Pharmacogenomics education in medical and pharmacy schools: conclusions of a global survey.

Aim: The need for pharmacogenomic education is becoming more and more urgent. Our aim was to evaluate the progress in pharmacogenomics education since then, and to put forward further recommendations. Methods: A survey was sent to 248 schools of medicine, pharmacy, nursing and health professions around the world. Results: The majority of the study programs (87%) include pharmacogenomics education, which is generally taught as part of the pharmacology curriculum. On average, educators and teachers have selected appropriate and highly relevant pharmacogenomics biomarkers to include in their teaching programs. Conclusions: Based on the results, we can conclude that the state of pharmacogenomics education at the surveyed universities has improved substantially since 2005.

Intramyocardial thrombin promotes angiogenesis and improves cardiac function in an experimental rabbit model of acute myocardial infarction.

OBJECTIVE: Thrombin has been reported to play a pivotal role in the initiation of angiogenesis by indirectly regulating and organizing a network of angiogenic molecules. On the basis of these reports, we investigated the angiogenic action of thrombin in a rabbit model of acute myocardial infarction. METHODS: A rabbit model of acute myocardial infarction was established by ligation of the left anterior descending coronary branch. Subjects were then divided into 2 groups and treated with intramyocardial administration of thrombin (2500 IU; n = 13) or an equal volume of normal saline (n = 13). Four weeks later, animals were euthanized and histopathologic analysis, immunohistochemical staining for endothelial markers CD31 and vascular endothelial growth factor-A, and electron microscopy examination were performed on excised hearts. Electrocardiography, cardiac enzymes, and assessment of cardiac function by measuring left ventricular end-diastolic pressure and ejection fraction were recorded before and after myocardial infarction, and both left ventricular end-diastolic pressure and ejection fraction were further measured on the day of euthanasia (n = 5-8 in each case). RESULTS: Increased levels of troponin, ST elevation, and histopathologically confirmed myocardial infarction were observed in all animals. A significant increase of microvessel density at the infarct border zone, as evaluated by CD31 immunohistochemistry, was observed in the thrombin-treated group compared with the control group (30.3 ± 12.8 vs 12.6 ± 4.8, P = .0065). A significantly higher number of vascular endothelial growth factor-A-positive vessels at the infarct border zone was observed in the thrombin-treated animals compared with the control group (21.8 ± 8.9 vs 5.6 ± 4.4; P = .0009). The thrombin-treated animals showed a statistically significant reduction in left ventricular end-diastolic pressure values (6.9 ± 1.8 mm Hg vs 12.7 ± 2.2 mm Hg, P = .0002) and significant improvement in left ventricular ejection fraction (59.8% ± 3.1% vs 42.2% ± 6.14%, P = .002) on the day of euthanasia compared with the post-infarct day, reflecting significantly improved cardiac function compared with control subjects that showed no significant change. CONCLUSIONS: Intramyocardial administration of thrombin seems to promote angiogenesis and improve cardiac function of the ischemic myocardium, which may provide a new therapeutic approach in patients with myocardial ischemia.

The plasticity of the 7TMR signaling machinery and the search for pharmacological selectivity.

Components of 7TMR signaling machinery once considered as rigid, fixed and inflexible entities, operating in a one-dimensional way, homogeneous spatially and temporally, are now proved to be structurally plastic, flexible and dynamic in space and time. 7TMRs are thought to exist as ensembles of multiple, inter-convertible, pre-existing conformations and this conformational diversity provides a structural plasticity and the molecular mechanism for the functional diversity of 7TMRs. Furthermore, 7TMRs appear to function not as monomers, but rather as higher order structures, within which allosteric mechanisms affect ligand binding, G protein selection and receptor mobility and signalling of GPCR protomers. Moreover, their function is regulated through compartmentalization of G protein receptor and effector molecules into specialized membrane microdomains, such as lipid rafts and caveolae. Different permutations of receptor localization and translocation in membrane microdomains and internalization patterns, employed by 7TMRs regulate their signalling. Finally, the previous clear distinction between cell signalling and endocytic membrane trafficking has been blurred by evidence that these processes are intertwined and bidirectionally linked. 7TMRs normally signaling from the plasma membrane can elicit signaling cascades from an intracellular location, with distinct biochemical outputs. All these developments have moved the search for selective drugs beyond the mere design of receptor subtype-selective ligands targeting their orthosteric site. Even the notion of ligand has been expanded, so as to include "superagonists" ", acting as "super" 7TMR agonists to confer sustained endosomal signaling and biased agonists targeting GPCRs signalling from intracellular sites, as well as pharmacochaperones restoring insufficiently folded or misfolded receptors. The plasticity of the 7TMR signaling machinery and its dynamics in space and time will most probably impact further on the search for 7TMR drug selectivity.

Tacrolimus and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors: An interaction study in CYP3A5 non-expressors, renal transplant recipients.

OBJECTIVES: Atherosclerosis is a significant factor affecting long-term outcome in renal transplant recipients. Studies have been conducted to determine the pharmacogenomic pathways involved in statin efficacy, efficiency, and adverse effect likelihood. However, little is known about the influence of statins on tacrolimus kinetics. The aim of this study was to investigate possible pharmacological interactions between tacrolimus and statins in CYP3A5 non-expressors, renal transplant recipients. MATERIALS AND METHODS: Twenty-four patients, treated with tacrolimus (n=24), methylprednisolone (n=24), and mycophenolate mofetil (n=19)/azathioprine (n=1)/everolimus (n=4), participated in the study. After an observation time of 112±36 days, statins, namely, atorvastatin (n=12), simvastatin (n=8), pravastatin (n=2), or fluvastatin (n=2), were administered for additional 101±34 days. DNA was extracted from whole blood sample and polymerase chain reaction followed by restriction fragment length polymorphism analysis was used for CYP3A5 genotyping. Student's t-test and Mann-Whitney test were used to test the significance of difference in variables that passed or did not pass Kolmogorov's normality test, respectively. RESULTS: No statistically significant difference was observed in tacrolimus daily dose, concentration, concentration/dose ratio, and volume of distribution before and during the administration of statins. Statistically significant decrease in serum cholesterol was observed after initiation of statins. Renal and hepatic function remained unchanged and no skeletal muscle abnormalities were reported. CONCLUSIONS: The results of this study show that tacrolimus and statins do not interact in terms of efficacy, efficiency, and adverse effect likelihood. No significant clinical interaction or effect was observed, even with the use of atorvastatin or simvastatin, which are metabolized by CYP3A4 such as tacrolimus.

Investigation of clinical interaction between omeprazole and tacrolimus in CYP3A5 non-expressors, renal transplant recipients.

BACKGROUND: As proton pump inhibitors share CYP3A4 enzyme with tacrolimus for their hepatic elimination, they potentially affect its pharmacokinetics, most prominently in patients with CYP2C19 or CYP3A5 gene mutations. Our aim was to investigate the impact of omeprazole on tacrolimus pharmacokinetics in CYP3A5 non-expressors, kidney transplant recipients. METHODS: Twelve patients (five males/seven females) were observed for 175 +/- 92.05 days. Omeprazole (20 mg pos) was administrated for 75.83 +/- 45.17 days. Immunosuppressant regimen consisted of tacrolimus (n = 12), methylprednisolone (n = 10), mycophenolate mofetil (n = 11), azathioprine (n = 1), and everolimus (n = 2). Patient's body weight, coadministered drugs, and tacrolimus trough levels were monitored. Aspartate and alanine aminotransferase, gamma-glutamyltransferase, and bilirubin were used for evaluating hepatic function. Tacrolimus kinetics were estimated with daily dose, concentration, dose adjusted concentration, and volume of distribution with and without coadministration of omeprazole. CYP3A5 genotyping was performed with PCR followed by restriction fragment length polymorphism analysis. Statistical analysis was performed with Prism 4 software (GraphPad Software, Inc). RESULTS: No statistically significant difference was observed in tacrolimus kinetics and hepatic function during coadministration of omeprazole. CONCLUSION: Our results let us propose that there is no need for more frequent therapeutic drug monitoring of tacrolimus when coadministrated with omeprazole in CYP3A5 nonexpressors, though prospective studies with more patients and longer observation period are needed to confirm these findings.

Factors affecting the long-term response to tacrolimus in renal transplant patients: pharmacokinetic and pharmacogenetic approach.

BACKGROUND: The aim of our study was to determine the impact of CYP3A5*1 and CYP3A5*3 on the kinetics of tacrolimus in renal transplant recipients. MATERIAL AND METHODS: Forty kidney recipients were selected to participate. Maintenance scheme consisted of tacrolimus, a purine inhibitor and a steroid. CYP3A5 genotyping was performed with PCR and RFLP. Pharmacokinetic model was developed with Linear Regression and General Linear Model repeated measures approach. The impact of sex, CYP3A5*1 allele, age at transplantation, hepatic and renal function on tacrolimus kinetics was examined. RESULTS: The frequency of CYP3A5*3/*3 and CYP3A5*1/*3 genotype was 35/40 and 5/40, respectively. No CYP3A5*1/*1 was detected. CYP3A5*1 variant was associated with significant lower TAC dose adjusted concentration at 3, 6, 12 and 36 months after transplantation. Hepatic and renal function showed a significant effect on tacrolimus dose adjusted concentration 3 months after transplantation (p=0.000 and 0.028, respectively). Sex did not show a significant impact on tacrolimus kinetics. Carriers of CYP3A5*1 allele had lower predicted measures for tacrolimus dose adjusted concentration and higher predicted measures for volume of distribution. CONCLUSION: We proved that CYP3A5*1 carriers need higher tacrolimus dose than CYP3A5*3 homozygotes to achieve the target blood concentration.

Lack of association between the cholesteryl ester transfer protein gene--TaqIB polymorphism and coronary restenosis following percutaneous transluminal coronary angioplasty and stenting: a pilot study.

BACKGROUND: The most widely studied variation at the cholesteryl ester transfer protein (CETP) gene locus is a silent base change called the Thermobius aquaticus IB (TaqIB) polymorphism. TaqIB has been shown to affect levels/activity of CETP, plasma levels of high-density lipoprotein cholesterol (HDL-C), and to contribute to the risk of developing atherosclerosis and coronary heart disease (CHD). Ongoing studies are investigating possible associations between CETP gene polymorphisms and the development of coronary restenosis following percutaneous transluminal coronary angioplasty (PTCA) and stenting. METHODS AND RESULTS: The primary objective of the present study was to investigate the frequency of TaqIB-polymorphism, and a possible association with post-PTCA coronary restenosis, in 204 Greek patients who had undergone PTCA and stenting. As a secondary objective, the analysis was extended to explore possible interacting or additive effects by various CHD risk factors, and a deletion in the alpha(2B)-adrenergic receptor gene. The frequency of TaqIB was 54%, similar to the frequency of the polymorphism in a group of 35 healthy controls. CONCLUSIONS: The results from this study do not indicate that the TaqIB variation at the CETP gene locus is a significant predictor for assessing the risk of developing coronary restenosis following PTCA and stenting. This result was not affected when considering any one of the additionally studied factors.

Parstatin, the cleaved peptide on proteinase-activated receptor 1 activation, is a potent inhibitor of angiogenesis.

The proteolytic activation by thrombin of the proteinase-activated receptor 1 unveils the tethered peptide ligand and cleaves a 41-amino acid peptide. In this report, we show that this peptide, which we have designated as "parstatin," is a potent inhibitor of angiogenesis. Synthesized parstatin suppressed both the basic angiogenesis and that stimulated by basic fibroblast growth factor and vascular endothelial growth factor in the chick embryo model in vivo and in the rat aortic ring assay. Parstatin also abrogated endothelial cell migration and capillary-like network formation on the Matrigel and fibrin angiogenesis models in vitro. Treatment of endothelial cells with parstatin resulted in inhibition of cell growth by inhibiting the phosphorylation of extracellular signal-regulated kinases in a specific and reversible fashion and by promoting cell cycle arrest and apoptosis through a mechanism involving activation of caspases. We have shown that parstatin acts as a cell-penetrating peptide, exerting its biological effects intracellularly. The uptake into cells and the inhibitory activity were dependent on parstatin hydrophobic region. These results support the notion that parstatin may represent an important negative regulator of angiogenesis with possible therapeutic applications.

High-throughput chemiluminometric genotyping of single nucleotide polymorphisms of histamine, serotonin, and adrenergic receptor genes.

Several pharmacogenetic studies are focused on the investigation of the relation between the efficacy of various antipsychotic agents (e.g., clozapine) and the genetic profile of the patient with an emphasis on genes that code for neurotransmitter receptors such as histamine, serotonin, and adrenergic receptors. We report a high-throughput method for genotyping of single nucleotide polymorphisms (SNPs) within the genes of histamine H2 receptor (HRH2), serotonin receptor (HTR2A1 and HTR2A2), and beta(3) adrenergic receptor (ADRB3). The method combines the high specificity of allele discrimination by oligonucleotide ligation reaction (OLR) and the superior sensitivity and simplicity of chemiluminometric detection in a microtiter well assay configuration. The genomic region that spans the locus of interest is first amplified by polymerase chain reaction (PCR). Subsequently, an oligonucleotide ligation reaction is performed using a biotinylated common probe and two allele-specific probes that are labeled at the 3' end with digoxigenin and fluorescein. The ligation products are immobilized in polystyrene wells via biotin-streptavidin interaction, and the hybrids are denatured. Detection is accomplished by the addition of alkaline phosphatase-conjugated anti-digoxigenin or anti-fluorescein antibodies in combination with a chemiluminogenic substrate. The ratio of the luminescence signals obtained from digoxigenin and fluorescein indicates the genotype of the sample. The method was applied successfully to the genotyping of 23 blood samples for all four SNPs. The results were in concordance with both PCR-restriction fragment length polymorphism analysis and sequencing.

Identification of single-nucleotide polymorphisms by the oligonucleotide ligation reaction: a DNA biosensor for simultaneous visual detection of both alleles.

Although single nucleotide polymorphisms (SNPs) can be identified by direct hybridization with allele-specific oligonucleotide probes, enzyme-based genotyping methods offer much higher specificity and robustness. Among enzymatic methods, the oligonucleotide ligation reaction (OLR) offers the highest specificity for allele discrimination because two hybridization events are required for ligation. We report the development of a DNA biosensor that offers significant advantages over currently available methods for detection of OLR products: It allows simultaneous visual discrimination of both alleles using a single ligation reaction. Detection is complete within minutes without the need for any specialized instruments. It does not involve multiple cycles of incubation and washing. The dry-reagent format minimizes the pipetting steps. The need for qualified personnel is much lower than current methods. The principle of the assay is as follows: Following PCR amplification, a single OLR is performed using a biotinylated common probe and two allele-specific probes labeled with the haptens digoxigenin and fluorescein. Ligation products corresponding to the normal and mutant allele are double-labeled with biotin and either digoxigenin or fluorescein, respectively. The products are captured by antidigoxigenin or antifluorescein antibodies, or both, that are immobilized at the two test zones of the biosensor and react with antibiotin-functionalized gold nanoparticle reporters. The excess nanoparticles bind to biotinylated albumin that is immobilized at the control zone of the biosensor. The genotype is assigned by the characteristic red lines that appear at the two test zones. The proposed DNA biosensor constitutes a significant step toward point-of-care SNP genotyping.

Thrombin mediates mitogenesis and survival of human endothelial cells through distinct mechanisms.

Thrombin has been reported to play a pivotal role in the initiation of angiogenesis by indirectly regulating and organizing a network of angiogenic molecules. In addition, it has been proposed that thrombin can directly activate endothelial cell proliferation. However, in this report it was shown that thrombin is a poor growth factor for human endothelial cells, and its modest mitogenic activity is mediated indirectly by the release of heparin-binding epidermal growth factor, subsequent to proteinase-activated receptor 1 (PAR1) activation. On the other hand, it was demonstrated that thrombin is a potent anti-apoptotic factor for endothelial cells, pointing to a novel role of thrombin in vascular protection. Analysis by annexin V-propidium iodide double staining revealed that thrombin, specifically, promoted survival of serum-starved endothelial cells in a concentration-dependent manner. In contrast to its mitogenic effect, the anti-apoptotic effect of thrombin was largely independent of its catalytic activity and was mediated through interaction with alphanubeta3 and alpha5beta1 integrins, whereas the involvement of PAR1 was limited. These results provide new insights in understanding the role of thrombin in endothelial cell signaling and vascular biology.

Statins and the risk of colorectal cancer: a meta-analysis of 18 studies involving more than 1.5 million patients.

PURPOSE: Statins have been suggested to prevent colorectal cancer. Several epidemiologic studies have evaluated this association, whereas randomized controlled trials (RCTs) on cardiovascular outcomes provide relevant data as a secondary end point. Our aim was to examine the strength of this association through a detailed meta-analysis of the studies published on the subject in peer-reviewed literature. METHODS: A comprehensive search for studies published up to December 2006 was performed, reviews of each study were conducted, and data were abstracted. Before meta-analysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk (RR) estimates with 95% CIs were calculated using the fixed- and random-effects models. RESULTS: Eighteen studies involving more than 1.5 million participants contributed to the analysis. They were grouped on the basis of study design, and separate meta-analyses were conducted. There was no evidence of an association between statin use and risk of colorectal cancer either among RCTs (RR = 0.95; 95% CI, 0.80 to 1.13; n = 6) or among cohort studies (RR = 0.96; 95% CI, 0.84 to 1.11; n = 3). However, statin use was associated with a modest reduction in the risk of colorectal cancer among case-control studies (RR = 0.91; 95% CI, 0.87 to 0.96; n = 9). Low evidence of publication bias or heterogeneity was found. CONCLUSION: Our meta-analysis results do not support the hypothesis that statins strongly reduce the risk of colorectal cancer, when taken for management of hypercholesterolemia. However, we cannot rule out a modest reduction in risk or an effect associated with higher doses of statins.

Rethinking target discovery in polygenic diseases.

Despite an extraordinary investment in R&D the yield of successful new drugs has been disproportionately low in recent years, suggesting that the whole process of drug development requires rethinking and reform. Most analyses on this issue focus on molecular target discovery considerations. Target identification is characterized by a surplus of potential targets, but there is a translational bottleneck primarily due to limitations of currently employed target validation platforms. Meanwhile, the clinical entities, to which treatments are directed, are also highly complex in terms of pathophysiologic mechanisms and manifestations. In the present study we discuss the limitations of current molecular target discovery approaches mainly in regard to selectivity and efficacy. We also describe the constraints imposed on drug development by the current diagnostic constructs and the tendency towards dissecting the complex clinical phenotypes to component intermediate phenotypes. Finally, we describe how the reconsideration of molecular and clinical targets in polygenic diseases may lead to new strategies of pharmacological intervention directed against component dysfunctions, rather than the whole complex phenotype. Such strategies involve the combination of single ligands that act selectively on multiple molecules involved in a particular disease, or the employment of "multi-targeted" drugs, i.e. single drug molecules that hit selectively multiple receptors sharing common binding sites.

Lack of association between alpha2B-adrenergic receptor polymorphism and risk of restenosis following coronary angioplasty and stent implantation--preliminary report.

BACKGROUND: A genetic association/prospective follow-up study was conducted to investigate whether genetic variation of the alpha(2B)-adrenergic receptor gene was associated with the risk of restenosis in 96 Greek coronary artery disease patients undergoing coronary angioplasty and stent implantation. METHODS: For comparison of genotype frequency, a control group of 83 asymptomatic individuals was also studied. The end-point of the current study was the incidence of restenosis at 7 months of clinical follow-up. RESULTS: The majority of patients (70/96) had the insertion/insertion genotype, fewer patients (23/96) had the insertion/deletion genotype and only 3/96 had the deletion/deletion genotype; overall the frequency distribution was not different from that of the control subjects. Restenosis occurred in 15 of the 96 patients. CONCLUSIONS: In the population studied, alpha(2B)-adrenoreceptor polymorphisms were not found to predispose patients to an increased incidence of restenosis. Nevertheless, these findings should be considered as preliminary, taking into account the small number of patients that were studied and the rarity of the deletion/deletion genotype.

Alpha2-adrenergic receptor subtype-specific activation of NF-kappaB in PC12 cells.

In the present study we sought to investigate the signal transduction mechanisms that underlie the alpha2-adrenergic receptor (AR)-induced, subtype-specific neuronal differentiation of PC12 cells. Alpha2-ARs induced NF-kappaB transcriptional activity and p21(waf-1) gene transcription in the same subtype-specific manner (alpha2A

Blockade of angiogenesis by small molecule antagonists to protease-activated receptor-1: association with endothelial cell growth suppression and induction of apoptosis.

Many studies support the notion that protease-activated receptor (PAR)-1 plays a pivotal role in angiogenesis. However, direct evidence and understanding the molecular mechanisms involved were limited because PAR-1-specific antagonists have been developed only recently. In the present study, we evaluated the effects of two well characterized PAR-1 antagonists, SCH79797 ((N-3-cyclopropyl-7-{[4-(1-methylethyl)phenyl]-methyl}-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine)) and RWJ56110 [(alphaS)-N-[(1S)-3-amino-1-[[(phenylmethyl)amino]carbonyl]propyl]-alpha-[[[[[1-(2,6-dichlorophenyl)methyl]-3-(1-pyrrolidinylmethyl)-1H-indol-6-yl]amino]carbonyl]amino]-3,4-difluorobenzenepropanamide], in the angiogenic cascade. These antagonists suppressed both the basic angiogenesis and that stimulated by thrombin in the chick chorioallantoic membrane model in vivo. PAR-1 antagonists also abrogated tube formation in the in vitro Matrigel system. These inhibitory effects were dose-dependent and well correlated with the inhibitory effects of SCH79797 and RWJ56110 on primary endothelial cell proliferation and on the initiation of apoptosis. PAR-1 blockage resulted in inhibition of endothelial cell growth by increasing the sub-G0/G1 fraction and reducing the percentage of cells in the S phase. Consistent with this, PAR-1 antagonists reduced incorporation of [3H]thymidine in endothelial cells and blocked the phosphorylation of extracellular signal-regulated kinases in a fashion depending specifically on PAR-1 activation. Analysis by annexin V/propidium iodide staining and poly(ADP-ribose) polymerase cleavage revealed that PAR-1 blockage increased apoptotic cell death by a mechanism involving caspases. These results provide further evidence that PAR-1 is a key receptor that mediates angiogenesis and suggest PAR-1 as target for developing antiangiogenic agents with potential therapeutic application in cancer and other angiogenesis-related diseases.

Thrombin functions through its RGD sequence in a non-canonical conformation.

Previous studies have suggested that thrombin interacts with integrins in endothelial cells through its RGD (Arg-187, Gly-188, Asp-189) sequence. All existing crystal structures of thrombin show that most of this sequence is buried under the 220-loop and therefore interaction via RGD implies either partial unfolding of the enzyme or its proteolytic digestion. Here, we demonstrate that surface-absorbed thrombin promotes attachment and migration of endothelial cells through interaction with alpha(v)beta(3) and alpha(5)beta(1) integrins. Using site-directed mutants of thrombin we prove that this effect is mediated by the RGD sequence and does not require catalytic activity. The effect is abrogated when residues of the RGD sequence are mutated to Ala and is not observed with proteases like trypsin and tissue-type plasminogen activator, unless the RGD sequence is introduced at position 187-189. The potent inhibitor hirudin does not abrogate the effect, suggesting that thrombin functions through its RGD sequence in a non-canonical conformation. A 1.9-Angstroms resolution crystal structure of free thrombin grown in the presence of high salt (400 mm KCl) shows two molecules in the asymmetric unit, one of which assumes an unprecedented conformation with the autolysis loop shifted 20 Angstroms away from its canonical position, the 220-loop entirely disordered, and the RGD sequence exposed to the solvent.

The emergence of a new paradigm of pharmacogenomics.

A series of qualitatively new properties of the complex polygenic systems are transforming the dominant, genome-centric approach of pharmacogenomics towards a more integrative, holistic paradigm. The recent concepts of interposition of regulatory networks between genotype and phenotype, and the emergence of epigenotype as the locus of integration of genetic background with nutritional and lifestyle influences, render problematic any prediction of the consequences of individual gene alterations. In addition, the redefinition of the traditional boundaries of clinical phenotypes, with the promotion of the endophenotypes as methodological strategy, and the initiative of the phenome elucidation, reshape both the research, as well as the application, of pharmacogenomics. These concepts and developments can explain some of the complexity, and the multifactorial nature, of most drug responses and imply another understanding of education in the field, which aims at stimulating a critical reflection on these major shifts prior to a practical training on the immediate application of pharmacogenomics.

New therapeutic options for the metabolic syndrome: what's next?

The metabolic syndrome (MSX), characterized by obesity, insulin resistance, dyslipidemia and hypertension, increases the risk of cardiovascular morbidity and mortality. It has recently been hypothesized that MSX and type 2 diabetes are caused by triglyceride and long-chain fatty acid accumulation in liver, muscle, pancreatic islets and selected brain areas. This lipocentric approach is integrated with analysis of inflammation associated with end-organ damage, including the vascular wall. Genes and proteins contributing to insulin resistance, beta cell dysfunction and vascular wall damage have been identified. Transcription factors and coactivators, including peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1 are crucial in mediating insulin resistance and accelerating vascular wall inflammation, and represent promising therapeutic targets. New pharmacological strategies include dual PPARalpha/gamma agonists, drugs with pleiotropic effects or combination therapies.