Plasma metabolites associated with type 2 diabetes in a Swedish population: a case–control study nested in a prospective cohort

Aims/hypothesis

The aims of the present work were to identify plasma metabolites that predict future type 2 diabetes, to investigate the changes in identified metabolites among individuals who later did or did not develop type 2 diabetes over time, and to assess the extent to which inclusion of predictive metabolites could improve risk prediction.

Methods

We established a nested case–control study within the Swedish prospective population-based Västerbotten Intervention Programme cohort. Using untargeted liquid chromatography-MS metabolomics, we analysed plasma samples from 503 case–control pairs at baseline (a median time of 7 years prior to diagnosis) and samples from a subset of 187 case–control pairs at 10 years of follow-up. Discriminative metabolites between cases and controls at baseline were optimally selected using a multivariate data analysis pipeline adapted for large-scale metabolomics. Conditional logistic regression was used to assess associations between discriminative metabolites and future type 2 diabetes, adjusting for several known risk factors. Reproducibility of identified metabolites was estimated by intra-class correlation over the 10 year period among the subset of healthy participants; their systematic changes over time in relation to diagnosis among those who developed type 2 diabetes were investigated using mixed models. Risk prediction performance of models made from different predictors was evaluated using area under the receiver operating characteristic curve, discrimination improvement index and net reclassification index.

Results

We identified 46 predictive plasma metabolites of type 2 diabetes. Among novel findings, phosphatidylcholines (PCs) containing odd-chain fatty acids (C19:1 and C17:0) and 2-hydroxyethanesulfonate were associated with the likelihood of developing type 2 diabetes; we also confirmed previously identified predictive biomarkers. Identified metabolites strongly correlated with insulin resistance and/or beta cell dysfunction. Of 46 identified metabolites, 26 showed intermediate to high reproducibility among healthy individuals. Moreover, PCs with odd-chain fatty acids, branched-chain amino acids, 3-methyl-2-oxovaleric acid and glutamate changed over time along with disease progression among diabetes cases. Importantly, we found that a combination of five of the most robustly predictive metabolites significantly improved risk prediction if added to models with an a priori defined set of traditional risk factors, but only a marginal improvement was achieved when using models based on optimally selected traditional risk factors.

Conclusions/interpretation

Predictive metabolites may improve understanding of the pathophysiology of type 2 diabetes and reflect disease progression, but they provide limited incremental value in risk prediction beyond optimal use of traditional risk factors.

     

Surgical treatment of skeletal metastases in 31 melanoma patients

The authors retrospectively studied 31 patients with malignant melanoma who were surgically treated for 34 skeletal metastases between 1987 and 2007. The aim was to evaluate the role of orthopaedic surgery and to identify factors related to survival. The patients were operated on for spinal cord compression (n = 12) and metastatic destruction in a long bone (n = 17), or other locations (n = 5). The median survival after surgery was 1.9 months (range: 0-40). The survival rate was 039 at 3 months, and 0.13 at 1 year. Four of 34 operations led to failure necessitating reoperation. A prolonged delay between diagnosis and surgery, radical excision, a solitary skeletal metastasis, radiotherapy, a perioperative lactate dehydrogenase (LDH) level < or = 8 microkat/L (p = 0.04) and a preoperative haemoglobin level > 11.5 mg/dL (p = 0.003) had a favourable prognostic impact. A vertebral localization was unfavourable. These prognostic factors may help identify which melanoma patients with symptomatic skeletal metastases will benefit from orthopaedic surgery. This study represents the largest reported cohort surgically treated for skeletal metastasis of malignant melanoma at a single institution.     

From the Cover: Dominant suppression of inflammation by glycan-hydrolyzed IgG

A unique anti-inflammatory property of IgG, independent of antigen specificity, is described. IgG with modification of the heavy-chain glycan on asparagine 297 by the streptococcal enzyme endo-β-N-acetylglucosaminidase (EndoS) induced a dominant suppression of immune complex (IC)-mediated inflammation, such as arthritis, through destabilization of local ICs by fragment crystallizable–fragment crystallizable (Fc-Fc) interactions. Small amounts (250 µg) of EndoS-hydrolyzed IgG were sufficient to inhibit arthritis in mice and most effective during the formation of ICs in the target tissue. The presence of EndoS-hydrolyzed IgG disrupted larger IC lattice formation both in vitro and in vivo, as visualized with anti-C3b staining. Neither complement binding in vitro nor antigen–antibody binding per se was affected.     

Plasma Concentrations of Short-Chain Fatty Acids in Active and Recovered Anorexia Nervosa

Anorexia nervosa (AN) is one of the most lethal psychiatric disorders. To date, we lack adequate knowledge about the (neuro)biological mechanisms of this disorder to inform evidence-based pharmacological treatment. Gut dysbiosis is a trending topic in mental health, including AN. Communication between the gut microbiota and the brain is partly mediated by metabolites produced by the gut microbiota such as short-chain fatty acids (SCFA). Previous research has suggested a role of SCFA in weight regulation (e.g., correlations between specific SCFA-producing bacteria and BMI have been demonstrated). Moreover, fecal SCFA concentrations are reported to be altered in active AN. However, data concerning SCFA concentrations in individuals who have recovered from AN are limited. In the present study, we analyzed and compared the plasma concentrations of seven SCFA (acetic-, butyric-, formic-, isobutyric-, isovaleric-, propionic-, and succinic acid) in females with active AN (n = 109), recovered from AN (AN-REC, n = 108), and healthy-weight age-matched controls (CTRL, n = 110), and explored correlations between SCFA concentrations and BMI. Significantly lower plasma concentrations of butyric, isobutyric-, and isovaleric acid were detected in AN as well as AN-REC compared with CTRL. We also show significant correlations between plasma concentrations of SCFA and BMI. These results encourage studies evaluating whether interventions directed toward altering gut microbiota and SCFA could support weight restoration in AN.     

Epitope‐specific recognition of type II collagen by rheumatoid arthritis antibodies is shared with recognition by antibodies that are arthritogenic in collagen‐induced arthritis in the mouse

Objective

To analyze the fine specificity of IgG autoantibodies in sera from rheumatoid arthritis (RA) patients for type II collagen (CII) epitopes that are arthritogenic in collagen‐induced arthritis (CIA), a relevant murine model of RA.

Methods

For enzyme‐linked immunosorbent assay (ELISA) analysis of conformation‐dependent autoantibody binding, recombinant chimeric collagens that harbor the respective CII epitopes as an insertion within the frame of a constant type X collagen triple helix were constructed. In addition, synthetic peptides mimicking the native collagen structures were applied for the first time in the ELISA assessment of humoral CII autoimmunity.

Results

The pathogenicity of IgG responses to certain CII determinants in CIA was demonstrated by arthritis development in BALB/c mice upon the combined transfer of 2 mouse monoclonal antibodies specific for precisely mapped conformational CII epitopes (amino acid residues 359–369 [C1^III] and 551–564 [J1]), whereas antibodies to another epitope (F4) were not arthritogenic. To test whether human autoimmune responses are similarly directed to these conserved CII determinants, serum IgG was analyzed. The prevalence of sera with increased IgG binding to the C1^III epitope was significantly higher in RA compared with sera from healthy donors or from patients with other rheumatic conditions, e.g., osteoarthritis (OA), systemic lupus erythematosus (SLE), or relapsing polychondritis (RP), whereas levels of antibodies specific for the nonarthritogenic F4 epitope were associated with OA rather than RA.

Conclusion

Autoimmunity to CII, although detectable in different rheumatic conditions, differs in fine specificity between distinct disease entities. In RA, in contrast to degenerative joint disease, RP, and SLE, autoantibody responses are directed to an evolutionary conserved CII structure that is also targeted by pathogenic autoimmune responses in murine models of arthritis.

     

Regional cerebral blood flow changes in schizophrenic patients detected by SPECT studies under resting and active conditions]

Brain SPECT studies in schizophrenia revealed changes in regional cerebral blood flow (rCBF). The rCBF changes can be detected more accurate by activating tests. The aim of this study was to assess rCBF changes under resting and activation condition by the Raven test. Four control patients (2 male, 2 female, average age 45 years, 26-57 years) and 11 chronic, treated schizophrenic patients (4 male, 7 female, average age: 46 years, 33-56 years) were studied in two HMPAO brain SPECT sessions, 48 hours apart, both resting and during activation task. The images were evaluated visually and semiquantitatively. Under resting condition in the control group, there were no significant rCBF changes. In the Raven activation test, a significantly higher blood flow in the prefrontal region was seen (p < 0.05). The schizophrenic group had a significantly lower rCBF in the temporal region under resting condition (p < 0.05): four patients displayed left, 4 right temporal hypoperfusion and 3 exhibited no rCBF abnormality. In the Raven activation tests 5 patients had prefrontal hyperperfusion, and the remaining 6 patients had no such activation answer. Five patients had hypoperfusion in the temporal region. In our sample, patients with chronic schizophrenia displayed significant temporal hypoperfusion. Moreover the chronic schizophrenic group exhibited a poor response to prefrontal activation compared to the control group.     

Concentration dependent mitochondrial effect of amiodarone

Although, the antiarrhythmic effect of amiodarone is well characterized, its effect on post-ischemic heart and cardiomyocytes, as well as the mechanism of its toxicity on extracardiac tissues is still poorly understood. In this study, we analyzed energy metabolism in situ during ischemia-reperfusion in Langendorff-perfused heart model by measuring the high-energy phosphate metabolites using 31P NMR spectroscopy. The toxicity of amiodarone on cardiomyocytes and cell lines of extracardiac origin, as well as direct effect of the drug on mitochondrial functions in isolated mitochondria was also analyzed. Amiodarone, when was present at low concentrations and predominantly in membrane bound form, protected heart and mitochondrial energy metabolism from ischemia-reperfusion-induced damages in Langendorff-perfused heart model. Toxicity of the drug was significantly higher on hepatocytes and pancreatic cells than on cardiomyocytes. In isolated mitochondria, amiodarone did not induce reactive oxygen species formation, while it affected mitochondrial permeability transition in a concentration dependent way. Up to the concentration of 10 microM, the drug considerably inhibited Ca(2+)-induced permeability transition, while at higher concentrations it induced a cyclosporin A independent permeability transition of its own. At concentrations where it inhibited the Ca(2+)-induced permeability transition (IC(50)=3.9+/-0.8 microM), it did not affect, between 6 and 30 microM it uncoupled, while, at higher concentrations it inhibited the respiratory chain. Thus, the concentration dependent nature of amiodarone's effect on permeability transition together with the different sensitivities of the tissues toward amiodarone can be involved in the beneficial cardiac and the simultaneous toxic extracardiac effects of the drug.