Differences In Metabolic Profile In the Testes of Streptozotocin Induced Diabetes Mellitus Mice As Detected By 1H NMR

Contrary to the traditional view, recent studies suggest that diabetes mellitus has an adverse influence on male reproductive function. Our aim was to determine the affect of diabetes on the testicular environment by identifying and then assessing perturbations in small molecule metabolites. Testes were obtained from control and streptozotocin induced diabetic C57BL/6 mice, two, four and eight weeks post treatment. Diabetic status was confirmed by HbA1c, non fasting blood glucose, physiological condition and body weight. Protein free, low molecular weight, water soluble extracts were assessed using 1H NMR spectroscopy. Principal Component Analysis of the derived profiles was used to classify any variations and specific metabolites were identified based on their spectral pattern. Characteristic metabolite profiles were identified for control and diabetic animals with the most distinctive being from mice with the greatest physical deterioration and loss of bodyweight. Eight streptozotocin treated animals did not develop diabetes and displayed profiles similar to controls. Diabetic mice had decreases in creatine, choline and carnitine and increases in lactate, alanine and myo-inositol. Betaine levels were found to be increased in the majority of diabetic mice but decreased in two animals with severe loss of body weight and physical condition. The association between perturbations in a number of small molecule metabolites known to be influential in sperm function, with diabetic status and physiological condition, adds further impetus to the proposal that diabetes influences important spermatogenic pathways and mechanisms in a subtle and previously unrecognised manner.

Metabolic profile changes in the testes of mice with streptozotocin-induced type 1 diabetes mellitus

Contrary to the traditional view, recent studies suggest that diabetes mellitus has an adverse influence on male reproductive function. Our aim was to determine the effect of diabetes on the testicular environment by identifying and then assessing perturbations in small molecule metabolites. Testes were obtained from control and streptozotocin-induced diabetic C57BL/6 mice, 2, 4 and 8 weeks post-treatment. Diabetic status was confirmed by glycated haemoglobin, non-fasting blood glucose, physiological condition and body weight. A novel extraction procedure was utilized to obtain protein free, low-molecular weight, water soluble extracts which were then assessed using H-1 nuclear magnetic resonance spectroscopy. Principal component analysis of the derived profiles was used to classify any variations, and specific metabolites were identified based on their spectral pattern. Characteristic metabolite profiles were identified for control and type 1 diabetic animals with the most distinctive being from mice with the largest physical deterioration and loss of body weight. Eight streptozotocin-treated animals did not develop diabetes and displayed profiles similar to controls. Diabetic mice had decreases in creatine, choline and carnitine and increases in lactate, alanine and myo-inositol. Betaine levels were found to be increased in the majority of diabetic mice but decreased in a few animals with severe loss of body weight and physical condition. The association between perturbations in a number of small molecule metabolites known to be influential in sperm function, with diabetic status and physiological condition, adds further impetus to the proposal that diabetes influences important spermatogenic pathways and mechanisms in a subtle and previously unrecognized manner.

Pharmacological interventions for dementia in people with Down Syndrome (Protocol).

Background: People with Down syndrome are vulnerable to developing dementia at an earlier age than the general population. Alzheimer’s disease and cognitive decline in people with Down syndrome can place a significant burden on both the person with Down syndrome and their family and carers. Various pharmacological interventions, including donepezil, galantamine, memantine and rivastigmine, appear to have some effect in treating cognitive decline in people without Down syndrome, but their effectiveness for those with Down syndrome remains unclear. Objectives: To assess the effectiveness of anti-dementia pharmacological interventions and nutritional supplements for treating cognitive decline in people with Down syndrome. Search methods In January 2015, we searched CENTRAL, ALOIS (the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group), Ovid MEDLINE, Embase, PsycINFO, seven other databases, and two trials registers. In addition, we checked the references of relevant reviews and studies and contacted study authors, other researchers and relevant drug manufacturers to identify additional studies. Selection criteria: Randomised controlled trials (RCTs) of anti-dementia pharmacological interventions or nutritional supplements for adults (aged 18 years and older) with Down syndrome, in which treatment was administered and compared with either placebo or no treatment. Data collection and analysis Two review authors independently assessed the risk of bias of included trials and extracted the relevant data. Review authors contacted study authors to obtain missing information where necessaryMain results Only nine studies (427 participants) met the inclusion criteria for this review. Four of these (192 participants) assessed the effectiveness of donepezil, two (139 participants) assessed memantine, one (21 participants) assessed simvastatin, one study (35 participants) assessed antioxidants, and one study (40 participants) assessed acetyl-L-carnitine. Five studies focused on adults aged 45 to 55 years, while the remaining four studies focused on adults aged 20 to 29 years. Seven studies were conducted in either the USA or UK, one between Norway and the UK, and one in Japan. Follow-up periods in studies ranged from four weeks to two years. The reviewers judged all included studies to be at low or unclear risk of bias. Analyses indicate that for participants who received donepezil, scores in measures of cognitive functioning (standardised mean difference (SMD) 0.52, 95% confidence interval (CI) -0.27 to 1.13) and measures of behaviour (SMD 0.42, 95% CI -0.06 to 0.89) were similar to those who received placebo. However, participants who received donepezil were significantly more likely to experience an adverse event (odds ratio (OR) 0.32, 95% CI 0.16 to 0.62). The quality of this body of evidence was low. None of the included donepezil studies reported data for carer stress, institutional/home care, or death. For participants who received memantine, scores in measures of cognitive functioning (SMD 0.05, 95% CI -0.43 to 0.52), behaviour (SMD -0.17, 95% CI -0.46 to 0.11), and occurrence of adverse events (OR 0.45, 95% CI 0.18 to 1.17) were similar to those who received placebo. The quality of this body of evidence was low. None of the included memantine studies reported data for carer stress, institutional/home care, or death. Due to insufficient data, it was possible to provide a narrative account only of the outcomes for simvastatin, antioxidants, and acetylL-carnitine. Results from one pilot study suggest that participants who received simvastatin may have shown a slight improvement in cognitive measures. Authors’ conclusions Due to the low quality of the body of evidence in this review, it is difficult to draw conclusions about the effectiveness of any pharmacological intervention for cognitive decline in people with Down syndrome.

Metabolic signatures of human Alzheimer's disease (AD): H-1 NMR analysis of the polar metabolome of post-mortem brain tissue

Brain tissue from so-called Alzheimer's disease (AD) mouse models has previously been examined using H-1 NMR-metabolomics, but comparable information concerning human AD is negligible. Since no animal model recapitulates all the features of human AD we undertook the first H-1 NMR-metabolomics investigation of human AD brain tissue. Human post-mortem tissue from 15 AD subjects and 15 age-matched controls was prepared for analysis through a series of lyophilised, milling, extraction and randomisation steps and samples were analysed using H-1 NMR. Using partial least squares discriminant analysis, a model was built using data obtained from brain extracts. Analysis of brain extracts led to the elucidation of 24 metabolites. Significant elevations in brain alanine (15.4 %) and taurine (18.9 %) were observed in AD patients (p ≤ 0.05). Pathway topology analysis implicated either dysregulation of taurine and hypotaurine metabolism or alanine, aspartate and glutamate metabolism. Furthermore, screening of metabolites for AD biomarkers demonstrated that individual metabolites weakly discriminated cases of AD [receiver operating characteristic (ROC) AUC <0.67; p < 0.05]. However, paired metabolites ratios (e.g. alanine/carnitine) were more powerful discriminating tools (ROC AUC = 0.76; p < 0.01). This study further demonstrates the potential of metabolomics for elucidating the underlying biochemistry and to help identify AD in patients attending the memory clinic