Nassim Dali-Youcef

Metabolic inflammation: Connecting obesity and insulin resistance

Insulin resistance is a pathological condition that arises when insulin signaling is impaired, forcing β-cells to produce more insulin in order to cope with body demands and to maintain glucose homeostasis. When the pancreas is no more able to support an appropriate insulin secretion, insulin resistance becomes decompensated and hyperglycemia is detected. One of the mechanisms leading to insulin resistance is low-grade inflammation that involves a number of protagonists such as inflammatory cytokines, lipids and their metabolites, reactive oxygen species (ROS), hypoxia and endoplasmic reticulum stress, and changes in gut microbiota profiles. We review here the molecular aspects of metabolic inflammation converging to insulin resistance and secondarily to type 2 diabetes. We also discuss the place of high-sensitivity C-reactive protein (hsCRP) in the assessment of metabolic inflammation and potential therapeutic interventions aimed to impede inflammation and therefore prevent insulin resistance.

Recognition and management of drug-induced cytopenias: the example of idiosyncratic drug-induced thrombocytopenia

Background: Several hundred drugs, toxins and herbs have been reported to cause blood abnormalities, and drugs account for 20 – 40% of all instances of cytopenias. Objective: In the present paper, we report and discuss the recognition and management of moderate to severe idiosyncratic drug-induced thrombocytopenia. Methods: A bibliographic search was performed on the PubMed database of the US National Library of Medicine for articles published from January 1990 to November 2008. Results/conclusions: Moderate to severe idiosyncratic drug-induced thrombocytopenia (platelet count < 100 × 109/l) is a relatively rare and potentially serious disorder. The origin may be myelosuppression or peripheral, owing to either the consumption of platelets or their immune-mediated destruction. The most common molecules responsible are heparins, quinidine, sulfonamides and gold salts. Clinically, the most classical symptom is a typical pattern of bleeding of variable intensity depending on the severity of thrombocytopenia and the molecule involved. Immune-mediated thrombocytopenia induced by heparin (type II) is more often associated with thrombotic events. The diagnosis is based on medical history and a set of clinical criteria, which also specify the level of imputability. Although the role of serological tests is not well established, they seem particularly valuable in some situations in which differential diagnosis is difficult or in type II heparin-induced thrombocytopenia. The treatment includes discontinuation of the suspected drug, and symptomatic measures that depend on the severity of clinical symptoms.

Cardiac Muscarinic Receptor Overexpression in Sudden Infant Death Syndrome

Background Sudden infant death syndrome (SIDS) remains the leading cause of death among infants less than 1 year of age. Disturbed expression of some neurotransmitters and their receptors has been shown in the central nervous system of SIDS victims but no biological abnormality of the peripheral vago-cardiac system has been demonstrated to date. The present study aimed to seek vago-cardiac abnormalities in SIDS victims. The cardiac level of expression of muscarinic receptors, as well as acetylcholinesterase enzyme activity were investigated. Methodology/Principal Findings Left ventricular samples and blood samples were obtained from autopsies of SIDS and children deceased from non cardiac causes. Binding experiments performed with [3H]NMS, a selective muscarinic ligand, in cardiac membrane preparations showed that the density of cardiac muscarinic receptors was increased as shown by a more than doubled Bmax value in SIDS (nu200a=u200a9 SIDS versus 8 controls). On average, the erythrocyte acetylcholinesterase enzyme activity was also significantly increased (nu200a=u200a9 SIDS versus 11 controls). Conclusions In the present study, it has been shown for the first time that cardiac muscarinic receptor overexpression is associated with SIDS. The increase of acetylcholinesterase enzyme activity appears as a possible regulatory mechanism.

Homozygosity for the V377I mutation in mevalonate kinase causes distinct clinical phenotypes in two sibs with hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS).

Objective Mevalonate kinase (MVK) deficiency is a rare autosomal recessive auto-inflammatory disorder characterised by recurring episodes of fever associated with multiple non-specific inflammatory symptoms and caused by mutations in the MVK gene. The phenotypic spectrum is wide and depends mostly on the nature of the mutations. Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) is a relatively mild presentation and predominantly associated with a c.1129G>A (p.V377I) mutation in the MVK gene. We report cases of two sisters homozygous for this mutation but exhibiting distinct (symptomatic vs asymptomatic) phenotypes. Methods Patient history was obtained; physical and clinical examination and laboratory tests were performed; lipopolysaccharide (LPS) response of peripheral blood mononuclear cells was quantified. Results Low MVK enzymatic activity is not necessarily associated with inflammatory symptoms. Increased inflammatory cytokine secretion in response to LPS is associated with symptomatic MVK deficiency. Conclusions Individuals who are homozygous for the common p.V377I mutation in the MVK gene may not display the characteristic inflammatory episodes diagnostic of MKD and thus may be lost for correct and timely diagnosis.

Constitutive overexpression of muscarinic receptors leads to vagal hyperreactivity.

Background Alterations in muscarinic receptor expression and acetylcholinesterase (AchE) activity have been observed in tissues from Sudden Infant Death Syndrome (SIDS). Vagal overactivity has been proposed as a possible cause of SIDS as well as of vasovagal syncopes. The aim of the present study was to seek whether muscarinic receptor overexpression may be the underlying mechanism of vagal hyperreactivity. Rabbits with marked vagal pauses following injection of phenylephrine were selected and crossed to obtain a vagal hyperreactive strain. The density of cardiac muscarinic receptors and acetylcholinesterase (AchE) gene expression were assessed. Blood markers of the observed cardiac abnormalities were also sought. Methodology/Principal Findings Cardiac muscarinic M2 and M3 receptors were overexpressed in hyperreactive rabbits compared to control animals (2.3-fold and 2.5-fold, respectively) and the severity of the phenylephrine-induced bradycardia was correlated with their densities. A similar overexpression of M2 receptors was observed in peripheral mononuclear white blood cells, suggesting that cardiac M2 receptor expression can be inferred with high confidence from measurements in blood cells. Sequencing of the coding fragment of the M2 receptor gene revealed a single nucleotide mutation in 83% of hyperreactive animals, possibly contributing for the transcript overexpression. Significant increases in AchE expression and activity were also assessed (AchE mRNA amplification ratio of 3.6 versus normal rabbits). This phenomenon might represent a compensatory consequence of muscarinic receptors overexpression. Alterations in M2 receptor and AchE expression occurred between the 5th and the 7th week of age, a critical period also characterized by a higher mortality rate of hyperreactive rabbits (52% in H rabbits versus 13% in normal rabbits) and preceeded the appearance of functional disorders. Conclusions/Significance The results suggest that cardiac muscarinic receptor overexpression plays a critical role in the development of vagal hyperreactivity, whereas AchE hyperactivity appears as a compensatory consequence of it. Since similar vagal disorders were observed recently by us in SIDS, muscarinic receptor overexpression could become a marker of risk of vasovagal syncopes and SIDS.

Signalling Networks Governing Metabolic Inflammation

Low-grade inflammation is an established pathological condition that contributes to the development of obesity, insulin resistance and type 2 diabetes. Metabolic inflammation is dependent on multiple signalling events. In an overnutrition state, canonical inflammatory pathways are induced by inflammatory cytokines and lipid species. They can also be triggered through inflammasome activation as well as through cellular stress provoked by the unfolded protein response at the endoplasmic reticulum as well as by reactive oxygen species. In this chapter, we summarize the current knowledge about signalling events within the cell and describe how they impact on metabolic inflammation and whole-body metabolism. We particularly highlight the interplay between different signalling pathways that link low-grade inflammation responses to the inactivation of the insulin receptor pathway, ultimately leading to insulin resistance, a hallmark of type 2 diabetes.

Imidazoline-like drugs improve insulin sensitivity through peripheral stimulation of adiponectin and AMPK pathways in a rat model of glucose intolerance

Altered adiponectin signaling and chronic sympathetic hyperactivity have both been proposed as key factors in the pathogenesis of metabolic syndrome. We recently reported that activation of I1 imidazoline receptors (I1R) improves several symptoms of the metabolic syndrome through sympathoinhibition and increases adiponectin plasma levels in a rat model of metabolic syndrome (Fellmann L, Regnault V, Greney H, et al. J Pharmacol Exp Ther 346: 370-380, 2013). The present study was designed to explore the peripheral component of the beneficial actions of I1R ligands (i.e., sympathoinhibitory independent effects). Aged rats displaying insulin resistance and glucose intolerance were treated with LNP509, a peripherally acting I1R agonist. Glucose tolerance, insulin sensitivity, and adiponectin signaling were assessed at the end of the treatment. Direct actions of the ligand on hepatocyte and adipocyte signaling were also studied. LNP509 reduced the area under the curve of the intravenous glucose tolerance test and enhanced insulin hypoglycemic action and intracellular signaling (Akt phosphorylation), indicating improved glucose tolerance and insulin sensitivity. LNP509 stimulated adiponectin secretion acting at I1R on adipocytes, resulting in increased plasma levels of adiponectin; it also enhanced AMPK phosphorylation in hepatic tissues. Additionally, I1R activation on hepatocytes directly enhanced AMPK phosphorylation. To conclude, I1R ligands can improve insulin sensitivity acting peripherally, independently of sympathoinhibition; stimulation of adiponectin and AMPK pathways at insulin target tissues may account for this effect. This may open a promising new way for the treatment of the metabolic syndrome.

NK Cells in Autoimmune and Inflammatory Diseases

The evidence of NK cell implication in human diseases has initially been shown for antiviral immunity and tumor surveillance. Nowadays, increased attention is being paid to the aspect of NK cells and innate immunity in studies on autoimmune diseases. However, despite a growing knowledge on NK cell function and regulation, their role in human autoimmune disease still remains controversial. In animal models, studies of NK cells have shown conflicting results toward a disease-promoting or disease-protective role. Similarly, in human diseases, available data suggest an unequivocal role of NK cells. Yet, the understanding of NK cell implication in human diseases is far from being achieved. We review here the current knowledge on NK cell biology in human autoimmune and inflammatory diseases and discuss their possible mechanisms of action in these complex pathologies.

129 : Cardiac muscarinic receptor overexpression as a possible cause of vagal hyperreactivity

1 Which importance for P 450 Cytochromes in drug interactions? A study from the French PharmacoVigilance Database AC Danton, A Sommet, G Durrieu, H Bagheri and JL Montastruc Service de Pharmacologie, Faculté de Médecine, Toulouse, France Objective: Cytochromes (CYPs) are a superfamily of isoenzymes involved in drug metabolism. The main isoenzymes are CYP 1A2, 2C9, 2D6 and 3A4. However, their relative importance in clinically significant interactions remains unknown. The aim of the present study was to investigate in the French PharmacoVigilance Database (FPVD) the number and characteristics of drug-drug interactions possibly explained by involvement of CYPs. Methods: Spontaneous notifications of Adverse Drug Reactions (ADRs) recorded by Toulouse Midi-Pyrénées PharmacoVigilance Centre between 1st January and 31st August 2008 were extracted from the FPVD. For each observation, we recorded the main characteristics of patients (age, gender), involved drug(s) (name, pharmacological class and involved CYP) and induced ADRs (type, ‘seriousness’, evolution). Results: Between 1st January and 31st August 2008, 1205 ADRs were registered by Toulouse Midi-Pyrénées PharmacoVigilance Centre into the FPVD. They involved 683 women (56.6%). In 12 cases, patients were less than 1 year old and in 14 cases, age was not informed. For other observations, mean age was 55.8 (median value: 58.0) years. Among these ADRs, 410 (34%) were ‘serious’ (including 24 fatal outcomes), 356 involved only one drug and 730 did not involve any drug interaction. Finally, 119 reports (i.e. 9.9% of registered ADRs) involved one (or more) drug interaction related to CYPs. Among these 119 notifications, the most frequently involved CYP was 3A4/5 (n = 81), followed by 2C19 (n = 20), 2C9 (n = 16), 2D6 (n = 16) and 2E1 (n = 1). In 13 notifications, several CYPs were involved. Drugs more frequently involved in this kind of drug interaction were amiodarone (n = 21) followed by proton pump inhibitors (n = 11), meprobamate (n = 9), antiretrovirals (n = 9) and rifampicine (n = 6). There was no major difference in ‘seriousness’ or evolution of ADRs between CYP-related interactions and others. In 22 cases, ADRs were possibly due to CYP-related drug interaction (18.5% of CYP-related drug interactions). Conclusion: CYP-related drug interactions are found in around 10% of ADRs registered in the FPVD. The most frequently involved CYPs are 3A4/5 (68%) followed by 2C19 (17%). This CYP-involving interaction leads to clinically significant consequences (ADR) in almost one case out of five. These data underline the importance of CYPs not only in drug interactions but also in mechanisms of ADRs.