Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Obese male rats of the JCR:LA-cp strain are insulin resistant, normoglycaemic, hypertriglyceridaemic, and atherosclerosis-prone. Such rats were treated from 6 to 39 weeks of age with 5 mg x kg(-1) x day(-1) of D-fenfluramine. The treatment normalised food intake, after 20 weeks of age, to that of lean control animals. At 39 weeks, treated rats weighed about 650 g compared to 800 g for untreated cp/cp rats and 400 g for +/+ controls. Fasting plasma glucose and triglyceride levels were not significantly affected; however, fasting insulin concentrations were lower and the size and volume density of the hyperplastic islets of Langerhans were markedly reduced. The severity of raised atherosclerotic lesions on the aortic arch was decreased by 39% (p < 0.01). Concomitantly, the occurrence of mature, scarred ischaemic myocardial lesions was virtually abolished (p < 0.01). Severe food restriction of the obese rats to normalise body weights to those of lean controls reduced plasma insulin and triglyceride concentrations at 26 weeks of age, but without a significant reduction in the frequency of myocardial lesions. Rats (with established insulin resistance) were treated from 6 to 12 weeks of age with 2.5 mg x kg(-1) x day(-1) of D-fenfluramine. Insulin-mediated glucose turnover during a euglycaemic insulin clamp was strongly increased (p < 0.05). Rats treated from 3 weeks of age (before development of the insulin resistance) showed a significant delay in the development of hyperinsulinaemia and a reduced postprandial increase in plasma insulin. In contrast, restriction of food to that consumed by rats treated with D-fenfluramine did not decrease post-absorptive hyperinsulinaemia. D-fenfluramine treatment markedly improved the maximum relaxant response of aortic rings to acetylcholine, indicating improvement of the defective endothelium-derived relaxation factor system. A matched-food restriction regimen had no effect on vascular relaxation. D-fenfluramine treatment thus improved insulin sensitivity and had anti-atherosclerotic and cardioprotective effects in the presence of continuing obesity and hyperlipidaemia. The results are consistent with the protection of the function and integrity of the vessel wall associated with a decreased hyperinsulinaemia. The results emphasise the importance of focussing treatment of the metabolic syndrome (obesity/insulin resistance/hyperlipidaemia) on improving insulin sensitivity and glycaemic control rather than on the simple normalisation of body weight.
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PMID:Improvement of insulin sensitivity and cardiovascular outcomes in the JCR:LA-cp rat by D-fenfluramine. 956 41

While the causes of obesity remain elusive, the relationship between obesity and insulin resistance is a well-established fact [1]. Insulin resistance is defined as a smaller than normal response to a certain dose of insulin, and contributes to several pathological problems of obese patients such as hyperlipidemia, arteriosclerosis and hypertension. Several pieces of evidence indicate that the cytokine tumor necrosis factor a (TNF-alpha) is an important player in the state of insulin resistance observed during obesity. In this review we will try to summarize what is known about the function of TNF-alpha in insulin resistance during obesity and how TNF-alpha interferes with insulin signaling.
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PMID:TNF-alpha and insulin resistance: summary and future prospects. 960 26

Insulin resistance is an important mechanism in the development of the insulin resistance syndrome and type 2 diabetes. Although treatment has hitherto been confined to metformin or non-pharmacological measures, efforts are now being made to discover new drugs active against insulin resistance, so-called insulin sensitisers, for instance among the thiazolidinedione group. These are beginning to be tested in larger clinical trials where they have manifested effects not only on glucose metabolism but also on other cardiovascular risk factors such as hyperlipidaemia, defective fibrinolysis, and hypertension. However, adverse reactions to one of these drugs, troglitazone, include severe hepatic effects in certain cases. Accordingly, registration of the product has been stopped for use in Europe, but not in the USA and Japan. It is likely to take some time before thiazolidinediones will be introduced for clinical use in this country, though research and development continue.
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PMID:[New drugs against insulin resistance]. 965 40

Moderate protein restriction throughout pregnancy in the rat leads to relative hyperlipidaemia and blunted insulin responsiveness of lipid fuel supply, and impairs foetal growth. The present study examined the basis for these changes. Isocaloric 8% (vs 20%) protein diets were provided throughout pregnancy. Rats were sampled at 19-20 days of gestation. Protein restriction enhanced triacylglycerol (TAG) secretion rates (estimated using Triton WR 1339) 1.6-fold (P < 0.05) in the post-absorptive state. Insulin infusion (4.2 mU/kg per min) decreased plasma TAG concentrations by 33% (P < 0.05) and 48% (P < 0.05) in control (C) and protein-restricted (PR) pregnant groups, an effect associated with suppression of TAG secretion by 42% (P < 0.05) and 51% (P < 0.01) respectively, in the C and PR groups. Since TAG concentrations decline more rapidly, while TAG secretion is enhanced, TAG utilisation during hyperinsulinaemia is enhanced in the PR group. We evaluated whether these changes were associated with dysregulation of lipolysis using adipocytes from two abdominal depots (mesenteric and parametrial). Noradrenaline-stimulated glycerol release was enhanced in parametrial adipocytes (by 40%; P < 0.05) from PR pregnant rats. The anti-lipolytic action of insulin at low concentrations (< or = 15 microU/ml) was impaired by protein restriction (adipocytes from both depots). There was no evidence for altered intra-hepatic regulation of fatty acid (FA) disposal at the level of carnitine palmitoyltransferase. Our results demonstrate increased post-absorptive production of non-carbohydrate energy substrates (TAG and FA) as a consequence of mild protein restriction during pregnancy. These adaptations contribute to a homeostatic strategy to reduce the maternal requirement for gluconeogenesis from available amino acids, optimising the foetal protein supply. Protein restriction also enhances TAG turnover during hyperinsulinaemia. This effect is not a consequence of abnormal regulation of hepatic lipid metabolism by insulin.
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PMID:Moderate protein restriction during pregnancy modifies the regulation of triacylglycerol turnover and leads to dysregulation of insulin's anti-lipolytic action. 978 99

1. The antihyperglycaemic effect and the possible mechanism of action of T-174, a novel thiazolidinedione derivative, was determined in vivo and in vitro. 2. Oral administration of T-174 markedly improved hyperglycaemia, hyperinsulinaemia, hyperlipidaemia, and glucose intolerance in genetically obese and diabetic yellow KK (KK-Ay) mice (0.2-15.5 mg kg(-1) day(-1), for 7 days) and Zucker fatty rats (1.4-11.4 mg kg(-1) day(-1), for 6 days). The ED50 values for the glucose lowering action of T-174 and pioglitazone, another thiazolidinedione antidiabetic, were 1.8 and 29 mg kg(-1) day(-1), respectively in KK-Ay mice; T-174 was about 16 times more potent than pioglitazone. 3. The hypoglycaemic effect of exogenous insulin in KK-Ay mice was enhanced after the administration of T-174. A hyperinsulinaemic euglycaemic clamp study in Zucker fatty rats showed an amelioration of whole-body insulin resistance by the T-174 treatment. 4. Insulin-stimulated glucose metabolism was enhanced in adipocytes from KK-Ay mice treated with T-174. The insulin receptor number of the adipocytes was increased without a change in the affinity of the receptor. 5. The hypomagnesaemia in KK-Ay mice was completely restored by T-174. 6. In cultured L6 myotubes, glucose consumption and [3H]-2-deoxy-glucose transport were enhanced by T-174 (EC50; 6 and 4 microM, respectively). Combination of insulin with T-174 was additive to stimulate glucose disposal. 7. These results suggest that the antihyperglycaemic effect of T-174 was mediated by enhanced insulin action. This was associated with amelioration of the hypomagnesaemia and T-174 directly increased basal and insulin-stimulated glucose utilization by cultured muscle cells.
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PMID:Actions of novel antidiabetic thiazolidinedione, T-174, in animal models of non-insulin-dependent diabetes mellitus (NIDDM) and in cultured muscle cells. 980 23

LDL cholesterol is the principal vascular risk factor but it is not the only one. Paradoxically, the atherogenic role of triglycerides or that of metabolic abnormalities of triglyceride-rich lipoproteins has been underestimated. It is convenient to use the term "second atherogenic phenotype" for those phenotypes associating a hypertriglyceridaemia, a low HDL-cholesterol, a moderate increase in LDL cholesterol composition (the small dense LDL). Insulin resistance could be the common denominator of these different abnormalities, increasing the production of triglyceride-rich lipoproteins and decreasing their catabolism. In this concept which remains hypothetical, insulin resistance would appear to be a vascular risk factor. Its role could be direct or indirect by the many risk factors described in the syndrome X. The taking into account of this second atherogenic phenotype of hyperlipidaemia has obvious therapeutic implications because of the choice of diet and treatment. Though stains represent the treatment of choice of high LDL cholesterol, the fibrates are useful in the treatment of hypertriglyceridaemia, low HDL-cholesterol and small and dense LDL. Therapeutic trials comparing the efficacy of statins and fibrates with respect to cardiovascular and global mortality should provide future information in this debate.
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PMID:[The "second atherogenic phenotype" or the role of insulin resistance in vascular risk]. 983 78

Postprandial lipemia is an inherent feature of diabetic dyslipidemia and highly prevalent in diabetic patients even with normal fasting triglyceride concentrations. Postprandial lipemia is characterized by long residence time of chylomicron and VLDL remnants in the circulation. Insulin resistance causes increased flux of free fatty acids, and thus enhanced VLDL apolipoprotein B (apo B) synthesis in the liver. Together with chylomicron and VLDL remnant competition for the common removal mechanisms the increased substrate input results in exaggerated and prolonged postprandial lipemia. Studies using both apo B-48 and retinyl esters as a marker for intestinally derived particles have shown that increased postprandial lipemia does not predict the presence or absence of coronary artery disease between non-insulin-dependent diabetes mellitus (NIDDM) subjects. Recent data have shown that postprandial triglyceride-rich remnants are atherogenic, and postprandial hypertriglyceridemia contributes to the metabolic disturbances transforming LDL and HDL subclasses into more atherogenic direction in diabetic subjects.
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PMID:Postprandial lipid metabolism in diabetes. 988 43

Prevalence of atherosclerotic vascular disease is markedly increased among individuals with diabetes-mellitus and hypertension. Its major clinical manifestations are consequences of atherosclerosis of coronary arteries, cerebral arteries and large arteries of lower extremities. Thus, atherosclerotic vascular disease is the major cause of mortality and significant morbidity in diabetes and hypertension. Dyslipidemia, hyperinsulinemia, and central obesity seem to be associated with increased risk of atherosclerosis, along with the development of hypertension and diabetes (NIDDM). Insulin resistance is the fundamental factor in this situation which has strong genetic predisposition. Accelerated atherosclerosis in diabetes due to mechanism unique to diabetes like non-enzymatic glycation of proteins, oxidative modification of lipoproteins, formation of lipoproteins immune complexes, lipoproteins aggregation, disturbances of cell replication and growth factors and propensity to thrombosis are clearly established. Therapeutic implication for the prevention of atherosclerosis in diabetes and hypertension clearly emphasizes the need to achieve tight control of hyperglycemia, hypertension, and hyperlipidemia in addition to avoiding cigarette smoking and developing obesity.
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PMID:Pathogenesis of atherosclerosis in diabetes and hypertension. 1005 43

Insulin resistance is an early and major feature in the development of non-insulin-dependent diabetes mellitus(NIDDM). It is also associated with hyperlipidemia, hypertension, obesity and cardiovascular disease. It is the clustor of the risk factors for atherosclerosis and recognized as 'insulin-resistance syndrome' (Syndrome X). Central (abdominal) obesity is much more strongly associated with insulin resistance than overall obesity. The increase of both the influx of free fatty acid to liver and the production of TNF-alpha in adipose tissue may play an important role in mechanism of insulin resistance associated with central obesity. Calorie restriction and weight loss improve insulin sensitivity in overweight humans. Exercise training also improves insulin sensitivity via increased oxidative enzymes, glucose transporters (GLUT4) and capillarity in muscle as well as by reducing abdominal fat. The new 'glitazones' (thiazolidinediones) is used clinically to improve insulin sensitivity.
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PMID:[Syndrome X]. 1019 44

Recent clinical studies showed that an independent association between hyper-insulinaemia and coronary heart disease (CHD) in men with normal glucose tolerance. In non-insulin-dependent diabetes mellitus (NIDDM) it is less clear. Therefore, we evaluated insulin-sensitivity index, plasma glucose, insulin, lipoproteins and apolipoproteins in 40 male NIDDM patients with CHD, and compared them with 36 male NIDDM patients without CHD. The insulin-sensitivity index determined by the reverse of fasting plasma glucose and insulin product. The results showed that the subjects with CHD had significantly lower insulin-sensitivity index (P < 0.01) compared to those without CHD. Using step-wise logistic regression analgsis, we found insulin-sensitivity indexes (OR 0.237, 95%CI 0.0909-0.6167, P = 0.0032) were negatively associated with CHD, and were independent from other cardiovascular risk factors such as age, body mass index, hypertension, and hyperlipemia. We conclude that in NIDDM patients with CHD are more insulin resistant compared to those without CHD. Insulin resistance is associated with CHD, and independent from other cardiovascular risk factors.
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PMID:[Relationship between insulin resistance and coronary heart disease in non-insulin-dependent diabetes mellitus patients]. 1037 10


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