Gene/Protein Disease Symptom Drug Enzyme Compound
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Asian ginseng (Panax ginseng) and its close relative North American ginseng (Panax quinquefolius) are perennial aromatic herbs that are widely used in Oriental medicine and have been acclaimed to have various health benefits including diabetes treatment. In this study, we compared the effects of a diet containing rosiglitazone to a diet containing ginseng (Panax quinquefolius) in male Zucker diabetic fatty (ZDF) rats. Animals were assigned to one of three diets: control, rosiglitazone (0.1 g/1 kg diet), or ginseng (10 g/1 kg diet). During the 11-week study, body weight, food intake, organ weight, blood glucose, plasma cholesterol, and plasma triglyceride levels were evaluated. Animals treated with rosiglitazone or ginseng exhibited increased body weight (p<0.05) and decreased kidney weight (p<0.05) compared to control animals. The rosiglitazone group demonstrated decreased food intake and plasma triglyceride levels versus the other groups (p<0.05). The ginseng group revealed decreased cholesterol levels relative to the control group (p<0.05). Furthermore, ginseng and rosiglitazone had marked effects on the expression of genes involved in PPAR actions and triglyceride metabolism compared to controls. In conclusion, ginseng modified the diabetic phenotype and genes associated with diabetes in the male ZDF rat. These data are encouraging, and warrant further research to determine the therapeutic value of this medicinal herb in treating human diabetes.
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PMID:Ginseng modifies the diabetic phenotype and genes associated with diabetes in the male ZDF rat. 1768 44

Obesity is an important component of metabolic syndrome X and predisposes to the development of type 2 diabetes mellitus. The incidence of obesity, type 2 diabetes mellitus and metabolic syndrome X is increasing, and the cause(s) for this increasing incidence is not clear. Although genetics could play an important role in the higher prevalence of these diseases, it is not clear how genetic factors interact with environmental and dietary factors to increase their incidence. We performed gene expression profile in subjects with obesity and type 2 diabetes mellitus with and without family history of these diseases. It was noted that genes involved in carbohydrate, lipid and amino acid metabolism pathways, glycan of biosynthesis, metabolism of cofactors and vitamin pathways, ubiquitin mediated proteolysis, signal transduction pathways, neuroactive ligand-receptor interaction, nervous system pathways, neurodegenerative disorders pathways are upregulated in obesity compared to healthy subjects. In contrast genes involved in cell adhesion molecules, cytokine-cytokine receptor interaction, insulin signaling and immune system pathways are downregulated in obese. Genes involved in signal transduction, regulation of actin cytoskeleton, antigen processing and presentation, complement and coagulation cascades, axon guidance and neurodegenerative disorders pathways are upregulated in subjects with type 2 diabetes with family history of diabetes compared to those who are diabetic but with no family history. Genes involved in oxidative phosphorylation, immune, nervous system, and metabolic disorders pathways are upregulated in those with diabetes with family history of diabetes compared to those with diabetes but with no family history. In contrast, genes involved in lipid and amino acid pathways, ubiquitin mediated proteolysis, signal transduction, insulin signaling and PPAR signaling pathways are downregulated in subjects with diabetes with family history of diabetes. It was noted that genes involved in inflammatory pathway are differentially expressed both in obesity and type 2 diabetes. These results suggest that genes concerned with carbohydrate, lipid and amino acid metabolic pathways, neuronal function and inflammation play a significant role in the pathobiology of obesity and type 2 diabetes.
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PMID:Gene expression profile in obesity and type 2 diabetes mellitus. 1807 24

Peroxisome proliferator-activated receptor gamma (PPARgamma) and dual PPARalpha and gamma agonists have been developed for use in the treatment of diabetes and hyperlipidemias. Vascular tumors were increased in mice treated with some PPAR agonists, but not in rats. Spontaneous hemangiosarcomas are common in several strains of mice, uncommon in rats, and rarely occur in humans. The objective of this study was to determine the endothelial cell proliferation rate in liver and adipose tissue of B6C3F1 mice, F344 rats, and humans to aid in investigations of the genesis and development of hemangiosarcoma formation, and to determine the relevance of the increased endothelial cell proliferation rate in drug-treated rodents in assessing the risk of these drugs in humans. We determined the endothelial cell labeling index (LI) in untreated mice, rats, and humans, in normal liver, brown fat (rats and mice only) and white fat by dual immunohistochemistry of CD31 and Ki-67. The LI, highest in mice and lowest in humans, was statistically significantly greater in the mouse compared to the human and rat. The increased rate of spontaneous or PPAR agonist-induced hemangiosarcoma formation in mice may be related to the higher background endothelial cell proliferation rate compared to rats and humans.
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PMID:Comparison of endothelial cell proliferation in normal liver and adipose tissue in B6C3F1 mice, F344 rats, and humans. 1809 37

The prevalence of the metabolic syndrome is rapidly increasing. This syndrome is characterized by metabolic disturbances, such as abnormal lipid and carbohydrate metabolism and a low-grade inflammatory state. PPARs play an important role in these metabolic processes, which makes them effective targets for treatment and prevention of the metabolic syndrome. Synthetic PPAR agonists, such as fibrates and thiazolidinediones are already used to treat hyperlipidemia and diabetes mellitus, respectively. Besides synthetic ligands, dietary fatty acids and fatty acid derivatives can also bind to an activate PPARs. As demonstrated with ligand-binding assays, PPARs have a clear preference of binding polyunsaturated fatty acids. Monounsaturated fatty acids are also very effective in binding PPARs, whereas saturated fatty acids are poor PPAR binders. However, ligand binding does not necessarily mean transcriptional activation. Therefore, it is important to investigate transactivation properties of dietary fatty acids as PPAR agonists and their role in metabolic reactions. Furthermore, human intervention studies comparing the effects of natural versus synthetic ligands side-by-side may reveal specific fatty acids that exert beneficial PPAR-mediated metabolic effects. The ability of PPARs to sense fatty acids and to mediate lipid metabolism, glucose metabolism and the inflammatory state makes them excellent targets for dietary modulation in order to prevent and treat the metabolic syndrome and associated diseases. This review discusses the role and function of PPARs and their ligands in light of the metabolic syndrome.
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PMID:Peroxisome proliferator-activated receptors and the metabolic syndrome. 1819 67

Obesity results from the complex interaction of environmental factors that act on a genetic background that determines the susceptibility to obesity. The identification of such obesity susceptibility genes can provide important insights into the mechanism underlying this condition. While candidate gene approaches have not been tremendously successful in identifying relevant genetic contributors to obesity, except PPAR , the advent of genome-wide strategies has recently revealed novel and unexpected genetic factors with strong associations with obesity and/or diabetes, i.e. FTO, TCF7L2, INSIG2, ENPP1, or FASN (reviewed herein), although some of them are not undebated. Considering the function of the encoded proteins, it will now be of interest to investigate the cellular and molecular mechanisms, how these genetic variations affect body weight, energy metabolism and/or obesity-associated morbidity.
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PMID:Polygenic contribution to obesity: genome-wide strategies reveal new targets. 1823 Aug 92

Evidence of the effectiveness of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) within continuum of atherothrombotic conditions and particularly in the treatment and prevention of coronary heart disease (CHD) is well established. Large-scale, randomized, prospective trials involving patients with CHD have shown that statins reduce the clinical consequences of atherosclerosis, including cardiovascular deaths, nonfatal myocardial infarction and stroke, hospitalization for acute coronary syndrome and heart failure, as well as the need for coronary revascularization. Direct testing of varying degrees of low-density lipoprotein (LDL)- cholesterol lowering has now been carried out in 4 large outcomes trials: PROVE IT-TIMI 22, A to Z, TNT and IDEAL. However, the question whether more aggressive LDL-cholesterol lowering by high-dose statins monotherapy is an appropriate strategy is still open: higher doses of statins are more effective mainly for the prevention of the nonfatal cardiovascular events but such doses are associated with an increase in hepatotoxicity, myopathy and concerns regarding noncardiovascular death. Moreover, despite the increasing use of statins, a significant number of coronary events still occur and many such events take place in patients presenting with type 2 diabetes and metabolic syndrome. More and more attention is now being paid to combined atherogenic dyslipidemia which typically presented in patients with type 2 diabetes and metabolic syndrome. This mixed dyslipidemia (or 'lipid quartet') - hypertriglyceridemia, low high-density lipoprotein (HDL)-cholesterol levels, a preponderance of small, dense LDL particles and an accumulation of cholesterol-rich remnant particles - emerged as the greatest 'competitor' of LDL-cholesterol among lipid risk factors for cardiovascular disease. Most recent extensions of the fibrates trials (BIP, HHS, VAHIT and FIELD) give further support to the hypothesis that patients with insulin-resistant syndromes such as diabetes and/or metabolic syndrome might be the ones to derive the most benefit from therapy with fibrates. However, different fibrates may have a somewhat different spectrum of effects. Other lipid-modifying strategies included using of niacin, ezetimibe, bile acid sequestrants, CETP inhibitors and omega-3 fatty acids. Particularly, ezetimibe/statins combinations provide superior lipid-modifying benefits compared Tenenbaum/Fisman/Motro/Adler 128 with any statins monotherapy in patients with atherogenic dyslipidemia. Atherogenic dyslipidemia is associated with increased levels of chylomicrons and their remnants containing 3 main components: apolipoprotein B-48, triglycerides and cholesterol ester of intestinal origin. Reduction in accessibility for one of them (specifically cholesteryl ester lessening due to ezetimibe administration) could lead to a decrease of the entire production of chylomicrons and result in a decrease of the hepatic body triglycerides pool as confirmed in number of clinical studies. However, the ENHANCE study showed no difference in the progression of carotid atherosclerosis between ezetimibe/simvastatin vs. simvastatin alone over a 2-year period. Conclusions regarding ezetimibe/statins combinations should not be made until the three large clinical outcome trials will be completed within the next 2-3 years. In addition, bezafibrate as a pan-PPAR activator has clearly demonstrated beneficial pleiotropic effects related to glucose metabolism, insulin sensitivity and pancreatic beta cell protection. Because fibrates, niacin, ezetimibe, omega-3 fatty acids and statins each regulate serum lipids by different mechanisms, combination therapy - selected on the basis of their safety and effectiveness, could be more helpful in achieving a comprehensive lipid control as compared with statins monotherapy.
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PMID:Optimal management of combined dyslipidemia: what have we behind statins monotherapy? 1823 Sep 60

Nonalcoholic fatty liver disease (NAFLD) is a group of diseases with excess fat in liver in the absence of a poorly defined limit of alcohol consumption. Most common variety, a universal public health problem, is associated with insulin resistance caused by a host of genetic and epigenetic defects modulated by life style and environmental factors. In fact the term NAFLD is loose to incorporate so many etiologies except alcoholism and few other etiologies, presenting as fat in liver. However as a sign fatty liver is very important in predicting the risk of diabetes, cardiovascular disease, stroke, cirrhosis and cancer. Abnormal fat accumulation can result from several defects in nuclear receptors associated with lipid sensing, synthesis and oxidation like LXR, FXR, SREBP, ChREBP and PPAR; defects in the lipid influx-efflux channels, insulin signaling, proteins involved in fatty acid catabolism, defects in adipose tissue development and function, inappropriate nutrition and finally defects in neural regulatory mechanisms. The progress of the disease is determined by the basic defects which results in fat accumulation, an individual's immunological response to the accumulated fat and its derivatives and the oxidant stress response. Congregation of unrelated genetic defects under same diagnosis 'NAFLD' can result in inefficient patient management. Further studies are required to understand the molecular basis of fatty liver to enable a personalized management of diseases presenting as fatty liver in the absence of alcohol abuse.
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PMID:The blind men 'see' the elephant-the many faces of fatty liver disease. 1824 Mar 40

Flaxseed lignan secoisolariciresinol diglucoside (SDG) has been reported to prevent and alleviate lifestyle-related diseases including diabetes and hypercholesterolaemic atherosclerosis. This study assesses the effect of SDG on the development of diet-induced obesity in mice and the effect of the SDG metabolite enterodiol (END) on adipogenesis in 3T3-L1 adipocytes. We compared body weight, visceral fat weight, liver fat content, serum parameters, mRNA levels of lipid metabolism-related enzymes and adiponectin in mice fed either a low-fat diet (5 % TAG), high-fat diet (30 % TAG) or high-fat diet containing 0.5 and 1.0 % (w/w) SDG for 4 weeks. Administration of SDG to mice significantly reduced high-fat diet-induced visceral and liver fat accumulation, hyperlipaemia, hypercholesterolaemia, hyperinsulinaemia and hyperleptinaemia. SDG also suppressed sterol regulatory element binding protein 1c mRNA level in the liver and induced increases in the adiponectin mRNA level in the white adipose tissue and carnitine palmitoyltransferase I mRNA level in the skeletal muscle. Differentiated 3T3-L1 adipocytes were treated with 0, 5, 10 and 20 mumol/l END and then assayed for mRNA expression of adipogenesis-related genes and DNA binding activity of PPARgamma to the PPAR response element consensus sequence. END induced adipogenesis-related gene mRNA expression including adiponectin, leptin, glucose transporter 4 and PPARgamma, and induced PPARgamma DNA binding activity in 3T3-L1 adipocytes. In conclusion, SDG induced adiponectin mRNA expression and showed beneficial effects on lipid metabolism in diet-induced obesity in mice. Flaxseed lignans are suggested to regulate adipogenesis-related gene expressions through an increase in PPARgamma DNA binding activity.
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PMID:Flaxseed lignan attenuates high-fat diet-induced fat accumulation and induces adiponectin expression in mice. 1825 24

Type-2 diabetes (T2D) is a complex metabolic disease characterized by insulin resistance in the liver and peripheral tissues accompanied by a defect in pancreatic beta-cell. Since their discovery three subtypes of Peroxisomes Proliferators Activated Receptors were identified namely PPARalpha, PPARgamma and PPARbeta/(delta). We were interested in designing novel PPARgamma selective agonists and/or dual PPARalpha/gamma agonists. Based on the typical topology of synthetic PPAR agonists, we focused our design approach on 4,4-dimethyl-1,2,3,4-tetrahydroquinoline as novel cyclic tail.
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PMID:4,4-Dimethyl-1,2,3,4-tetrahydroquinoline-based PPARalpha/gamma agonists. Part I: synthesis and pharmacological evaluation. 1825 90

Investigating the metabolic functions of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) has been extremely rewarding over the past years. Uncovering the biologic roles of PPARgamma and its mechanism of action has greatly advanced our understanding of the transcriptional control of lipid and glucose metabolism, and compounds such as thiazolidinediones which directly regulate PPARgamma have proven to exhibit potent insulin-sensitizer effects in the treatment of diabetes. We review here recent advances on the emerging role of growth hormone releasing peptides in regulating PPARgamma through interaction with scavenger receptor CD36 and ghrelin GHS-R1a receptor. With the impact that these peptides exert on the metabolic pathways involved in lipid metabolism and energy homeostasis, it is hoped that the development of novel approaches in the regulation of PPAR functions will bring additional therapeutic possibilities to face problems related to metabolic diseases.
PPAR Res 2008
PMID:Hexarelin Signaling to PPARgamma in Metabolic Diseases. 1828 86


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