Effects of inhaled salmeterol and salbutamol (albuterol) on morning dips compared in intensive care patients recovering from an acute severe asthma attack

Objective: To assess the effect of a long-acting inhaled β 2-agonist, salmeterol (SM), compared to a short-acting inhaled β 2-agonist, salbutamol (or albuterol, SB), on the occurrence of morning dip (MD) in patients recovering from an acute severe asthma attack (ASA). Design: Prospective study Setting: 18-bed, medical intensive care unit (ICU) in a university hospital. Patients: 19 patients suffering from an ASA. Interventions: Serial measurements of the peak expiratory flow rate (PEFR), arterial blood gases, vital capacity and forced expiratory volume in one second (FEV1) were performed from admission. All patients were first treated with i. v. methyl prednisolone and i.v. SB. Once the PEFR was stable and > 35 % of predicted value, i. v. SB was stopped while i. v. steroids were maintained, and patients were randomised to either inhaled SB (9 patients, 400 μg every 4 h) or inhaled SM (10 patients, 100 μg every 12 h). Results: The mean admission PEFR was 26.1 ± 11.7 % of the predicted value and was not different between the two groups. MD was more frequent with SB (6/9 patients) than with SM (4/10). The severity of MD, expressed in 1/min fall in PEFR, was higher in SB than in SM (106 ± 25 vs 55±37;p<0.05). Discussion: MD is frequent in ASA. In ASA, SM appears to reduce the frequency and the severity of MD more than SB. The clinical implications of this observation, particularly a lowering of mortality and a shortening of the ICU stay, remain to be investigate

Oxidative phosphorylation flexibility in the liver of mice resistant to high-fat diet-induced hepatic steatosis.

OBJECTIVE To identify metabolic pathways that may underlie susceptibility or resistance to high-fat diet-induced hepatic steatosis. RESEARCH DESIGN AND METHODS We performed comparative transcriptomic analysis of the livers of A/J and C57Bl/6 mice, which are, respectively, resistant and susceptible to high-fat diet-induced hepatosteatosis and obesity. Mice from both strains were fed a normal chow or a high-fat diet for 2, 10, and 30 days, and transcriptomic data were analyzed by time-dependent gene set enrichment analysis. Biochemical analysis of mitochondrial respiration was performed to confirm the transcriptomic analysis. RESULTS Time-dependent gene set enrichment analysis revealed a rapid, transient, and coordinate upregulation of 13 oxidative phosphorylation genes after initiation of high-fat diet feeding in the A/J, but not in the C57Bl/6, mouse livers. Biochemical analysis using liver mitochondria from both strains of mice confirmed a rapid increase by high-fat diet feeding of the respiration rate in A/J but not C57Bl/6 mice. Importantly, ATP production was the same in both types of mitochondria, indicating increased uncoupling of the A/J mitochondria. CONCLUSIONS Together with previous data showing increased expression of mitochondrial β-oxidation genes in C57Bl/6 but not A/J mouse livers, our present study suggests that an important aspect of the adaptation of livers to high-fat diet feeding is to increase the activity of the oxidative phosphorylation chain and its uncoupling to dissipate the excess of incoming metabolic energy and to reduce the production of reactive oxygen species. The flexibility in oxidative phosphorylation activity may thus participate in the protection of A/J mouse livers against the initial damages induced by high-fat diet feeding that may lead to hepatosteatosis

Ins1 (Cre) knock-in mice for beta cell-specific gene recombination.

AIMS/HYPOTHESIS: Pancreatic beta cells play a central role in the control of glucose homeostasis by secreting insulin to stimulate glucose uptake by peripheral tissues. Understanding the molecular mechanisms that control beta cell function and plasticity has critical implications for the pathophysiology and therapy of major forms of diabetes. Selective gene inactivation in pancreatic beta cells, using the Cre-lox system, is a powerful approach to assess the role of particular genes in beta cells and their impact on whole body glucose homeostasis. Several Cre recombinase (Cre) deleter mice have been established to allow inactivation of genes in beta cells, but many show non-specific recombination in other cell types, often in the brain. METHODS: We describe the generation of Ins1 (Cre) and Ins1 (CreERT2) mice in which the Cre or Cre-oestrogen receptor fusion protein (CreERT2) recombinases have been introduced at the initiation codon of the Ins1 gene. RESULTS: We show that Ins1 (Cre) mice induce efficient and selective recombination of floxed genes in beta cells from the time of birth, with no recombination in the central nervous system. These mice have normal body weight and glucose homeostasis. Furthermore, we show that tamoxifen treatment of adult Ins1 (CreERT2) mice crossed with Rosa26-tdTomato mice induces efficient recombination in beta cells. CONCLUSIONS/INTERPRETATION: These two strains of deleter mice are useful new resources to investigate the molecular physiology of pancreatic beta cells

P-73AN INVESTIGATION OF ADDICTIONS (SUBSTANCES AND BEHAVIORS) IN A COMMUNITY SAMPLE

Chemical and behavioral addictions are highly prevalent in our societies. Nevertheless, studies investigating a large panel of addictive behaviors in a community sample are lacking from the current literature on the topic. The aim of the current study is to explore addictive behaviors prevalence, characteristics, and interrelations in a sample of French speaking adults from the general population. Both substances (alcohol, tobacco, cannabis, drugs) and behaviors (gambling, Internet, buying, sport, work, mobile phone, eating) were considered. Several features of these addictive behaviors (involved in the triggering of the behaviors) were considered, namely, frequency, loss of control, hedonic aspects, craving, impact upon the daily living, and emotional contexts. 770 subjects answered to the online survey. Descriptive results will be presented for each conducts and their related features (prevalence, comorbidities, specific characteristics associated with each addictive behaviors). Our study thus provides a detailed overview of the current conducts' prevalence along with their co-occurrences. It also sheds some lights on how these behaviors may have an impact upon the daily living, and eventually turn into problematic behaviors. A particular emphasis is set on some behavioral conducts, like Internet gaming which is particularly salien

SY38-2IMPULSIVITY, MOTIVATIONS AND ADDICTION TO ONLINE GAMES

Introduction. Problematic engagement in online video gaming has been considered recently in the appendix of the DSM-5. Underpinning psychological factors are yet to be clarified, mostly in adult populations. We present data from two studies investigating links between motives to play and impulsivity in one hand and excessive gaming in another hand. Methods. Online studies have been conducted on adult gamers in France (n = 516) and Switzerland (n = 1057). Problematic engagement has been assessed in France by DSM-IV-TR adapted substance dependence criteria (DAS) and by IAT in Switzerland. Motivations have been investigated using Yee's model. Impulsivity has been evaluated using respectively BIS-10 and UPPS-P. The French sample has been compared to heroin users and to healthy controls regarding impulsivity. In the Swiss study, cluster analysis has been conducted to identify subgroups of players regarding their engagement in-game, their motivations to play and their impulsivity. Results. DAS has been found to be predicted by BIS high scores as well as by competition and advancement. Problematic gamers presented higher levels of impulsivity than controls but less than heroin dependents. Three of five clusters were identified to be problematic and linked to high levels of impulsivity, achievement and escapism. Conclusion. Achievement motives to play and high impulsivity have been linked to problematic engagement in online videogames in two different samples evaluated by two different methods. Addiction to online gaming showed a difference in impulsivity traits with substance dependence and healthy controls and subgroups of problem gamers has been characterized. These data could help to design tailored treatments for excessive online gamer

A Genetic Screen Identifies Hypothalamic Fgf15 as a Regulator of Glucagon Secretion.

The counterregulatory response to hypoglycemia, which restores normal blood glucose levels to ensure sufficient provision of glucose to the brain, is critical for survival. To discover underlying brain regulatory systems, we performed a genetic screen in recombinant inbred mice for quantitative trait loci (QTL) controlling glucagon secretion in response to neuroglucopenia. We identified a QTL on the distal part of chromosome 7 and combined this genetic information with transcriptomic analysis of hypothalami. This revealed Fgf15 as the strongest candidate to control the glucagon response. Fgf15 was expressed by neurons of the dorsomedial hypothalamus and the perifornical area. Intracerebroventricular injection of FGF19, the human ortholog of Fgf15, reduced activation by neuroglucopenia of dorsal vagal complex neurons, of the parasympathetic nerve, and lowered glucagon secretion. In contrast, silencing Fgf15 in the dorsomedial hypothalamus increased neuroglucopenia-induced glucagon secretion. These data identify hypothalamic Fgf15 as a regulator of glucagon secretion

Glucagon receptor family in GtoPdb v.2021.3

The glucagon family of receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on the Glucagon receptor family [162]) are activated by the endogenous peptide (27-44 aa) hormones glucagon, glucagon-like peptide 1, glucagon-like peptide 2, glucose-dependent insulinotropic polypeptide (also known as gastric inhibitory polypeptide), GHRH and secretin. One common precursor (GCG) generates glucagon, glucagon-like peptide 1 and glucagon-like peptide 2 peptides [119]. For a recent review on the current understanding of the structures of GLP-1 and GLP-1R, the molecular basis of their interaction, and the associated signaling events see de Graaf et al., 2016 [89]

Glucagon receptor family in GtoPdb v.2023.1

The glucagon family of receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on the Glucagon receptor family [165]) are activated by the endogenous peptide (27-44 aa) hormones glucagon, glucagon-like peptide 1, glucagon-like peptide 2, glucose-dependent insulinotropic polypeptide (also known as gastric inhibitory polypeptide), GHRH and secretin. One common precursor (GCG) generates glucagon, glucagon-like peptide 1 and glucagon-like peptide 2 peptides [121]. For a recent review on the current understanding of the structures of GLP-1 and GLP-1R, the molecular basis of their interaction, and the associated signaling events see de Graaf et al., 2016 [90]

Selective disruption of Tcf7l2 in the pancreatic β cell impairs secretory function and lowers β cell mass.

Type 2 diabetes (T2D) is characterized by β cell dysfunction and loss. Single nucleotide polymorphisms in the T-cell factor 7-like 2 (TCF7L2) gene, associated with T2D by genome-wide association studies, lead to impaired β cell function. While deletion of the homologous murine Tcf7l2 gene throughout the developing pancreas leads to impaired glucose tolerance, deletion in the β cell in adult mice reportedly has more modest effects. To inactivate Tcf7l2 highly selectively in β cells from the earliest expression of the Ins1 gene (∼E11.5) we have therefore used a Cre recombinase introduced at the Ins1 locus. Tcfl2(fl/fl)::Ins1Cre mice display impaired oral and intraperitoneal glucose tolerance by 8 and 16 weeks, respectively, and defective responses to the GLP-1 analogue liraglutide at 8 weeks. Tcfl2(fl/fl)::Ins1Cre islets displayed defective glucose- and GLP-1-stimulated insulin secretion and the expression of both the Ins2 (∼20%) and Glp1r (∼40%) genes were significantly reduced. Glucose- and GLP-1-induced intracellular free Ca(2+) increases, and connectivity between individual β cells, were both lowered by Tcf7l2 deletion in islets from mice maintained on a high (60%) fat diet. Finally, analysis by optical projection tomography revealed ∼30% decrease in β cell mass in pancreata from Tcfl2(fl/fl)::Ins1Cre mice. These data demonstrate that Tcf7l2 plays a cell autonomous role in the control of β cell function and mass, serving as an important regulator of gene expression and islet cell coordination. The possible relevance of these findings for the action of TCF7L2 polymorphisms associated with Type 2 diabetes in man is discussed

Glucagon receptor family (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The glucagon family of receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on the Glucagon receptor family [159]) are activated by the endogenous peptide (27-44 aa) hormones glucagon, glucagon-like peptide 1, glucagon-like peptide 2, glucose-dependent insulinotropic polypeptide (also known as gastric inhibitory polypeptide), GHRH and secretin. One common precursor (GCG) generates glucagon, glucagon-like peptide 1 and glucagon-like peptide 2 peptides [116]. For a recent review on review the current understanding of the structures of GLP-1 and GLP-1R, the molecular basis of their interaction, and the signaling events associated with it, see de Graaf et al., 2016 [87]