Blood-based analysis of type-2 diabetes mellitus susceptibility genes identifies specific transcript variants with deregulated expression and association with disease risk

Despite significant progress by genome-wide association studies, the ability of genetic variants to conduce to the prediction or prognosis of type-2 diabetes (T2D) is weak. Expression analysis of the corresponding genes may suggest possible links between single-nucleotide polymorphisms and T2D phenotype and/or risk. Herein, we investigated the expression patterns of 24 T2D-susceptibility genes, and their individual transcript variants (tv), in peripheral blood of T2D patients and controls (CTs), applying RNA-seq and real-time qPCR methodologies, and explore possible associations with disease features. Our data revealed the deregulation of certain transcripts in T2D patients. Among them, the down-regulation of CAPN10 tv3 was confirmed as an independent predictor for T2D. In patients, increased expression of CDK5 tv2, CDKN2A tv3 or THADA tv5 correlated positively with serum insulin levels, of CDK5 tv1 positively with % HbA1c levels, while in controls, elevated levels of TSPAN8 were associated positively with the presence of T2D family history. Herein, a T2D-specific expression profile of specific transcripts of disease-susceptibility genes is for the first time described in human peripheral blood. Large-scale studies are needed to evaluate the potential of these molecules to serve as disease biomarkers

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Electrophysiological study of the neurosecretory system of the salivary glands of the snail Helix lucorum

The neural system of the Mollusks offers an excellent experimental model for the study of the properties, the organization and the function of the neural tissue. In the study of the properties of neural tissue, the ganglia of Mollusks have been widely used in order to answer same basic questions, regarding the ionic mechanisms of the stimulation or the cellular mechanisms of learning and memory (Bailey, C.H. και Kandel, E.R. 1993, Frost, W.N. και Kandel, E.R. 1995). The neural system of Mollusks has been, among others, used in toxicological studies, for example the effect of action of the insecticides (Gomori 1995, Cohen JL, και συν. 1978, Cottrell GA. και συν. 1974). In spite the fact, that epilepsy is not a phenomenon observed, under normal conditions, in Mollusks the experimental Neurophysiology uses the ganglia of Gastropods as an alternative model for the study of the mechanisms involved in epilepsy (Altrup, U. και Speckmann. E.-J.1988 Altrup, U. και συν.1991, Speckmann. E.-J. και Caspers, H. 1973, Wiemann, M. και συν. 1996). The advantages of the Mollusk's neural system are: i) A, relatively, simple organization compared to the one of the superior animals. ii) The existence of giant neurons in ganglia. These cells are approximately 100nm and are located superficially in the ganglion. These neurons are easily distinguishable and can be studied with intracellular electrodes. iii) The evolutionary stability of the structure and the function of the neural system within the Phylum of Mollusks. Despite, the great number of evolutionary adaptations existing in the different classes of the Mollusks, the basic model of the neural system remains remarkably stable. This stability allows wide homologies among the ganglia of species originating from different classes. A very interesting question, in the field of Comparative Neurobiology, deriving from these homologies, is the search for identification of one specific neuron among representatives of a wide taxon. This search makes valuables the studies in the different species of Mollusks that are focused in the declaration of Physiology and function of the neurons that participate in specific neural networks.Το νευρικό σύστημα των Μαλακίων προσφέρει ένα καλό πειραματικό μοντέλο για την εν γένει μελέτη των ιδιοτήτων, της οργάνωσης και της λειτουργίας του νευρικού ιστού. Στην έρευνα των ιδιοτήτων του νευρικού ιστού έχουν ευρέως χρησιμοποιηθεί τα γάγγλια των Μαλακίων, προκειμένου να απαντηθούν ορισμένα βασικά ερωτήματα, όπως οι ιοντικοί μηχανισμοί της διέγερσης ή οι κυτταρικοί μηχανισμοί της μάθησης και της μνήμης (Bailey, C.H. και Kandel, E.R. 1993, Frost, W.N. και Kandel, E.R. 1995). Το νευρικό σύστημα των Μαλακίων έχει, εξάλλου, χρησιμοποιηθεί σε τοξικολογικές μελέτες, παραδείγματος χάριν, στη μελέτη της επίδρασης εντομοκτόνων (Gomori 1995, Cohen JL, και συν. 1978, Cottrell GA. και συν. 1974). Παρότι, η παροξυσμική δραστηριότητα είναι ένα φαινόμενο που δεν παρατηρείται στο νευρικό σύστημα των Μαλακίων σε κανονικές συνθήκες, η πειραματική νευροφυσιολογία χρησιμοποιεί τα γάγγλια των Γαστερόποδων ως εναλλακτικό μοντέλο μελέτης των μηχανισμών που ενέχονται στην παροξυσμική δραστηριότητα (Altrup, U. και Speckmann. E.-J.1988 Altrup, U. και συν.1991, Speckmann. E.-J. και Caspers, H. 1973, Wiemann, M. και συν. 1996). Τα πλεονεκτήματα του νευρικού συστήματος των Μαλακίων συνίστανται στα εξής: i) Σχετικά απλή οργάνωση, συγκρινόμενη με το νευρικό σύστημα ανώτερων ζώων, ii) Ύπαρξη γιγαντιαίων νευρώνων στα γάγγλια. Τα κύτταρα αυτά έχουν τάξη μεγέθους 100 nm και συνήθως επιφανειακή θέση. Ορισμένοι από αυτούς τους νευρώνες διαθέτουν χρωστικές. Οι νευρώνες αυτοί είναι ευδιάκριτοι και μπορούν εύκολα να μελετηθούν με ενδοκυτταρικά ηλεκτρόδια, iii) Εξελικτική σταθερότητα της δομής και της λειτουργίας του νευρικού συστήματος μέσα στο φύλο των Μαλακίων. Παρά το μεγάλο εύρος των εξελικτικών προσαρμογών που εμφανίζουν οι διάφορες κλάσεις μέσα στο φύλο των Μαλακίων το βασικό μοντέλο του νευρικού συστήματος των Μαλακίων έχει παραμείνει εκπληκτικά σταθερό. Η σταθερότητα αυτή επιτρέπει ευρείες ομολογίες ανάμεσα στα γάγγλια των εκπροσώπων των διαφόρων τάξεων. Ένα πολύ ενδιαφέρον ερώτημα της Συγκριτικής Νευροβιολογίας, το οποίο προέρχεται από τη δυνατότητα να αναγνωρίζουμε συγκεκριμένους νευρώνες, είναι η δυνατότητα να αναγνωριστεί ένας συγκεκριμένος νευρώνας ανάμεσα στους εκπροσώπους μιας ευρύτερης ταξινομικής ομάδας. Το γεγονός αυτό καθιστά πολύτιμες τις μελέτες που έχουν πραγματοποιηθεί στα διάφορα είδη Μαλακίων προκειμένου να διευκρινιστεί η φυσιολογία και ο λειτουργικός ρόλος των νευρώνων που συμμετέχουν σε συγκεκριμένα νευρωνικά κυκλώματα

Association of Glycemic Indices (Hyperglycemia, Glucose Variability, and Hypoglycemia) with Oxidative Stress and Diabetic Complications

Oxidative stress (OS) is defined as a disturbance in the prooxidant-antioxidant balance of the cell, in favor of the former, which results in the antioxidant capacity of the cell to be overpowered. Excess reactive oxygen species (ROS) production is very harmful to cell constituents, especially proteins, lipids, and DNA, thus causing damage to the cell. Oxidative stress has been associated with a variety of pathologic conditions, including diabetes mellitus (DM), cancer, atherosclerosis, neurodegenerative diseases, rheumatoid arthritis, ischemia/reperfusion injury, obstructive sleep apnea, and accelerated aging. Regarding DM specifically, previous experimental and clinical studies have pointed to the fact that oxidative stress probably plays a major role in the pathogenesis and development of diabetic complications. It is postulated that hyperglycemia induces free radicals and impairs endogenous antioxidant defense systems through several different mechanisms. In particular, hyperglycemia promotes the creation of advanced glycation end-products (AGEs), the activation of protein kinase C (PKC), and the hyperactivity of hexosamine and sorbitol pathways, leading to the development of insulin resistance, impaired insulin secretion, and endothelial dysfunction, by inducing excessive ROS production and OS. Furthermore, glucose variability has been associated with OS as well, and recent evidence suggests that also hypoglycemia may be playing an important role in favoring diabetic vascular complications through OS, inflammation, prothrombotic events, and endothelial dysfunction. The association of these diabetic parameters (i.e., hyperglycemia, glucose variability, and hypoglycemia) with oxidative stress will be reviewed here

Insulin effects in muscle and adipose tissue

The major effects of insulin on muscle and adipose tissue are: (1) Carbohydrate metabolism: (a) it increases the rate of glucose transport across the cell membrane, (b) it increases the rate of glycolysis by increasing hexokinase and 6-phosphofructokinase activity, (c) it stimulates the rate of glycogen synthesis and decreases the rate of glycogen breakdown. (2) Lipid metabolism: (a) it decreases the rate of lipolysis in adipose tissue and hence lowers the plasma fatty acid level, (b) it stimulates fatty acid and triacylglycerol synthesis in tissues, (c) it increases the uptake of triglycerides from the blood into adipose tissue and muscle, (d) it decreases the rate of fatty acid oxidation in muscle and liver. (3) Protein metabolism: (a) it increases the rate of transport of some amino acids into tissues, (b) it increases the rate of protein synthesis in muscle, adipose tissue, liver, and other tissues, (c) it decreases the rate of protein degradation in muscle (and perhaps other tissues). These insulin effects serve to encourage the synthesis of carbohydrate, fat and protein, therefore, insulin can be considered to be an anabolic hormone. (C) 2011 Elsevier Ireland Ltd. All rights reserved

Interleukin-1 Beta in Peripheral Blood Mononuclear Cell Lysates as a Longitudinal Biomarker of Response to Antidepressants: A Pilot Study

Interleukin-1 beta (IL1 beta) is primarily produced by monocytes in the periphery and the brain. Yet, IL1 beta protein levels have to date been investigated in major depressive disorder (MDD) and antidepressant response using either plasma or serum assays although with contradictory results, while mononuclear cell assays are lacking despite their extensive use in other contexts. In this pilot study, we comparatively assessed IL1 beta in mononuclear lysates and plasma in depressed MDD patients over treatment and healthy controls (HC). We recruited 31 consecutive adult MDD inpatients and 25 HC matched on age, sex, and BMI. Twenty-six patients completed an 8-week follow-up under treatment. IL1 beta was measured in both lysates and plasma in patients at baseline (T0) and at study end (T1) as well as in HC. We calculated Delta IL1 beta(%) for both lysates and plasma as IL1 beta percent changes from T0 to T1. Seventeen patients (65.4% of completers) were responders at T1 and had lower baseline BMI than non-responders (p = 0.029). Baseline IL1 beta from either plasma or lysates could not efficiently discriminate between depressed patients and HC, or between responders and non-responders. However, the two response groups displayed contrasting IL1 beta trajectories in lysates but not in plasma assays (response group by time interactions, p = 0.005 and 0.96, respectively). Delta IL1 beta(%) in lysates predicted response (p = 0.025, AUC = 0.81; accuracy = 84.6%) outperforming Delta IL1 beta(%) in plasma (p = 0.77, AUC=0.52) and was robust to adjusting for BMI. In conclusion, Delta IL1 beta(%) in mononuclear lysates may be a longitudinal biomarker of antidepressant response, potentially helpful in avoiding untimely switching of antidepressants, thereby warranting further investigation

Increases in muscle blood flow after a mixed meal are impaired at all stages of type 2 diabetes

Objective In type 2 diabetes, although the impairment of postprandial muscle blood flow response is well established, information on the effect of this impairment on glucose uptake and lipid metabolism is controversial. Design Postprandial forearm blood flow responses and metabolic parameters were assessed in a cross-sectional study of subjects at various stages of insulin resistance. Patients Eleven healthy subjects (CONTROLS), 11 first-degree relatives of type-2 diabetics (RELATIVES), 10 patients with impaired glucose tolerance (IGT), 10 diabetic patients with postprandial hyperglycaemia (DMA), and 13 diabetic patients with both fasting and postprandial hyperglycaemia (DMB). Measurements All subjects received a meal. Blood was drawn from a forearm deep vein and the radial artery at specific time-points during a period of 360 min for measurements of glucose, insulin, triglycerides and nonesterified-fatty acids. Forearm muscle blood flow was measured with strain-gauge plethysmography. Glucose uptake and ISI Index were calculated. Results Peak-baseline muscle blood flow was higher in CONTROLS (3.32 +/- 0.4) than in RELATIVES (0.53 +/- 0.29), IGT (0.82 +/- 0.2), DMA (1.44 +/- 0.34), DMB (1.23 +/- 0.35 ml/min/100 ml tissue), P < 0.001. Glucose uptake (AUC0-360,mu mol/100 ml tissue) was higher in CONTROLS (1023 +/- 132) than in RELATIVES (488 +/- 42), IGT (458 +/- 43), DMA (347 +/- 63), DMB (543 +/- 53), P < 0.001. ISI index, postprandial triglycerides and nonesterified-fatty acids behaved in a similar way. Peak-baseline muscle blood flow correlated positively with glucose uptake (r = 0.440, P = 0.001) and ISI index (r = 0.397, P = 0.003), and negatively with postprandial triglycerides (r = -0.434, P = 0.001) and nonesterified-fatty acids (r = -0.370, P = 0.005). Conclusions These results suggest that increase in muscle blood flow after a meal is impaired at all stages of type-2 diabetes. This defect influences glucose uptake and is associated with impaired lipid metabolism in the postprandial state