Human metabolic individuality in biomedical and pharmaceutical research.

Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 show effect sizes that are unusually high for GWAS and account for 10-60% differences in metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism and Crohn's disease. The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research.

Metabolic syndrome according to different definitions in a rapidly developing country of the African region

AIMS: We examined, in a country of the African region, i) the prevalence of the metabolic syndrome (MetS) according to three definitions (ATP, WHO and IDF); ii) the distribution of the MetS criteria; iii) the level of agreement between these three definitions and iv) we also examined these issues upon exclusion of people with diabetes. METHODS: We conducted an examination survey on a sample representative of the general population aged 25-64 years in the Seychelles (Indian Ocean, African region), attended by 1255 participants (participation rate of 80.3%). RESULTS: The prevalence of MetS increased markedly with age. According to the ATP, WHO and IDF definitions, the prevalence of MetS was, respectively, 24.0%, 25.0%, 25.1% in men and 32.2%, 24.6%, 35.4% in women. Approximately 80% of participants with diabetes also had MetS and the prevalence of MetS was approximately 7% lower upon exclusion of diabetic individuals. High blood pressure and adiposity were the criteria found most frequently among MetS holders irrespective of the MetS definitions. Among people with MetS based on any of the three definitions, 78% met both ATP and IDF criteria, 67% both WHO and IDF criteria, 54% both WHO and ATP criteria and only 37% met all three definitions. CONCLUSION: We identified a high prevalence of MetS in this population in epidemiological transition. The prevalence of MetS decreased by approximately 32% upon exclusion of persons with diabetes. Because of limited agreement between the MetS definitions, the fairly similar proportions of MetS based on any of the three MetS definitions classified, to a substantial extent, different subjects as having MetS.

Gestational diabetes mellitus and the risk of metabolic syndrome: a population-based study in Lausanne, Switzerland.

AIMS: To investigate the relationships between gestational diabetes mellitus (GDM) and the metabolic syndrome (MS), as it was suggested that insulin resistance was the hallmark of both conditions. To analyse post-partum screening in order to identify risk factors for the subsequent development of type 2 diabetes mellitus (DM). METHODS: A retrospective analysis of all singleton pregnancies diagnosed with GDM at the Lausanne University Hospital for 3 consecutive years. Pre-pregnancy obesity, hypertension and dyslipidaemia were recorded as constituents of the MS. RESULTS: For 5788 deliveries, 159 women (2.7%) with GDM were identified. Constituents of the MS were present before GDM pregnancy in 26% (n = 37/144): 84% (n = 31/37) were obese, 38% (n = 14/37) had hypertension and 22% (n = 8/37) had dyslipidaemia. Gestational hypertension was associated with obesity (OR = 3.2, P = 0.02) and dyslipidaemia (OR = 5.4, P=0.002). Seventy-four women (47%) returned for post-partum OGTT, which was abnormal in 20 women (27%): 11% (n = 8) had type 2 diabetes and 16% (n = 12) had impaired glucose tolerance. Independent predictors of abnormal glucose tolerance in the post-partum were: having > 2 abnormal values on the diagnostic OGTT during pregnancy and presenting MS constituents (OR = 5.2, CI 1.8-23.2 and OR = 5.3, CI 1.3-22.2). CONCLUSIONS: In one fourth of GDM pregnancies, metabolic abnormalities precede the appearance of glucose intolerance. These women have a high risk of developing the MS and type 2 diabetes in later years. Where GDM screening is not universal, practitioners should be aware of those metabolic risks in every pregnant woman presenting with obesity, hypertension or dyslipidaemia, in order to achieve better diagnosis and especially better post-partum follow-up and treatment.

Utilization of dietary glucose in the metabolic syndrome

This review is focused on the fate of dietary glucose under conditions of chronically high energy (largely fat) intake, evolving into the metabolic syndrome. We are adapted to carbohydrate-rich diets similar to those of our ancestors. Glucose is the main energy staple, but fats are our main energy reserves. Starvation drastically reduces glucose availability, forcing the body to shift to fatty acids as main energy substrate, sparing glucose and amino acids. We are not prepared for excess dietary energy, our main defenses being decreased food intake and increased energy expenditure, largely enhanced metabolic activity and thermogenesis. High lipid availability is a powerful factor decreasing glucose and amino acid oxidation. Present-day diets are often hyperenergetic, high on lipids, with abundant protein and limited amounts of starchy carbohydrates. Dietary lipids favor their metabolic processing, saving glucose, which additionally spares amino acids. The glucose excess elicits hyperinsulinemia, which may derive, in the end, into insulin resistance. The available systems of energy disposal could not cope with the excess of substrates, since they are geared for saving not for spendthrift, which results in an unbearable overload of the storage mechanisms. Adipose tissue is the last energy sink, it has to store the energy that cannot be used otherwise. However, adipose tissue growth also has limits, and the excess of energy induces inflammation, helped by the ineffective intervention of the immune system. However, even under this acute situation, the excess of glucose remains, favoring its final conversion to fat. The sum of inflammatory signals and deranged substrate handling induce most of the metabolic syndrome traits: insulin resistance, obesity, diabetes, liver steatosis, hyperlipidemia and their compounded combined effects. Thus, a maintained excess of energy in the diet may result in difficulties in the disposal of glucose, eliciting inflammation and the development of the metabolic syndrome

Metabolic effects of a mixed and a high-carbohydrate low-fat diet in man, measured over 24 h in a respiration chamber.

1. The relation between dietary carbohydrate: lipid ratio and the fuel mixture oxidized during 24 h was investigated in eleven healthy volunteers (six females, and five males) in a respiration chamber. Values of the fuel mixture oxidized were estimated by continuous indirect calorimetry and urinary nitrogen measurements. 2. The subjects, were first given a mixed diet for 7 d and spent the last 24 h of the 7 d period in a respiration chamber for continuous gas-exchange measurement. The fuels oxidized during 2.5 h or moderate exercise were also measured in the respiration chamber. After an interval of 2 weeks from the end of the mixed-diet period, the same subjects were given an isoenergetic high-carbohydrate low-fat diet for 7 d, and the same experimental regimen was repeated. 3. Dietary composition markedly influenced the fuel mixture oxidized during 24 h and this effect was still present 12 h after the last meal in the postabsorptive state. However, the diets had no influence on the substrates oxidized above resting levels during exercise. With both diets, the 24 h energy balance was slightly negative and the energy deficit was covered by lipid oxidation. 4. With the high-carbohydrate low-fat diet, the energy expenditure during sleep was found to be higher than that with the mixed diet. 5. It is concluded that: (a) the composition of the diet did not influence the fuel mixture utilized for moderate exercise, (b) the energy deficit calculated for a 24 h period was compensated by lipid oxidation irrespective of the carbohydrate content of the diet, (c) energy expenditure during sleep was found to be higher with the high-carbohydrate low-fat diet than with the mixed diet.

Network-based scoring system for genome-scale metabolic reconstructions

Background: Network reconstructions at the cell level are a major development in Systems Biology. However, we are far from fully exploiting its potentialities. Often, the incremental complexity of the pursued systems overrides experimental capabilities, or increasingly sophisticated protocols are underutilized to merely refine confidence levels of already established interactions. For metabolic networks, the currently employed confidence scoring system rates reactions discretely according to nested categories of experimental evidence or model-based likelihood. Results: Here, we propose a complementary network-based scoring system that exploits the statistical regularities of a metabolic network as a bipartite graph. As an illustration, we apply it to the metabolism of Escherichia coli. The model is adjusted to the observations to derive connection probabilities between individual metabolite-reaction pairs and, after validation, to assess the reliability of each reaction in probabilistic terms. This network-based scoring system uncovers very specific reactions that could be functionally or evolutionary important, identifies prominent experimental targets, and enables further confirmation of modeling results. Conclusions: We foresee a wide range of potential applications at different sub-cellular or supra-cellular levels of biological interactions given the natural bipartivity of many biological networks.

Surface structure and stability of PdZn and PtZn alloys: Density-functional slab model studies

Geometric parameters of binary (1:1) PdZn and PtZn alloys with CuAu-L10 structure were calculated with a density functional method. Based on the total energies, the alloys are predicted to feature equal formation energies. Calculated surface energies of PdZn and PtZn alloys show that (111) and (100) surfaces exposing stoichiometric layers are more stable than (001) and (110) surfaces comprising alternating Pd (Pt) and Zn layers. The surface energy values of alloys lie between the surface energies of the individual components, but they differ from their composition weighted averages. Compared with the pure metals, the valence d-band widths and the Pd or Pt partial densities of states at the Fermi level are dramatically reduced in PdZn and PtZn alloys. The local valence d-band density of states of Pd and Pt in the alloys resemble that of metallic Cu, suggesting that a similar catalytic performance of these systems can be related to this similarity in the local electronic structures.

Apports de la médecine nucléaire en cardiologie préventive: l'exemple du syndrome métabolique [Value of nuclear medicine in preventive cardiology: the metabolic syndrome example]

Metabolic syndrome represents a grouping of risk factors closely linked to cardiovascular diseases and diabetes. At first, nuclear medicine has no direct application in cardiology at the level of primary prevention, but positron emission tomography is a non invasive imaging technique that can assess myocardial perfusion as well as the endothelium-dependent coronary vasomotion--a surrogate marker of cardiovascular event rate--thus finding an application in studying coronary physiopathology. As the prevalence of the metabolic syndrome is still unknown in Switzerland, we will estimate it from data available in the frame of a health promotion program. Based on the deleterious effect on the endothelium already observed with two components, we will estimate the number of persons at risk in Switzerland.

Hypobaric versus normobaric hypoxia: same effects on postural stability?

AIMS: To test the hypothesis that postural stability would be more affected during acute exposure in hypobaric (HH) than in normobaric (NH) hypoxia.¦METHODS: In separate trials, 12 subjects stood on a posturographic platform for two successive 25.6 sec tests in three conditions: eyes open (EO), eyes closed (EC), and verbal dual task (DT). Ambient pressure in O(2) was matched between HH and NH at 1700 and 3000 m, respectively.¦RESULTS: Compared to NH, the length of Centre of Pression trajectory in Y-axis was increased (p<0.05) in HH for EO at 1700 m, EC at 1700 and 3000 m, and for DT at 1700 m, whereas the variance of speed of CoP was decreased (p<0.05) in EO, EC, and DT at 1700 m. Compared to normobaric normoxia (NN; 400 m), the surface of CoP trajectory was increased (p<0.05) in HH in EO and EC at 3000 m.¦CONCLUSIONS: HH deteriorated postural stability in the antero-posterior plane, for the variance of speed and the surface of CoP in 3 conditions, whereas no difference was observed between NH and NN. These results suggest that hypobaria instead of hypoxia per se plays an important role to the altered balance classically reported in altitude.

Le syndrome métabolique: des spécialistes au médecin de premier recours [Metabolic syndrome: from specialists to the first aid physician]

Numerous algorithms originating from evidence-based medicine already exist; in spite of this, metabolic syndrome management remains problematical and needs to be improved. Specialists, working interactively and referring to clinical scenarios, pooled their specific areas of expertise in a transverse perspective of the metabolic syndrome management by the primary care physician. This concerted multidisciplinary approach has clearly revealed that a bio-psycho-social approach is absolutely essential in the management of this type of patients.

Clinal variation in a brown lemur (Eulemur spp.) hybrid zone: Combining morphological, genetic and climatic data to examine stability.

Studies of hybrid zones can inform our understanding of reproductive isolation and speciation. Two species of brown lemur (Eulemur rufifrons and E. cinereiceps) form an apparently stable hybrid zone in the Andringitra region of south-eastern Madagascar. The aim of this study was to identify factors that contribute to this stability. We sampled animals at 11 sites along a 90-km transect through the hybrid zone and examined variation in 26 microsatellites, the D-loop region of mitochondrial DNA, six pelage and nine morphological traits; we also included samples collected in more distant allopatric sites. Clines in these traits were noncoincident, and there was no increase in either inbreeding coefficients or linkage disequilibrium at the centre of the zone. These results could suggest that the hybrid zone is maintained by weak selection against hybrids, conforming to either the tension zone or geographical selection-gradient model. However, a closer examination of clines in pelage and microsatellites indicates that these clines are not sigmoid or stepped in shape but instead plateau at their centre. Sites within the hybrid zone also occur in a distinct habitat, characterized by greater seasonality in precipitation and lower seasonality in temperature. Together, these findings suggest that the hybrid zone may follow the bounded superiority model, with exogenous selection favouring hybrids within the transitional zone. These findings are noteworthy, as examples supporting the bounded superiority model are rare and may indicate a process of ecologically driven speciation without geographical isolation.