Profibrinolytic effect of the epigenetic modifier valproic acid in man.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.The aim of the study was to test if pharmacological intervention by valproic acid (VPA) treatment can modulate the fibrinolytic system in man, by means of increased acute release capacity of tissue plasminogen activator (t-PA) as well as an altered t-PA/Plasminogen activator inhibitor -1 (PAI-1) balance. Recent data from in vitro research demonstrate that the fibrinolytic system is epigenetically regulated mainly by histone deacetylase (HDAC) inhibitors. HDAC inhibitors, including VPA markedly upregulate t-PA gene expression in vitro.The trial had a cross-over design where healthy men (n = 10), were treated with VPA (Ergenyl Retard) 500 mg depot tablets twice daily for 2 weeks. Capacity for stimulated t-PA release was assessed in the perfused-forearm model using intra-brachial Substance P infusion and venous occlusion plethysmography. Each subject was investigated twice, untreated and after VPA treatment, with 5 weeks wash-out in-between. VPA treatment resulted in considerably decreased levels of circulating PAI-1 antigen from 22.2 (4.6) to 10.8 (2.1) ng/ml (p<0.05). It slightly decreased the levels of circulating venous t-PA antigen (p<0.05), and the t-PA:PAI-1 antigen ratio increased (p<0.01). Substance P infusion resulted in an increase in forearm blood flow (FBF) on both occasions (p<0.0001 for both). The acute t-PA release in response to Substance P was not affected by VPA (p = ns).Valproic acid treatment lowers plasma PAI-1 antigen levels and changes the fibrinolytic balance measured as t-PA/PAI-1 ratio in a profibrinolytic direction. This may in part explain the reduction in incidence of myocardial infarctions by VPA treatment observed in recent pharmacoepidemiological studies.The EU Clinical Trials Register 2009-011723-31.Swedish Heart-Lung Foundation Swedish Research Council Emelle Foundatio

Amino Acid Signatures to Evaluate the Beneficial Effects of Weight Loss

Aims. We investigated the relationship between circulating amino acid levels and obesity; to what extent weight loss followed by weight maintenance can correct amino acid abnormalities; and whether amino acids are related to weight loss. Methods:. Amino acids associated with waist circumference (WC) and BMI were studied in 804 participants from the Malmö Diet and Cancer Cardiovascular Cohort (MDC-CC). Changes in amino acid levels were analyzed after weight loss and weight maintenance in 12 obese subjects and evaluated in a replication cohort (n = 83). Results:. Out of the eight identified BMI-associated amino acids from the MDC-CC, alanine, isoleucine, tyrosine, phenylalanine, and glutamate decreased after weight loss, while asparagine increased after weight maintenance. These changes were validated in the replication cohort. Scores that were constructed based on obesity-associated amino acids and known risk factors decreased in the ≥10% weight loss group with an associated change in BMI (R2 = 0.16–0.22, p < 0.002), whereas the scores increased in the <10% weight loss group (p < 0.0004). Conclusions:. Weight loss followed by weight maintenance leads to differential changes in amino acid levels associated with obesity. Treatment modifiable scores based on epidemiological and interventional data may be used to evaluate the potential metabolic benefit of weight loss

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Cost-Effectiveness Analysis of Insulin Detemir Compared to Neutral Protamine Hagedorn (NPH) in Patients with Type 1 and Type 2 Diabetes Mellitus in Spain

Introduction: An Excel® (Microsoft Corporation) model was adapted to estimate the short-term (1-year) cost effectiveness of insulin detemir (IDet) versus neutral protamine Hagedorn (NPH) insulin in patients initiating insulin treatment with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) in Spain. Methods: Clinical benefits included the non-severe hypoglycemia rate for T1DM and T2DM, and weight change for T2DM. Three scenarios were included with different hypoglycemia rates estimated on the basis of clinical trials and observational studies. Costs, estimated from perspective of the Spanish Public Healthcare System (Euros 2014), included insulin treatment and non-severe hypoglycemia management costs. Non-severe hypoglycemia, defined as a self-managed event, implied the use of extra glucose testing strips and a general practitioner visit during the week following the event for 25% of patients. An average disutility value was associated to non-severe hypoglycemia events and, for T2DM, to one body mass index unit gain to calculate quality-adjusted life years (QALYs). Results: For the three scenarios a range of 0.025–0.076 QALYs for T1DM and 0.014–0.051 QALYs for T2DM were gained for IDet versus NPH due to non-severe hypoglycemia and weight gain avoidance, in return of an incremental cost of €145–192 for T1DM and €128–206 for T2DM. This resulted in the IDet versus NPH incremental cost-effectiveness ratio (ICER) ranging between €1910/QALY and €7682/QALY for T1DM and €2522/QALY and €15,009/QALY for T2DM. Conclusion: IDet was a cost-effective alternative to NPH insulin in the first year of treatment of patients with T1DM and patients with T2DM in Spain, with ICERs under the threshold value commonly accepted in Spain (€30,000/QALY)

Genetic Variance in the Adiponutrin Gene Family and Childhood Obesity

AIM: The adiponutrin gene family consists of five genes (PNPLA1-5) coding for proteins with both lipolytic and lipogenic properties. PNPLA3 has previously been associated with adult obesity. Here we investigated the possible association between genetic variants in these genes and childhood and adolescent obesity. METHODS/RESULTS: Polymorphisms in the five genes of the adiponutrin gene family were selected and genotyped using the Sequenom platform in a childhood and adolescent obesity case-control study. Six variants in PNPLA1 showed association with obesity (rs9380559, rs12212459, rs1467912, rs4713951, rs10947600, and rs12199580, p0.05). When analyzing these SNPs in relation to phenotypes, two SNPs in the PNPLA3 gene showed association with insulin sensitivity (rs12483959: beta = -0.053, p = 0.016, and rs2072907: beta = -0.049, p = 0.024). No associations were seen for PNPLA2, PNPLA4, and PNPLA5. CONCLUSIONS: Genetic variation in the adiponutrin gene family does not seem to contribute strongly to obesity in children and adolescents. PNPLA1 exhibited a modest effect on obesity and PNPLA3 on insulin sensitivity. These data, however, require confirmation in other cohorts and ethnic groups

Profiles of glucose metabolism in different prediabetes phenotypes, classified by fasting glycemia, 2-hour OGTT, glycated hemoglobin, and 1-hour OGTT:An IMI DIRECT study

Differences in glucose metabolism among categories of prediabetes have not been systematically investigated. In this longitudinal study, participants (N = 2,111) underwent a 2-h 75-g oral glucose tolerance test (OGTT) at baseline and 48 months. HbA1c was also measured. We classified participants as having isolated prediabetes defect (impaired fasting glucose [IFG], impaired glucose tolerance [IGT], or HbA1c indicative of prediabetes [IA1c]), two defects (IFG+IGT, IFG+IA1c, or IGT+IA1c), or all defects (IFG+IGT+IA1c). β-Cell function (BCF) and insulin sensitivity were assessed from OGTT. At baseline, in pooling of participants with isolated defects, they showed impairment in both BCF and insulin sensitivity compared with healthy control subjects. Pooled groups with two or three defects showed progressive further deterioration. Among groups with isolated defect, those with IGT showed lower insulin sensitivity, insulin secretion at reference glucose (ISRr), and insulin secretion potentiation (P &lt; 0.002). Conversely, those with IA1c showed higher insulin sensitivity and ISRr (P &lt; 0.0001). Among groups with two defects, we similarly found differences in both BCF and insulin sensitivity. At 48 months, we found higher type 2 diabetes incidence for progressively increasing number of prediabetes defects (odds ratio &gt;2, P &lt; 0.008). In conclusion, the prediabetes groups showed differences in type/degree of glucometabolic impairment. Compared with the pooled group with isolated defects, those with double or triple defect showed progressive differences in diabetes incidence.</p

Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice

<p>Abstract</p> <p>Background</p> <p>Type 2 diabetes (T2D) is the most common form of diabetes in humans and is closely associated with dyslipidemia and obesity that magnifies the mortality and morbidity related to T2D. The genetic contribution to human T2D and related metabolic disorders is evident, and mostly follows polygenic inheritance. The TALLYHO/JngJ (TH) mice are a polygenic model for T2D characterized by obesity, hyperinsulinemia, impaired glucose uptake and tolerance, hyperlipidemia, and hyperglycemia.</p> <p>Results</p> <p>In order to determine the genetic factors that contribute to these T2D related characteristics in TH mice, we interbred TH mice with C57BL/6J (B6) mice. The parental, F1, and F2 mice were phenotyped at 8, 12, 16, 20, and 24 weeks of age for 4-hour fasting plasma triglyceride, cholesterol, insulin, and glucose levels and body, fat pad and carcass weights. The F2 mice were genotyped genome-wide and used for quantitative trait locus (QTL) mapping. We also applied a genetical genomic approach using a subset of the F2 mice to seek candidate genes underlying the QTLs. Major QTLs were detected on chromosomes (Chrs) 1, 11, 4, and 8 for hypertriglyceridemia, 1 and 3 for hypercholesterolemia, 4 for hyperglycemia, 11 and 1 for body weight, 1 for fat pad weight, and 11 and 14 for carcass weight. Most alleles, except for Chr 3 and 14 QTLs, increased phenotypic values when contributed by the TH strain. Fourteen pairs of interacting loci were detected, none of which overlapped the major QTLs. The QTL interval linked to hypercholesterolemia and hypertriglyceridemia on distal Chr 1 contains <it>Apoa2 </it>gene. Sequencing analysis revealed polymorphisms of <it>Apoa2 </it>in TH mice, suggesting <it>Apoa2 </it>as the candidate gene for the hyperlipidemia QTL. Gene expression analysis added novel information and aided in selection of candidates underlying the QTLs.</p> <p>Conclusions</p> <p>We identified several genetic loci that affect the quantitative variations of plasma lipid and glucose levels and obesity traits in a TH × B6 intercross. Polymorphisms in <it>Apoa2 </it>gene are suggested to be responsible for the Chr 1 QTL linked to hypercholesterolemia and hypertriglyceridemia. Further, genetical genomic analysis led to potential candidate genes for the QTLs.</p