Aims/hypothesis Decreased levels of brain-derived neurotrophic factor (BDNF) have been implicated in the pathogenesis of Alzheimer's disease and depression. These disorders are associated with type 2 diabetes, and animal models suggest that BDNF plays a role in insulin resistance. We therefore explored whether BDNF plays a role in human glucose metabolism. Subjects and methods We included (Study 1) 233 humans divided into four groups depending on presence or absence of type 2 diabetes and presence or absence of obesity; and (Study 2) seven healthy volunteers who underwent both a hyperglycaemic and a hyperinsulinaemic-euglycaemic clamp.Results Plasma levels of BDNF in Study 1 were decreased in humans with type 2 diabetes independently of obesity. Plasma BDNF was inversely associated with fasting plasma glucose, but not with insulin. No association was found between the BDNF G196A (Val66Met) polymorphism and diabetes or obesity. In Study 2 an output of BDNF from the human brain was detected at basal conditions. This output was inhibited when blood glucose levels were elevated. In contrast, when plasma insulin was increased while maintaining normal blood glucose, the cerebral output of BDNF was not inhibited, indicating that high levels of glucose, but not insulin, inhibit the output of BDNF from the human brain. Conclusions/interpretation Low levels of BDNF accompany impaired glucose metabolism. Decreased BDNF may be a pathogenetic factor involved not only in dementia and depression, but also in type 2 diabetes, potentially explaining the clustering of these conditions in epidemiological studies.

Muscle specific miRNAs, myomiRs, have been shown to control muscle development in vitro and are differentially expressed at rest in diabetic skeletal muscle. Therefore, we investigated the expression of these myomiRs, including miR-1, miR-133a, miR-133b and miR-206 in muscle biopsies from vastus lateralis of healthy young males (n = 10) in relation to a hyperinsulinaemic-euglycaemic clamp as well as acute endurance exercise before and after 12 weeks of endurance training. The subjects increased their endurance capacity,V O 2 max (l min −1 ) by 17.4% (P < 0.001), and improved insulin sensitivity by 19% (P < 0.01). While myomiR expression remained stable during a hyperinsulinaemic-euglycaemic clamp, an acute bout of exercise increased mir-1 (P < 0.05) and mir-133a (P < 0.05) expression before, but not after, training. In resting biopsies, endurance training for 12 weeks decreased basal expression of all four myomiRs (P < 0.05). Interestingly, all myomiRs reverted to their pre-training expression levels 14 days after ceasing the training programme. Components of major pathways involved in endurance adaptation such as MAPK and TGF-β were predicted to be targeted by the myomiRs examined. Tested predicted target proteins included Cdc42 and ERK 1/2. Although these proteins were downregulated between post-training period and 2 weeks of cessation, an inverse correlation between myomiR and target proteins was not found. In conclusion, our data suggest myomiRs respond to physiological stimuli, but their role in regulating human skeletal muscle adaptation remains unknown.

BackgroundSkeletal muscle insulin resistance (IR) is considered a critical component of type II diabetes, yet to date IR has evaded characterization at the global gene expression level in humans. MicroRNAs (miRNAs) are considered fine-scale rheostats of protein-coding gene product abundance. The relative importance and mode of action of miRNAs in human complex diseases remains to be fully elucidated. We produce a global map of coding and non-coding RNAs in human muscle IR with the aim of identifying novel disease biomarkers.MethodsWe profiled >47,000 mRNA sequences and >500 human miRNAs using gene-chips and 118 subjects (n = 71 patients versus n = 47 controls). A tissue-specific gene-ranking system was developed to stratify thousands of miRNA target-genes, removing false positives, yielding a weighted inhibitor score, which integrated the net impact of both up- and down-regulated miRNAs. Both informatic and protein detection validation was used to verify the predictions of in vivo changes.ResultsThe muscle mRNA transcriptome is invariant with respect to insulin or glucose homeostasis. In contrast, a third of miRNAs detected in muscle were altered in disease (n = 62), many changing prior to the onset of clinical diabetes. The novel ranking metric identified six canonical pathways with proven links to metabolic disease while the control data demonstrated no enrichment. The Benjamini-Hochberg adjusted Gene Ontology profile of the highest ranked targets was metabolic (P < 7.4 × 10-8), post-translational modification (P < 9.7 × 10-5) and developmental (P < 1.3 × 10-6) processes. Protein profiling of six development-related genes validated the predictions. Brain-derived neurotrophic factor protein was detectable only in muscle satellite cells and was increased in diabetes patients compared with controls, consistent with the observation that global miRNA changes were opposite from those found during myogenic differentiation.ConclusionsWe provide evidence that IR in humans may be related to coordinated changes in multiple microRNAs, which act to target relevant signaling pathways. It would appear that miRNAs can produce marked changes in target protein abundance in vivo by working in a combinatorial manner. Thus, miRNA detection represents a new molecular biomarker strategy for insulin resistance, where micrograms of patient material is needed to monitor efficacy during drug or life-style interventions.

FSP27 (fat-specific protein 27) is a member of the cell deathinducing DNA fragmentation factor-␣-like effector (CIDE) family. Although Cidea and Cideb were initially characterized as activators of apoptosis, recent studies have demonstrated important metabolic roles for these proteins. In this study, we investigated the function of another member of this family, FSP27 (Cidec), in apoptosis and adipocyte metabolism. Although overexpression of FSP27 is sufficient to increase apoptosis of 293T and 3T3-L1 cells, more physiological levels of expression stimulate spontaneous lipid accumulation in several cell types without induction of adipocyte genes. Increased triacylglycerol is likely due to decreased ␤-oxidation of nonesterified fatty acids. Altered flux of fatty acids into triacylglycerol may be a direct effect of FSP27 function, which is localized to lipid droplets in 293T cells and 3T3-L1 adipocytes. Stable knockdown of FSP27 during adipogenesis of 3T3-L1 cells substantially decreases lipid droplet size, increases mitochondrial and lipid droplet number, and modestly increases glucose uptake and lipolysis. Expression of FSP27 in subcutaneous adipose tissue of a human diabetes cohort decreases with total fat mass but is not associated with measures of insulin resistance (e.g. homeostasis model assessment). Together, these data indicate that FSP27 binds to lipid droplets and regulates their enlargement.The cell death-inducing DNA fragmentation factor-␣-like effector (CIDE) 5 family of proteins shares sequence similarity with DNA fragmentation factors and was initially characterized as mitochondrial activators of apoptosis (1, 2). However, strong metabolic phenotypes of mice lacking Cidea and Cideb indicate that this family plays critical roles in energy balance (3, 4). Cidea knock-out mice are lean and resistant to diet-induced obesity because of increased lipolysis and mitochondrial uncoupling in brown adipose tissue (3). Although expression of Cidea is limited to brown adipocytes in mice, humans express CIDE-A in white adipose tissue, where lower levels are observed with obesity and insulin resistance (5, 6). Although a coding variant of CIDE-A, V115F, is associated with human obesity (7), knockdown of CIDE-A in human adipocytes enhances lipolysis (5).Cideb knock-out mice are also lean and resistant to diet-induced obesity; however, this family member is expressed highly in liver, and the phenotype is because of decreased hepatic lipogenesis, increased fatty acid oxidation, and increased whole body energy expenditure (4). Thus, through a number of mechanisms, the CIDE family appears to have important roles in lipid metabolism. FSP27 (fat-specific protein of 27 kDa or Cidec) is the third member of the CIDE family. FSP27 was identified prior to the other family members based upon induction during adipogenesis (8). CIDE-3, the human version of FSP27, was characterized as 66% homologous to mouse and as an activator of apoptosis when expressed in 293T cells (9). However, the lack of function ascribed to FSP27 limit...

Our results suggest that administration of vitamins C and E to individuals with no previous vitamin deficiencies has no effect on physical adaptations to strenuous endurance training.

Unemployment has a substantial influence on diet composition, but effects vary with duration of the unemployment period, which may have potential health implications. This ought to be taken into consideration in evaluations of existing reforms and in future reforms of welfare systems.

Aims/hypothesis Soluble CD163 (sCD163) was recently identified as a strong risk marker for developing type 2 diabetes. We hypothesised that sCD163 independently associates with insulin resistance. Methods This cross-sectional study includes 234 participants: 96 with type 2 diabetes, 34 with impaired glucose tolerance (IGT) and 104 with normal glucose tolerance (NGT), matched for sex and BMI. Glucose-lowering medication was paused for 1 week before plasma samples were obtained for determination of sCD163 and other inflammatory and metabolic variables. Insulin resistance was estimated by homeostasis model assessment of insulin resistance (HOMA-IR).

Aims/hypothesis Clear evidence exists that TNF-α inhibits insulin signalling and thereby glucose uptake in myocytes and adipocytes. However, conflicting results exist with regard to the role of TNF-α in type 2 diabetes. Methods We obtained blood and biopsy samples from skeletal muscle and subcutaneous adipose tissue in patients with type 2 diabetes (n=96) and healthy controls matched for age, sex and BMI (n=103). Results Patients with type 2 diabetes had higher plasma levels of fasting insulin (p<0.0001) and glucose (p<0.0001) compared with controls, but there was no difference between groups with regard to fat mass. Plasma levels of TNF-α (p=0.0009) and soluble TNF receptor 2 (sTNFR2; p = 0.002) were elevated in diabetic patients. Insulin sensitivity was correlated with quartiles of plasma TNF-α after adjustment for age, sex, obesity, WHR, neutrophils,