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

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. The 3 PPAR isotypes, PPAR-alpha, PPAR-gamma, and PPAR-delta, play a key role in the regulation of lipid and glucose metabolism. Obesity and the interrelated disorders of the metabolic syndrome have become a major worldwide health problem. In this review, we summarize the critical role of PPARs in regulating inflammation, lipoprotein metabolism, and glucose homeostasis and their potential implications for the treatment of obesity, diabetes, and atherosclerosis.
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PMID:Obesity, peroxisome proliferator-activated receptor, and atherosclerosis in type 2 diabetes. 1655 57

Hypertriglyceridemia is an independent risk factor for the development of cardiovascular disease and is often associated with diabetes, inflammation and the metabolic syndrome. Recently, apolipoprotein A5 (APOA5) was identified as a novel member of the APOA1/C3/A4 gene cluster. Data from mice over-expressing or lacking APOA5 provide direct evidence that this apolipoprotein plays a role in triglyceride metabolism. Moreover, plasma triglyceride levels were found to be strongly associated with APOA5 polymorphisms. The human APOA5 gene is regulated by transcription factors known to affect triglyceride metabolism such as PPARa, RORa, LXR and SREBP-1c and this supports its function. Insulin and interleukins regulate APOA5 gene expression and provide novel clues for the role of this apolipoprotein. To date, the triglyceride lowering action of apoA-V is attributed to the activation of lipoprotein lipase and an acceleration of very low density lipoprotein catabolism. Recent findings indicate that APOA5 could also influence cholesterol homeostasis and probably play a role in hypertriglyceridemia associated with diabetes and inflammation. This review aims to give a comprehensive summary of the current literature and supports the view that APOA5 plays a relevant role in lipid metabolism.
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PMID:Is apolipoprotein A5 a novel regulator of triglyceride-rich lipoproteins? 1644 83

Activated endothelial cells express monocyte chemoattractant protein-1 (MCP-1), a chemokine which is reportedly involved in the recruitment of plasma monocytes in the early stages of atherosclerosis. Since accelerated atherosclerosis is the main complication of diabetes and both diseases encompass an inflammatory reaction, we hypothesized that the anti-inflammatory drugs, aspirin and peroxisome proliferator-activated receptor (PPAR-alpha) activators (fenofibrate and clofibrate), could have an effect on the high glucose-induced MCP-1 expression in endothelial cells. To test this assumption, as well as the possible mechanisms involved, the MCP-1 expression and secretion, the reactive oxygen species levels, nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) expression were determined in human endothelial cells exposed to high glucose concentrations in the presence of aspirin, fenofibrate and clofibrate. Human endothelial cells kept in normal glucose concentration in the absence of drugs were used as control. The results showed that (i) aspirin, fenofibrate and clofibrate decrease significantly the MCP-1 expression and secretion in human endothelial cells; (ii) the high glucose up-regulated expression of MCP-1 in endothelial cells was significantly reduced by inhibitors of NF-kB and reactive oxygen species; (iii) all drugs notably decrease the level of the reactive oxygen species and activation of NF-kB and AP-1. Together, the findings indicate that in endothelial cells aspirin and PPAR-alpha activators reduce the high glucose-increased expression of MCP-1 by a mechanism that includes the inhibition of reactive oxygen species, and decrease of AP-1 and NF-kB activation.
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PMID:Aspirin and PPAR-alpha activators inhibit monocyte chemoattractant protein-1 expression induced by high glucose concentration in human endothelial cells. 1660 Jun 94

Fibrate peroxisome proliferator-activated receptor (PPAR)-alpha ligands are mainly used as hypolipidemic drugs. But this commentary highlights their potential in treating insulin resistance, dyslipidemia, and hypertension and in preventing diabetic nephropathy, inflammation, and cardiovascular disease. Because diabetes is a major contributor to chronic kidney disease and cardiovascular disease, PPAR-alpha agonists may provide greater opportunities for hitting multiple targets in this complex metabolic disease.
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PMID:The PPARalpha ligand fenofibrate: meeting multiple targets in diabetic nephropathy. 1667 21

There are 40 million people with diabetes in China, and the projected increase in the rates of obesity and premature cardiovascular disease is alarming. Most patients prefer to combine traditional Chinese medicine with Western medicine, but there is little or no information about the risks and benefits of this approach. Traditional Chinese medicine identifies three patterns of 'depletion-thirst' syndrome and therapy is aimed at reversing the deficiency in yin and qi, using a combination of products tailored to the symptoms and clinical features of individual patients. In Western medicine a number of new oral and injectable antidiabetic therapies are likely to enter routine clinical practice over the next 5 years, for example long-acting GLP-1 analogues, DPP-IV inhibitors and dual PPAR-alpha, PPAR-gamma agonists. To make best use of these agents in China and to promote diabetes education and health service development, there is a need for improved communication and collaboration between universities and hospitals both inside and outside China; and Western pharmacologists and clinicians need a better understanding of traditional Chinese medicine. There are several examples of institutional cooperation that should further diabetes research in China, for example the Beijing Chaoyang Diabetes Hospital linked with Imperial College, London, and the University of Nottingham, which has a new campus in Ningbo, south of Shanghai.
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PMID:Type 2 diabetes in China: partnerships in education and research to evaluate new antidiabetic treatments. 1672 32

Hyperglycaemia in Type 2 diabetes has a major role in the development of microvascular complications, whereas the dyslipidaemia is the major cause of macrovascular complications. In patients with Type 2 diabetes, activation of PPAR-alpha and PPAR-gamma with the fibrates and glitazones improves dyslipidaemia and increases insulin sensitivity, respectively. Muraglitazar is an agonist at both of these receptors and has been shown to increase high-density lipoprotein cholesterol, decrease triglycerides and improve insulin sensitivity. However, there is also some evidence that muraglitazar has detrimental effects on the cardiovascular system. Before muraglitazar is widely used in the treatment of Type 2 diabetes, more safety testing needs to be undertaken.
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PMID:Muraglitazar: beneficial or detrimental in the treatment of Type 2 diabetes? 1673 9

Flexibility in substrate selection is essential for the heart to maintain production of energy and contractile function, and is managed through multiple mechanisms including PPAR-alpha and AMP-activated protein kinase (AMPK). Rats injected with 55 mg/kg STZ (D55) were kept for 4 days (acute diabetes; D55-A) prior to termination. Fatty acid (FA) oxidation increased in D55-A hearts, with no significant change in gene expression of PPAR-alpha, or its downstream targets. However, both AMPK and ACC phosphorylation were significantly higher in these hearts, effects that were reversed by insulin. Unexpectedly, when the duration of diabetes in D55 rats was extended to 6 weeks (chronic diabetes; D55-C), AMPK and ACC phosphorylation were comparable in control and D55-C hearts. In D55-C rat hearts, lack of AMPK activation was closely associated to an overload of plasma and cardiac lipids. To validate the relationship between lipids and cardiac AMPK activation, we either induced more severe diabetes (100 mg/kg STZ to provoke both hyperglycemia and hyperlipidemia acutely; D100-A) or infused intralipid (IL) to enlarge circulating lipids. There was no difference in cardiac AMPK and ACC phosphorylation in D100-A rats compared to control. Measurement of AMPK and ACC phosphorylation in control and D55-A hearts revealed that their phosphorylation was inhibited by acute intralipid infusion. Our data suggest that activation of AMPK is an adaptation that would ensure adequate cardiac energy production when glucose utilization is compromised. However, in severe diabetes, with the addition of augmented plasma and heart lipids, AMPK activation is prevented, and control of FA oxidation is likely through alternate mechanisms. Given that AMPK plays an important role in preventing cardiac ischemic/reperfusion damage, it is possible that in these diabetic hearts, the accelerated damage observed during exposure to ischemia/reperfusion could be a likely outcome of a compromised activation of AMPK.
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PMID:AMPK control of myocardial fatty acid metabolism fluctuates with the intensity of insulin-deficient diabetes. 1718 7

Recent studies have suggested that n-3 fatty acids, abundant in fish oil, protect against high-fat diet-induced insulin resistance through peroxisome proliferator-activated receptor (PPAR)-alpha activation and a subsequent decrease in intracellular lipid abundance. To directly test this hypothesis, we fed PPAR-alpha null and wild-type mice for 2 weeks with isocaloric high-fat diets containing 27% fat from either safflower oil or safflower oil with an 8% fish oil replacement (fish oil diet). In both genotypes the safflower oil diet blunted insulin-mediated suppression of hepatic glucose production (P < 0.02 vs. genotype control) and PEPCK gene expression. Feeding wild-type mice a fish oil diet restored hepatic insulin sensitivity (hepatic glucose production [HGP], P < 0.002 vs. wild-type mice fed safflower oil), whereas in contrast, in PPAR-alpha null mice failed to counteract hepatic insulin resistance (HGP, P = NS vs. PPAR-alpha null safflower oil-fed mice). In PPAR-alpha null mice fed the fish oil diet, safflower oil plus fish oil, hepatic insulin resistance was dissociated from increases in hepatic triacylglycerol and acyl-CoA but accompanied by a more than threefold increase in hepatic diacylglycerol concentration (P < 0.0001 vs. genotype control). These data support the hypothesis that n-3 fatty acids protect from high-fat diet-induced hepatic insulin resistance in a PPAR-alpha-and diacylglycerol-dependent manner.
Diabetes 2007 Apr
PMID:n-3 Fatty acids preserve insulin sensitivity in vivo in a peroxisome proliferator-activated receptor-alpha-dependent manner. 1725 Dec 75

Adiponectin plays a central role as an antidiabetic and antiatherogenic adipokine. AdipoR1 and AdipoR2 serve as receptors for adiponectin in vitro, and their reduction in obesity seems to be correlated with reduced adiponectin sensitivity. Here we show that adenovirus-mediated expression of AdipoR1 and R2 in the liver of Lepr(-/-) mice increased AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor (PPAR)-alpha signaling pathways, respectively. Activation of AMPK reduced gluconeogenesis, whereas expression of the receptors in both cases increased fatty acid oxidation and lead to an amelioration of diabetes. Alternatively, targeted disruption of AdipoR1 resulted in the abrogation of adiponectin-induced AMPK activation, whereas that of AdipoR2 resulted in decreased activity of PPAR-alpha signaling pathways. Simultaneous disruption of both AdipoR1 and R2 abolished adiponectin binding and actions, resulting in increased tissue triglyceride content, inflammation and oxidative stress, and thus leading to insulin resistance and marked glucose intolerance. Therefore, AdipoR1 and R2 serve as the predominant receptors for adiponectin in vivo and play important roles in the regulation of glucose and lipid metabolism, inflammation and oxidative stress in vivo.
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PMID:Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. 1759 32

Type 2 diabetes mellitus is a disease of complex pathogenesis and pleiotropic clinical manifestations. The greatest clinical challenge in this disease is the prevention of the long-term complications, many of which involve cardiovascular outcomes. The peroxisome proliferator-activated receptor (PPAR) alpha and gamma isoforms of the family of nuclear transcription factors are pharmaceutical targets for therapeutic intervention because they can potentially ameliorate not only the hyperglycemia of diabetes, but also the dyslipidemia that is characteristic of this disorder (low high-density lipoprotein cholesterol, high triglycerides, small, dense low-density lipoprotein particles). Novel drugs with dual PPAR alpha and gamma activity have been under clinical development for type 2 diabetes, and they have shown promise in early studies with regard to glucose lowering and improved lipid profile when compared with the PPAR-gamma-specific thiazolidinediones. Unfortunately, the dual PPARs available to date have some of the PPAR-gamma-associated side effect profile, including fluid retention and weight gain, which have limited the further clinical development of higher doses that show improved efficacy. This review will briefly summarize our understanding of the pathogenesis of type 2 diabetes, the role of the PPAR family of receptors, and the potential for clinical use of this novel emerging class of agents that serve as dual activators of both PPAR-alpha and PPAR-gamma.
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PMID:Dual PPAR alpha/gamma agonists: promises and pitfalls in type 2 diabetes. 1730 76


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