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)

Obesity is associated with a number of pathological disorders such as non-insulin-dependent diabetes, hypertension, hyperlipidemia, and cardiovascular diseases. alpha-Lipoic acid (LA) has been demonstrated to activate the insulin signaling pathway and to exert insulin-like actions in adipose and muscle cells. Based on this similarity LA is expected to promote adipogenesis in pre-adipocytes. Here, however, we report that LA inhibited differentiation of 3T3-L1 pre-adipocytes induced by a hormonal mixture or troglitazone. Northern blot analysis of cells demonstrated that this inhibition was accompanied with attenuated expression of adipocyte-specific fatty acid-binding protein and lipoprotein lipase. Electrophoretic mobility shift assay and Western blot analysis of cells demonstrated that LA modulates transcriptional activity and/or expression of a set of anti- or pro-adipogenic transcription factors. LA treatment of 3T3-L1 pre-adipocytes also resulted in prolonged activation of major mitogen-activated protein kinase signaling pathways but showed little or no effect on the activity of the insulin receptor/Akt signaling pathway. These findings suggest that LA inhibits insulin or the hormonal mixture-induced differentiation of 3T3-L1 pre-adipocytes by modulating activity and/or expression of pro- or anti-adipogenic transcription factors mainly through activating the MAPK pathways.
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PMID:Alpha-lipoic acid inhibits adipocyte differentiation by regulating pro-adipogenic transcription factors via mitogen-activated protein kinase pathways. 1283 69

Chromium was known for many years to be an element causing allergic reactions and having neurotoxic and carcinogenic effects. These effects can be observed especially in the case of hexavalent chromium. Only a little more than four decades ago trivalent chromium has been known as an essential element with relation to glycide and lipid metabolism. And only during several last years this chromium function has been revealed on a molecular level. After absorption in the gastrointestinal tract, chromium is most likely transported to cells bound to the plasma protein transferrin. Insulin initiates chromium transport into the cells where it is bound to the oligopeptide apochromodulin. This oligopeptide combined with four chromium(III) atoms forms chromodulin, which is important for amplifying the insulin signalling effect. After binding to insulin-activated receptor, chromodulin increases tyrosine kinase activity by one order. This enzyme forms a part of intracellular portion of insulin receptor. Chromium supplementation in people with chromium deficiency can improve glucose tolerance and some lipid metabolism parameters. The supplementation is indicated in persons with impaired glucose tolerance both in preclinical and manifested stadium of type 2 diabetes mellitus where increased lost of chromium in urine was documented. In these patients, chromium deficiency can participate in insulin resistance and hyperlipidaemia. Chromium is usually applied in the form of organic compounds: yeast extract or chromium(III) picolinate. Cr(III) picolinate can be reduced to compounds of Cr(II) in the cells which can then produce free hydroxyl radical in the so called Fenton reaction.
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PMID:[Chromium as an essential element]. 1292 32

Insulin resistance and compensatory hyperinsulinemia are recognized not only in type 2 diabetes mellitus(DM) but also in essential hypertension(EHT), hyperlipidemia and obesity; these are known as the components of metabolic syndrome and accumulation of these components increase risk of cardiovascular diseases(CVD). When coronary angiographic findings were evaluated in patients with coronary artery disease(CAD), the severity was higher in CAD with DM than that without DM. Even in CAD without DM, the severity of coronary angiographic findings was higher in CAD with insulin resistance than that without insulin resistance. When residents of rural communities in Japan were followed 8 years, the incidence of CVD was 3.5 times higher in subjects with insulin resistance than those without insulin resistance. One of the intracellular signal transduction of insulin receptor; MAP kinase may be concerned atherosclerotic mechanisms of insulin resistance. These findings suggest that insulin resistance is a significant background of atherosclerosis, and insulin resistance is one of the major facilitation factors of genesis and progression of CVD.
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PMID:[Significance of insulin resistance to atherosclerotic complications in essential hypertension]. 1473 36

Insulin resistance clusters with hyperlipidemia, impaired glucose tolerance, and hypertension as metabolic syndrome X. We tested a low molecular weight insulin receptor activator, demethylasterriquinone B-1 (DMAQ-B1), and a novel indole peroxisome proliferator-activated receptor gamma agonist, 2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid (PPEIA), in spontaneously hypertensive obese rats (SHROB), a genetic model of syndrome X. Agents were given orally for 19 days. SHROB showed fasting normoglycemia but impaired glucose tolerance after an oral load, as shown by increased glucose area under the curve (AUC) [20,700 mg x min/ml versus 8100 in lean spontaneously hypertensive rats (SHR)]. Insulin resistance was indicated by 20-fold excess fasting insulin and increased insulin AUC (6300 ng x min/ml versus 990 in SHR). DMAQ-B1 did not affect glucose tolerance (glucose AUC = 21,300) but reduced fasting insulin 2-fold and insulin AUC (insulin AUC = 4300). PPEIA normalized glucose tolerance (glucose AUC = 9100) and reduced insulin AUC (to 3180) without affecting fasting insulin. PPEIA also increased food intake, fat mass, and body weight gain (81 +/- 12 versus 45 +/- 8 g in untreated controls), whereas DMAQ-B1 had no effect on body weight but reduced subscapular fat mass. PPEIA but not DMAQ-B1 reduced blood pressure. In skeletal muscle, insulin-stimulated phosphorylation of the insulin receptor and insulin receptor substrate protein 1-associated phosphatidylinositol 3-kinase activity were decreased by 40 to 55% in SHROB relative to lean SHR. PPEIA, but not DMAQ-B1, enhanced both insulin actions. SHROB also showed severe hypertriglyceridemia (355 +/- 42 mg/dl versus 65 +/- 3 in SHR) attenuated by both agents (DMAQ-B1, 228 +/- 18; PPEIA, 79 +/- 3). Both these novel antidiabetic agents attenuate insulin resistance and hypertriglyceridemia associated with metabolic syndrome but via distinct mechanisms.
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PMID:Therapeutic actions of an insulin receptor activator and a novel peroxisome proliferator-activated receptor gamma agonist in the spontaneously hypertensive obese rat model of metabolic syndrome X. 1583 94

Insulin resistance plays an important role in the development of such abnormalities as impaired glucose tolerance, type 2 diabetes, obesity, and hyperlipidemia. The rates of these diseases are increasing and their cardiovascular complications are among the most common causes of death worldwide. The discovery of protein tyrosine phosphatase (PTP-1B) seems to be a milestone in the investigation of insulin signaling transmission. PTP-1B is considered a negative regulator of insulin signaling, mainly through insulin receptor dephosphorylation. In animal model studies (Elchebly et al.) there was a significant increase in insulin sensitivity of PTP-1B knock-out mice. There is also evidence that higher expression of the PTP-1B gene causes insulin resistance in humans. PTP-1B inhibitors could thus be promising drugs for insulin resistance therapy. The object of this review is to present current evidence of PTP-1B's role in the pathophysiology of insulin resistance abnormalities and the potential treatment of these disorders.
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PMID:[The role of protein tyrosine phosphatase (PTP-1B) in insulin resistance]. 1592 4

Studies of pioglitazone, troglitazone, BRL 49653 and other thiazolidinediones in preclinical animal models of non-insulin dependent diabetes mellitus (NIDDM) and obesity led to the observation that these compounds were effective in reducing hyperglycaemia and hyperlipidaemia. In these models, animals treated with thiazolidinediones had notable improvements in blood glucose levels, hepatic glucose output, peripheral insulin resistance, and serum lipid levels. Mechanistic studies indicate that thiazolidinediones act at many intracellular sites and can influence several processes to increase cell sensitivity to insulin. These include influence on insulin receptor kinase activity, control of insulin receptor phosphorylation, change in number of insulin receptors, quantity and activity of GLUT-4, modulation of tumour necrosis factor (TNF) activity, activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and alteration of hepatic glucose metabolism. Available data on pioglitazone and troglitazone from clinical studies support the efficacy and safety of this class of compounds in reducing hyperglycaemia, hypertriglyceridaemia and insulin resistance associated with NIDDM. Currently, only troglitazone is approved for use in the United States and only in combination with insulin. This new pharmacological class of drugs has great promise for the treatment of NIDDM and also as a valuable research tool to further the understanding of the mechanisms that underlie NIDDM and insulin resistance syndrome.
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PMID:Mechanisms and clinical effects of thiazolidinediones. 1598 61

In the last few decades, more vitamin-mediated effects have been discovered at the level of gene expression. Increasing knowledge on the molecular mechanisms of these vitamins has opened new perspectives that form a connection between nutritional signals and the development of new therapeutic agents. Besides its role as a carboxylase prosthetic group, biotin regulates gene expression and has a wide repertoire of effects on systemic processes. The vitamin regulates genes that are critical in the regulation of intermediary metabolism: Biotin has stimulatory effects on genes whose action favors hypoglycemia (insulin, insulin receptor, pancreatic and hepatic glucokinase); on the contrary, biotin decreases the expression of hepatic phosphoenolpyruvate carboxykinase, a key gluconeogenic enzyme that stimulates glucose production by the liver. The findings that biotin regulates the expression of genes that are critical in the regulation of intermediary metabolism are in agreement with several observations that indicate that biotin supply is involved in glucose and lipid homeostasis. Biotin deficiency has been linked to impaired glucose tolerance and decreased utilization of glucose. On the other hand, the diabetic state appears to be ameliorated by pharmacological doses of biotin. Likewise, pharmacological doses of biotin appear to decrease plasma lipid concentrations and modify lipid metabolism. The effects of biotin on carbohydrate metabolism and the lack of toxic effects of the vitamin at pharmacological doses suggest that biotin could be used in the development of new therapeutics in the treatment of hyperglycemia and hyperlipidemia, an area that we are actively investigating.
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PMID:Pharmacological effects of biotin. 1599 83

Non-alcoholic steatohepatitis (NASH) is one of the most common liver disorders. This is highly prevalent in obese and diabetic subjects. Persons with central obesity are at particular risk. Other clinical predictors are age more than 40-50 years and hyperlipidemias, but none of these factors is invariable for causation of NASH. Other reported associations are, celiac disease, Wilson's Disease and few other metabolic diseases. Drugs, particularly amiodarone, tamoxifen, nucleoside analogues and methotrxate have also been linked to NASH. The disease is evenly distributed in both sexes but advanced disease is more common in women. Ethnic variation exists and African Americans are less affected than Hispanic Americans. Specific clinical features of NASH are infrequent. Patients usually come to clinical attention by elevated liver enzymes found on routine evaluation but on history, about two third of patients will admit to have mild fatigue and about half will report right upper quadrant pain. Rarely, patient may present with a complication of cirrhosis. Physical examination may reveal hepatomegaly and splenomegaly. Research in last few years has stressed that development of steatosis, stetohepatitis, fibrosis with subsequent cirrhosis are most probably the result of insulin resistance. Therefore, clinical features may reflect existence of insulin resistance. Obesity, particularly central obesity is most important of these. Patients may have sleep apnea syndrome. Hypertension and manifestations of diabetes mellitus like polyuria, polydypsia, and neurological deficits may occur. Patients may have varying combination of obesity, diabetes, hyperlipidemia, hypertension and impaired fibrinolysis (syndrome X). Children with insulin resistance may show acanthosis nigricance. Patients with polycystic ovary syndrome, which consists of insulin resistance, diabetes, obesity, hirsutism, oligo or polymenorrha and hyperlipidemia may have NASH. Other rare manifestations of insulin resistance, which can be seen in patients of NASH are lipomatosis, lipoatrophy/lipodystrophy and panniculitis. Most other rare conditions known to cause NASH like peroxisomal diseases, mitochondialpathies, Weber-Christian disease, Mauriac syndrome, Madelung's lipomatosis and abetaliopprotenemia also have insulin resistance. This is believed that primary defect underlying insulin resistance is impairment in postreceptor pathways (through tyrosine kinase activity) of insulin action. Primary defect in insulin receptors appear uncommon. This results in down regulation of insulin receptor substance 1 (IRS-1) signaling by excess free fatty acids. In muscle, activated IRS-1 promotes translocation of glucose transporter protein 4 (GLUT4) to cell membrane. As a result, monocyte glucose uptake by GLUT4 increases glucose disposal from blood and reduced need for insulin. PKC-0 is a likely candidate as serine kinase in muscle regulated by fatty acids that can impair the activation of IRS-1. Insulin resistance is usually evaluated by fasting insulin levels, Quantitative Insulin Check Index (QUICKI) and Homeostasis Model Assessment of Insulin Resistance (HOMA), C-peptid/insulin ratio oral glucose tolerance test and hyper insulinemic euglycemic clamp. The clamp technique is considered the gold standard.
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PMID:Insulin resistance and clinical aspects of non-alcoholic steatohepatitis (NASH). 1619 20

Melatonin, which is synthesized in the pineal gland and other tissues, has a variety of physiological, immunological, and biochemical functions. It is a direct scavenger of free radicals and has indirect antioxidant effects due to its stimulation of the expression and activity of antioxidative enzymes such as glutathione peroxidase, superoxide dismutase and catalase, and NO synthase, in mammalian cells. Melatonin also reduces serum lipid levels in mammalian species, and helps to prevent oxidative stress in diabetic subjects. Long-term melatonin administration to diabetic rats reduced their hyperlipidemia and hyperinsulinemia, and restored their altered ratios of polyunsaturated fatty acid in serum and tissues. It was recently reported that melatonin enhanced insulin-receptor kinase and IRS-1 phosphorylation, suggesting the potential existence of signaling pathway cross-talk between melatonin and insulin. Because TNF-alpha has been shown to impair insulin action by suppressing insulin receptor-tyrosine kinase activity and its IRS-1 tyrosine phosphorylation in peripheral tissues such as skeletal muscle cells, it was speculated that melatonin might counteract TNF-alpha-associated insulin resistance in type 2 diabetes. This review will focus on the physiological and metabolic effects of melatonin and highlight its potential use for the treatment of cholesterol/lipid and carbohydrate disorders.
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PMID:Metabolic effects of melatonin on oxidative stress and diabetes mellitus. 1621 26

Recent studies suggest that adipose tissue hormones ("adipokines") are involved in the pathogenesis of various complications of obesity, including hyperlipidemia, diabetes mellitus, arterial hypertension, atherosclerosis, and heart failure. Apelin and visfatin are two recently described adipokines, although they are also synthesized outside adipose tissue. Apelin exists in at least three forms, consisting of 13, 17, or 36 amino acids, all originating from a common 77-amino-acid precursor. In the cardiovascular system, apelin elicits endothelium-dependent, nitric oxide-mediated vasorelaxation and reduces arterial blood pressure. In addition, apelin demonstrates potent and long-lasting positive inotropic activity which is preserved even in injured myocardium and is not accompanied by myocardial hypertrophy. Apelin synthesis in adipocytes is stimulated by insulin, and plasma apelin level markedly increases in obesity associated with insulin resistance and hyperinsulinemia. In addition to regulating cardiovascular function, apelin inhibits water intake and vasopressin production. Visfatin, previously recognized as a pre-B cell colony-enhancing factor (PBEF), is abundantly expressed in visceral adipose tissue and is upregulated in some, but not all, animal models of obesity. Preliminary studies suggest that plasma visfatin concentration is also increased in humans with abdominal obesity and/or type 2 diabetes mellitus. Visfatin binds to the insulin receptor at a site distinct from insulin and exerts hypoglycemic effect by reducing glucose release from hepatocytes and stimulating glucose utilization in peripheral tissues. Thus, apelin and visfatin are unique among adipose tissue hormones in that they are upregulated in the obese state and both exert primarily beneficial effects.
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PMID:Apelin and visfatin: unique "beneficial" adipokines upregulated in obesity? 1694 Sep 39


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