Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Agonists of PPARalpha and PPARgamma are currently approved for use in treating, respectively, dyslipidemia and type 2 diabetes. Agonists of PPARbeta/delta are currently in development by several pharmaceutical companies. Despite their therapeutic importance, there are dose limiting side effects associated with PPAR drug treatments, thus a new generation of safer PPAR drugs are being actively sought after. In this review we will discuss the side effects associated the PPARs, how the current drugs in clinical development were discovered and new concepts in how to screen for PPAR drugs.
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PMID:The next generation of PPAR drugs: do we have the tools to find them? 1760 66

Activation of the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma) plays an important role in adipogenesis, insulin resistance, and glucose homeostasis. Activators of PPARgamma include the anti-diabetic thiazolidinediones (TZDs), drugs that are in clinical use to treat patients with type 2 diabetes mellitus. Experimental as well as clinical data gathered over the last decade suggest that PPARgamma activators may exert direct modulatory function in the vasculature in addition to their metabolic effects. PPARgamma is expressed in all vascular cells, where its activators exhibit anti-inflammatory and anti-atherogenic properties, suggesting that PPARgamma ligands could influence important processes in all phases of atherogenesis. Results from clinical trials demonstrated that TZDs reduce blood levels of inflammatory biomarkers of arteriosclerosis, improve endothelial function, and directly influence lesion morphology and plaque stability, underscoring that PPAR activators may have direct effects in the vasculature in humans. This review will focus on the vascular effects of PPARgamma activators and summarize the current knowledge of their modulatory function on atherogenesis and vascular disease.
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PMID:Vascular effects of PPARgamma activators - from bench to bedside. 1763 78

This study assessed the effects of tesaglitazar (0.5 or 1 mg/day), a dual peroxisome proliferator-activated receptor alpha/gamma agonist, when added to maximally tolerated metformin (2-2.5 g/day) in patients with poorly controlled type 2 diabetes. The primary end point of this 24-week, randomised, placebo-controlled study was the absolute change from baseline in glycosylated haemoglobin (HbA1C). Tesaglitazar significantly reduced HbA1C, fasting plasma glucose and insulin levels compared with placebo (p<0.0001 for all) when added to metformin. Triglycerides, high-density lipoprotein cholesterol (HDL-C) and non-HDL-C levels also improved with tesaglitazar treatment (p<0.0001 for all). Adverse events were generally similar across treatments, except for higher frequencies of peripheral oedema and weight gain in the tesaglitazar 1 mg group. Although reversibility was not fully evaluated, dose-dependent changes in mean serum creatinine levels and haematology measures tended to return towards baseline at follow-up. Despite the clinical discontinuation of tesaglitazar, this study has demonstrated the potential benefits of dual PPAR agonism as add-on therapy to metformin, in patients with poorly controlled type 2 diabetes.
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PMID:The effects of tesaglitazar as add-on treatment to metformin in patients with poorly controlled type 2 diabetes. 1790 10

A series of 1,3-dioxane carboxylic acid derivatives was synthesized and evaluated for human PPAR transactivation activity. Structure-activity relationships on the phenyloxazole moiety of the lead compound 3 revealed that the introduction of small hydrophobic substituents at the 4-position of the terminal phenyl ring increased the PPARalpha agonist activity, and that the oxazole heterocycle was essential to the maintenance of both potency and PPARalpha subtype-selectivity. This investigation led to the identification of 14d (NS-220) and 14i as highly potent and selective human PPARalpha agonists. In KK-A(y) type 2 diabetic mice, these compounds significantly lowered plasma triglyceride and very-low-density plus low-density lipoprotein cholesterol levels while simultaneously raising HDL cholesterol levels. Our results suggest that highly potent and subtype-selective PPARalpha agonists will be promising drugs for the treatment of metabolic disorders in type 2 diabetes.
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PMID:Structure-activity studies on 1,3-dioxane-2-carboxylic acid derivatives, a novel class of subtype-selective peroxisome proliferator-activated receptor alpha (PPARalpha) agonists. 1796 92

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

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

In recent years new pharmacological agents have emerged, which enable us to widen the spectrum of diabetes management based on clear pathophysiological concepts. One should first of all mention the DPP4-inhibitors and the incretin mimetics, which have the potential of restoring the incretin effect in patients with type 2 diabetes mellitus. Moreover, it has been shown that the agent rimonabant, which was first used in order to achieve weight reduction, also contributed to the significant improvement of metabolic syndrome's parameters. Recent studies have shown that the dual alpha/gamma-PPAR-agonists have serious adverse effects. The thiazolidinediones (glitazones) significantly improve insulin sensitivity, diminish fat accumulation in the liver and increase circulating levels of adiponectin. Various adverse effects of glitazones have been described in recent studies. In the near future one should await the discovery of more oral antidiabetic agents acting through modulation of important enzymes in glucose metabolism and transport pathways.
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PMID:[New oral antidiabetic agents--clinical perspectives]. 1833 May 34

Resveratrol was reported to increase insulin sensitivity accompanied with the activation of AMP-activated protein kinase (AMPK), which is a key regulator of energy balance and an important drug target for type 2 diabetes. However, the effect of resveratrol structural analogs on AMPK activity and insulin sensitivity is still largely unknown. In this study, we analyzed the effect of several resveratrol structural analogs on AMPK activity in HepG2 cells, and combretastatin A-4 (CA-4) was identified as an activator of AMPK determined by its phosphorylation. AMPK activation was further confirmed by the phosphorylation of downstream acetyl-CoA carboxylase (ACC) and the decrease of upstream ATP level. Further investigation showed that CA-4 activates PPAR transcriptional activity in vitro with the luciferase reporter assay. In addition, we showed that CA-4 activated AMPK and downregulated gluconeogenic enzyme mRNA levels in liver, and improved the fasting blood glucose level in diabetic db/db mice. These results suggested that resveratrol analogs, such as CA-4, can function similarly as resveratrol and may provide important tools for improving insulin sensitivity.
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PMID:Combretastatin A-4 activates AMP-activated protein kinase and improves glucose metabolism in db/db mice. 1843 88

Adiponectin is an adipocyte hormone that links visceral adiposity with insulin resistance and atherosclerosis. It is unique among adipocyte-derived hormones in that its circulating concentrations are inversely proportional to adiposity, and low adiponectin concentrations predict the development of type 2 diabetes and cardiovascular disease. Consequently, in the decade since its discovery, adiponectin has generated immense interest as a potential therapeutic target for the metabolic syndrome and diabetes. This review summarizes current research regarding the regulation of circulating adiponectin concentrations by physiological, pharmacological, and nutritional factors, with an emphasis on human studies. In humans, plasma adiponectin concentrations are influenced by age and gender, and are inversely proportional to visceral adiposity. In vitro studies suggest that adiponectin production may be determined primarily by adipocyte size and insulin sensitivity, with larger, insulin-resistant adipocytes producing less adiponectin. While adiponectin concentrations are unchanged after meal ingestion, they are increased by significant weight loss, such as after bariatric surgery. In addition, adiponectin production is inhibited by a number of hormones, including testosterone, prolactin, glucocorticoids and growth hormone, and by inflammation and oxidative stress in adipose tissue. Smoking decreases, while moderate alcohol consumption increases, circulating adiponectin concentrations. Dietary fatty acid composition in rodents influences adiponectin production via ligand-activated nuclear receptors (PPARs); however, current evidence in humans is equivocal. In addition to PPAR agonists (such as thiazolidinediones and fibrates), a number of pharmacological agents (angiotensin receptor type 1 blockers, ACE inhibitors, and cannabinoid receptor antagonists) used in treatment of the metabolic syndrome also increase adiponectin concentrations in humans.
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PMID:Physiological, pharmacological, and nutritional regulation of circulating adiponectin concentrations in humans. 1851 Apr 34

PPARgamma and PPARdelta agonists represent unique classes of drugs that act through their ability to modulate gene transcription associated with intermediary metabolism, differentiation, tumor suppression, and in some instances proliferation and cell adhesion. PPARgamma agonists are used by millions of people each year to treat type 2 diabetes but may also find additional utility as relatively nontoxic potentiators of chemotherapy. PPARdelta agonists produce complex actions as shown by their tumor promoting effects in rodents and their cholesterol-lowering action in dyslipidemias. There is now emerging evidence that PPARs regulate tumor suppressor genes and developmental pathways associated with transformation and cell fate determination. This review discusses the role of PPARgamma and PPARdelta agonists as modulators of these processes.
PPAR Res 2008
PMID:PPARgamma and PPARdelta as Modulators of Neoplasia and Cell Fate. 1856 86


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