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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Here we propose that glucose metabolism can be understood on the basis of three concept-derived axioms: (I) A hierarchy exists among the glucose-utilizing organs with the brain served first, followed by muscle and fat. (II) Tissue-specific glucose transporters allocate glucose among organs in order to maintain brain glucose concentrations. (III) Exogenous carbohydrate supply compensates for glucose alterations that can temporarily occur in muscle and fat. Derived from the control theory, the simplest solution of allocating supply to 2 organs, e.g. brain and muscle, is a "fishbone"-structured model. We reviewed the literature, searching for neuroendocrine and metabolic mechanisms that can fulfill control functions in such a model: The tissue-specific glucose transporters are differentially regulated. GLUT 1, carrying glucose across the blood-brain-barrier, is independent of insulin. Instead, this trans-endothelial glucose transporter is rather dependent on potent regulators of blood vessel function like vascular endothelial growth factor - a pituitary counterregulatory hormone. GLUT 4, carrying glucose across the membranes of muscle and fat cells, depends on insulin. Thereby, insulin allocates glucose to muscle and fat. The hypothalamus-pituitary-adrenal (HPA) axis, the sympathetic nervous system (SNS), and vascular endothelial growth factor allocate glucose to the brain. Multiple "sensors" (some of which have only recently been identified as ATP sensitive potassium channels) measure glucose or glucose equivalents at various sites of the body: the ventromedial hypothalamus, the lateral hypothalamus, portal vein, pancreatic beta cell, renal tubule, muscle and adipose tissue. Feedback pathways both from the brain and from muscle and fat are involved in regulating glucose allocation and exogenous glucose supply. The main feedback signal from the brain is found to be glucose, that from muscle and fat appears to be leptin. In fact, the literature search revealed two or more biological mechanisms for the function of each component in the model, finding glucose regulation highly redundant. This review focuses on "brain glucose" control. The concept of glucose allocation presented here challenges the common opinion of "blood glucose" being the main parameter controlled. According to the latter opinion, hyperglycemia in the metabolic syndrome is due to a putative defect located within the closed loop including the beta cell, muscle and fat cells. That traditional view leaves some peculiarities of e.g. the metabolic syndrome unexplained. The concept of glucose allocation, however, would predict that weight gain - with abundance of glucose in muscle and fat - increases feedback to the brain (via hyperleptinemia) which in turn results in HPA-axis and SNS overdrive, impaired insulin secretion, and insulin resistance. HPA-axis overdrive would account for metabolic abnormalities such as central adiposity, hyperglycemia, dyslipidemia, and hypertension, that are well known clinical aspects the metabolic syndrome. This novel viewpoint of "brain glucose" control may shed new light on the pathogenesis of the metabolic syndrome and type 2 diabetes.
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PMID:The neuroendocrine control of glucose allocation. 1214 83

Adipocytes have traditionally been considered to be the primary site for whole body energy storage mainly in the form of triglycerides and fatty acids. This occurs through the ability of insulin to markedly stimulate both glucose uptake and lipogenesis. Conventional wisdom held that defects in fuel partitioning into adipocytes either because of increased adipose tissue mass and/or increased lipolysis and circulating free fatty acids resulted in dyslipidemia, obesity, insulin resistance and perhaps diabetes. However, it has become increasingly apparent that loss of adipose tissue (lipodystrophies) in both animal models and humans also leads to metabolic disorders that result in severe states of insulin resistance and potential diabetes. These apparently opposite functions can be resolved by the establishment of adipocytes not only as a fuel storage depot but also as a critical endocrine organ that secretes a variety of signaling molecules into the circulation. Although the molecular function of these adipocyte-derived signals are poorly understood, they play a central role in the maintenance of energy homeostasis by regulating insulin secretion, insulin action, glucose and lipid metabolism, energy balance, host defense and reproduction. The diversity of these secretory factors include enzymes (lipoprotein lipase (LPL) and adipsin), growth factors [vascular endothelial growth factor (VEGF)], cytokines (tumor necrosis factor-alpha, interleukin 6) and several other hormones involved in fatty acid and glucose metabolism (leptin, Acrp30, resistin and acylation stimulation protein). Despite the large number of molecules secreted by adipocytes, our understanding of the pathways and mechanisms controlling intracellular trafficking and exocytosis in adipocytes is poorly understood. In this article, we will review the current knowledge of the trafficking and secretion processes that take place in adipocytes, focusing our attention on two of the best characterized adipokine molecules (leptin and adiponectin) and on one of the most intensively studied regulated membrane proteins, the GLUT4 glucose transporter.
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PMID:An adipocentric view of signaling and intracellular trafficking. 1239 77

Statins and fibrates influence endothelial activity and consequently atherogenesis but the mechanisms are not well understood. Twenty Type 2 diabetic patients with dyslipidemia were treated 3 months with simvastatin (20 mg daily) and then 3 months with fenofibrate (200 mg daily) with 2 months of wash-out between the two treatments. Laboratory parameters of oxidative stress, fibrinolysis and endothelial function were evaluated before and at the end of each treatment period. The significant decrease in serum total and LDL-cholesterol concentrations (P<0.0001) caused by simvastatin was associated with an increase in serum N-acetyl-beta-glucosaminidase activity (P<0.001), ascorbic acid (P<0.001), plasminogen activator inhibitor (PAI-1) (P<0.01), vonWillebrand factor (P<0.05), E-selectin (P<0.01) and vascular endothelial growth factor (P<0.05) concentrations and with a decrease in plasma glutathione (P<0.01) levels. Fenofibrate caused a significant decrease in serum triglyceride concentration (P<0.0001) associated with a decrease in plasma malondialdehyde (P<0.001) and an increase in plasma PAI-1 (P<0.05) and P-selectin (P<0.05) concentrations. We conclude that simvastatin and fenofibrate interact, by different mechanisms, with oxidative stress, a key factor in the modification of fibrinolysis and endothelial function in Type 2 diabetes.
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PMID:Effect of simvastatin and fenofibrate on endothelium in Type 2 diabetes. 1518 81

The results of new investigations have demonstrated that the appearance of microalbuminuria (urinary albumin excretion rate, UAER>30 mg/24 h) in patients with diabetes increases constantly in about 30% of them only, leading to development of renal failure. In the majority of patients, the contemporary methods of treatment permit the normalization of UAER or the inhibition of progression to macroalbuminuria (UAER>300 mg/24 h). Therefore the actual diagnostic criterion for diabetic nephropathy consists of demonstration of persistent macroalbuminuria (or proteinuria > 0,5 g/24h) and diabetic retinopathy when other kidney or urinary tract diseases can be excluded. Persistent micro- or macroalbuminuria are contemporary considered as the markers of generalized vascular endothelial damage, reflecting increased vascular wall permeability for albumin, which is early event in development of atherosclerosis. An association of several traditional risk factors for atherogenesis, including elevated blood pressure levels, dyslipidemia, procoagulatory state, chronic inflammation and increased production of vascular endothelial growth factor (VEGF), with micro- and macro-albuminuria, was demonstrated. The presence of multiple risk factors for atherogenesis and micro- or macro-albuminuria in patients with diabetes is associated with increased incidence of cardiovascular complications and mortality when compared to normoalbuminuric patients. The effective intervention against all factors involved in the development of vascular changes in patients with diabetes is the main target for therapeutic intervention.
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PMID:[What is new in the treatment of diabetes?--The importance of nephro- and cardioprotective management]. 1566 3

Diabetic nephropathy is diagnosed either when persistent increase of urinary albumin excretion rate (UAER) above 30 mg/24h in a patient with diabetes was discovered (early or incipient nephropathy) or when UAER values are persistently elevated above 300 mg/24h (overt or clinical nephropathy). In both situations the additional criteria of presence of diabetic retinopathy and the absence of the evidence of other kidney or renal tract disease should be fulfilled. It was found that the excess of cardiovascular events and mortality occurs already in diabetic patients with persistent microalbuminuria, but is particularly evident in macroalbuminuric diabetic patients and results not only from end-stage renal failure (ESRF) but rather from cardiovascular disease (CVD), the latter mainly in type 2 diabetic patients. Several traditional risk factor for atherosclerosis has been identified in diabetic patients with micro- or macroalbuminuria including elevated blood pressure levels, dyslipidemia and procoagulatory state associated with endothelial dysfunction. Microalbuminuria is currently regarded as a marker of generalized endothelial damage, it reflects transvascular albumin leakage, now recognized as an early event in atherogenesis. Recently the association of microalbuminuria with the marker of chronic inflammation (C-reactive protein) and with increased production of vascular endothelial growth factor (VEGE) was described. Thus, multiple mechanisms are involved in the development and progression of cardiovascular complications both in micro- and macroalbuminuric diabetic patients and all these mechanisms should be regarded as the target for therapeutic intervention.
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PMID:Diabetic nephropathy and cardiovascular diseases. 1635 50

While diabetes mellitus is most often associated with hypertension, dyslipidemia, and obesity, these factors do not fully account for the increased burden of cardiovascular disease in patients with the disease. This strengthens the need for comprehensive studies investigating the underlying mechanisms mediating diabetic cardiovascular disease and, more specifically, diabetes-associated atherosclerosis. In addition to the recognized metabolic abnormalities associated with diabetes mellitus, upregulation of putative pathological pathways such as advanced glycation end products, the renin-angiotensin system, oxidative stress, and increased expression of growth factors and cytokines have been shown to play a causal role in atherosclerotic plaque formation and may explain the increased risk of macrovascular complications. This review discusses the methods used to assess the development of atherosclerosis in the clinic as well as addressing novel biomarkers of atherosclerosis, such as low-density lipoprotein receptor-1. Experimental models of diabetes-associated atherosclerosis are discussed, such as the streptozocin-induced diabetic apolipoprotein E knockout mouse. Results of major clinical trials with inhibitors of putative atherosclerotic pathways are presented. Other topics covered include the role of HMG-CoA reductase inhibitors and fibric acid derivatives with respect to their lipid-altering ability, as well as their emerging pleiotropic anti-atherogenic actions; the effect of inhibiting the renin-angiotensin system by either ACE inhibition or angiotensin II receptor antagonism; the effect of glycemic control and, in particular, the promising role of thiazolidinediones with respect to their direct anti-atherogenic actions; and newly emerging mediators of diabetes-associated atherosclerosis, such as advanced glycation end products, vascular endothelial growth factor and platelet-derived growth factor. Overall, this review aims to highlight the observation that various pathways, both independently and in concert, appear to contribute toward the pathology of diabetes-associated atherosclerosis. Furthermore, it reflects the need for combination therapy to combat this disease.
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PMID:Diabetes mellitus-associated atherosclerosis: mechanisms involved and potential for pharmacological invention. 1648 46

Independent of the association of obesity with dyslipidemia, hypertension, and increased propensity for diabetes, fatness per se is increasingly recognized as a cardiovascular offender. That adipose tissue releases a wide range of adipokines, growth factors, enzymes, and enzyme substrates linked to vascular injury provides a plausible explanation for the role of fat in vascular disease: tumor necrosis factor-alpha, leptin, resistin, interleukin-1, -6, -8, and -18, serum amyloid A, monocyte chemoattractant protein I, macrophage inhibitory factor, aortic carboxypeptidase, hepa-rin-binding epidermal growth factor-like growth factor, vascular endothelial growth factor, transforming growth factor beta, angiotensinogen, cathepsin S, estradiol, cortisol, mineralocorticoid releasing factor, and calcitonin peptides are probable fat-derived prothrombotic, proinflammatory, and proatherosclerotic agents acting in a paracrine and/or endocrine manner. Other adipocyte products such as adiponectin, transforming growth factor beta, and interleukin-10 exert some antiatherogenic effects. The following is a short overview of how adipose tissue products affect the vasculature.
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PMID:Fat cell-derived modulators of vascular cell pathophysiology: the list keeps growing. 1767 16

Diabetic retinopathy is the most common microvascular complication of diabetes mellitus and is the leading cause of blindness amongst working-age adults in Western countries. Large observational and randomized studies have consistently shown that optimal blood glucose and blood pressure control is the key component of intervention strategies aimed to halt or regress the disease, and limit the risk of progression to the proliferative stage, with consequent visual loss up to blindness in most severe cases. Amelioration of dyslipidemia by statins, especially if combined with fenofibrate, may also ameliorate retinopathy in line with a potential pathogenic role of hyperlipidemia. Recently, evidence has also emerged that renin-angiotensin system (RAS) inhibitors may electively prevent or delay progression of retinopathy, possibly because of specific protective effect against the structural and functional retinal changes sustained by local RAS activation. Thus, metabolic and blood pressure control by RAS inhibition is to prevent or limit the onset of retinopathy and its progression towards visual-threatening stages. Topic treatment with anti-vascular endothelial growth factor (VEGF) agents is emerging as a treatment option for retinopathy in advanced stages to limit the need for laser photocoagulation. This option however should be considered with caution due to the risk of systemic adverse events.
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PMID:Prevention and treatment of diabetic retinopathy: evidence from clinical trials and perspectives. 2143 51

Diabetic vascular complications are among the leading causes of morbidity and mortality in diabetic patients. In the past, many studies have focused on the mechanisms of hyperglycemia-induced chronic vascular complications via the formation of toxic metabolites such as oxidative stress, advanced glycosylated end products, persistent activation of protein kinase C, and increased sorbitol concentrations. However, vascular complications result from imbalances caused by increases in systemic toxic metabolites, such as those that occur under conditions of hyperglycemia and dyslipidemia, and by reductions in endogenous protective factors such as insulin, vascular endothelial growth factor, and platelet derived growth factor. This review outlines some of the evidence supporting the importance of enhancing endogenous regenerative factors.
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PMID:New perspectives on diabetic vascular complications: the loss of endogenous protective factors induced by hyperglycemia. 2153 7

Diabetic retinopathy (DR) remains a leading cause of preventable vision loss, despite advances in diabetes care. The burden of DR is likely to increase as the evolving pandemic of type 2 diabetes progresses. Tight control of blood glucose levels and blood pressure are essential for preventing or arresting the development of diabetic retinopathy, but are often difficult to achieve, and DR thus develops in a high proportion of patients. Current treatments for DR such as laser photocoagulation, intravitreous injections of corticosteroids or anti-vascular endothelial growth factor (VEGF) agents are indicated for advanced DR and have significant adverse effects. Therefore, new pharmacological treatments for the early stages of DR are needed. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial included a lipid management arm, in which patients satisfying additional inclusion criteria for the atherogenic dyslipidemia phenotype were randomly assigned to fenofibrate or placebo, each with a statin. In the ACCORD-EYE substudy, randomization to fenofibrate was associated with a significant reduction in the risk of progression of DR. These data confirm and extend the results of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, in which type 2 diabetes patients randomized to fenofibrate benefitted from a significantly lower incidence of laser treatment for retinopathy, progression of retinopathy or a composite measure of retinopathy outcomes. The results of ACCORD-EYE, together with those of FIELD, identify a place for fenofibrate for the prevention of retinopathy alongside intensive management of traditional risk factors, such as hyperglycemia and high blood pressure.
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PMID:Prevention and treatment of diabetic retinopathy: evidence from large, randomized trials. The emerging role of fenofibrate. 2186 48


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