E-deficient (apoE-/-) mice were fed a high-fat, high-carbohydrate diet (diabetogenic diet), and the development of obesity, diabetes, and hypertriglyceridemia was examined. Wild-type mice became obese and developed hyperglycemia, but not hypertriglyceridemia, in response to this diet. LDLR-/- mice fed the diabetogenic diet became more obese than wild-type mice and developed severe hypertriglyceridemia and hyperleptinemia. Surprisingly, glucose levels were only modestly higher and insulin levels and insulin-to-glucose ratios were not strikingly different from those of wild-type mice. In contrast, diabetogenic diet-fed apoE-/- mice were resistant to changes in glucose and lipid homeostasis despite becoming obese. These data suggest that modifications in lipoprotein profiles associated with loss of the LDL receptor or apoE function have profound and unique consequences on susceptibility to diet-induced obesity and type 2 diabetic phenotypes.
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PMID:LDL receptor but not apolipoprotein E deficiency increases diet-induced obesity and diabetes in mice. 1173 2

Recent large-scale clinical trials indicate that hypertriglyceridemia is a risk factor in coronary artery disease; however, the mechanism has not yet been completely clarified. We are currently studying the metabolism of triglyceride-rich lipoproteins and their role in atherosclerosis. Remnants, one of atherogenic lipoproteins, showed a marked increase and remained high even 8 hours after fat loading, especially in patients with coronary artery disease or diabetes mellitus. This shows that the postprandial state persists almost the whole day in these patients. Accordingly, it may be important to assess post-prandial remnant concentrations when evaluating risk factors for atherosclerosis. We identified apo B100 expression in the epithelial cells of the small intestine by immunoblotting with anti-apo B100 monoclonal antibody and dot-blotting of PCR-amplified cDNA. This indicates that not only apo B48, but also apo B100 is expressed in human small intestinal epithelium. The expression of apo B100 suggests that dietary VLDL may be synthesized in human small intestinal epithelium and converted into LDL, which may play an important role in atherosclerosis. A new receptor, apo B48, which binds and internalizes triglyceride-rich lipoproteins via a domain in apo B48, was identified in human monocyte-macrophages. The receptor differs from the scavenger receptor family and LDL receptor family because it does not bind acetyl LDL and it does bind VLDL devoid of apo E. Immunohistochemical studies indicate colocalization of anti-apo B48 receptor antibody in human atherosclerotic lesion foam cells, suggesting that apo B48 receptor may contribute to foam cell formation and atherosclerosis.
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PMID:Metabolism of triglyceride-rich lipoproteins and their role in atherosclerosis. 1179 68

We present a 59-year-old woman with severe diabetic scleredema (DS) associated with heterozygous familial hypercholesterolemia (FH). She had been treated with drugs to lower blood glucose, with insulin for diabetes mellitus (DM), and with low-density lipoprotein (LDL) apheresis therapy monthly or every 2 weeks in addition to drugs to lower serum lipids for FH. However, her scleredema had not improved. After we had tried weekly LDL apheresis therapy for a period of 3 years to treat her hyperlipidemia, the levels of her serum lipids were reduced to normal ranges, and scleredema in her nape improved. We also demonstrated the histopathological improvement in dermis of her cervical skin. We conclude that weekly LDL apheresis therapy is effective for diabetic scleredema that is resistant to conventional treatments.
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PMID:Beneficial effect of aggressive low-density lipoprotein apheresis in a familial hypercholesterolemic patient with severe diabetic scleredema. 1180 90


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