Direct reprogramming of human fibroblasts into insulin-producing cells using transcription factors.

Direct lineage reprogramming of one somatic cell into another without transitioning through a progenitor stage has emerged as a strategy to generate clinically relevant cell types. One cell type of interest is the pancreatic insulin-producing ß cell whose loss and/or dysfunction leads to diabetes. To date it has been possible to create ß-like cells from related endodermal cell types by forcing the expression of developmental transcription factors, but not from more distant cell lineages like fibroblasts. In light of the therapeutic benefits of choosing an accessible cell type as the cell of origin, in this study we set out to analyze the feasibility of transforming human skin fibroblasts into ß-like cells. We describe how the timed-introduction of five developmental transcription factors (Neurog3, Pdx1, MafA, Pax4, and Nkx2-2) promotes conversion of fibroblasts toward a ß-cell fate. Reprogrammed cells exhibit ß-cell features including ß-cell gene expression and glucose-responsive intracellular calcium mobilization. Moreover, reprogrammed cells display glucose-induced insulin secretion in vitro and in vivo. This work provides proof-of-concept of the capacity to make insulin-producing cells from human fibroblasts via transcription factor-mediated direct reprogramming.

Remission of obesity and insulin resistance is not sufficient to restore mitochondrial homeostasis in visceral adipose tissue.

Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and an apparent global healthy phenotype, obesity triggered a cascade of events in visceral adipose tissue progressing from mitochondrial metabolic and proteostatic alterations to widespread cellular stress, which compromises its biosynthetic and recycling capacity. In humans, weight loss after bariatric surgery showed a transcriptional signature in visceral adipose tissue similar to our mouse model of obesity reversion. Overall, our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in visceral adipose tissue.

Glycaemia Fluctuations Improvement in Old-Age Prediabetic Subjects Consuming a Quinoa-Based Diet: A Pilot Study.

This study aimed to observe if quinoa could produce a benefit on postprandial glycemia that would result in less progression to type 2 diabetes (T2D). A cross-over design pilot clinical study with a nutritional intervention for 8 weeks was performed: 4 weeks on a regular diet (RD) and 4 weeks on a quinoa diet (QD). Nine subjects aged ≥65 years with prediabetes were monitored during the first 4 weeks of RD with daily dietary records and FreeStyle Libre®. Subsequently, participants started the QD, where quinoa and 100% quinoa-based products replaced foods rich in complex carbohydrates that they had consumed in the first 4 weeks of RD. The glycemic measurements recorded by the sensors were considered as functions of time, and the effects of nutrients consumed at the intended time period were analyzed by means of a function-on-scalar regression (fosr) model. With QD participants, decreased body weight (−1.6 kg, p = 0.008), BMI (−0.6 kg/m2p = 0.004) and waist circumference (−1.5 cm, p = 0.015) were observed. Nutrients intake changed during QD, namely, decreased carbohydrates (p = 0.004) and increased lipids (p = 0.004) and some amino acids (p < 0.05). The fosr model showed a reduction in postprandial glycemia in QD despite intrapersonal differences thanks to the joint action of different nutrients and the suppression of others consumed on a regular diet. We conclude that in an old age and high T2D-risk population, a diet rich in quinoa reduces postprandial glycemia and could be a promising T2D-preventive strategy.

Low Percentage of Vegetable Fat in Red Blood Cells Is Associated with Worse Glucose Metabolism and Incidence of Type 2 Diabetes.

The identification of nutritional patterns associated with the development of type 2 diabetes (T2D) might help lead the way to a more efficient and personalized nutritional intervention. Our study is aimed at evaluating the association between fatty acids (FA) in red blood cell (RBC) membranes, as a quantitative biomarker of regular dietary fat intake, and incident type 2 diabetes in a Spanish population. We included 1032 adult Spaniards (57% women, age 49 ± 15 years, 18% prediabetes), without diabetes at study entry, from the Di@bet.es cohort. Incident diabetes was diagnosed at the end of the study follow-up. The FA percentage in RBC was determined at baseline by gas chromatography. Participants were followed on average 7.5 ± 0.6 years. Lower percentages of linoleic acid (LA), α-linolenic (ALA), and eicosapentaenoic acid (EPA), and higher percentages of docosahexaenoic acid (DHA) in RBC membranes were associated, independently of classical risk factors, with worse glucose metabolism at the end of the study follow-up. In addition, higher percentages of ALA and EPA, and moderate percentages of DHA, were associated with lower risk of diabetes. No significant associations were found for LA and diabetes risk. Dietary patterns rich in vegetables are independently associated with lower risk of both deterioration of glucose regulation and incident diabetes, and should be reinforced for the prevention of diabetes.

Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca2+ homeostasis with adipose tissue lipolysis.

Appropriate cristae remodeling is a determinant of mitochondrial function and bioenergetics and thus represents a crucial process for cellular metabolic adaptations. Here, we show that mitochondrial cristae architecture and expression of the master cristae-remodeling protein OPA1 in proopiomelanocortin (POMC) neurons, which are key metabolic sensors implicated in energy balance control, is affected by fluctuations in nutrient availability. Genetic inactivation of OPA1 in POMC neurons causes dramatic alterations in cristae topology, mitochondrial Ca2+ handling, reduction in alpha-melanocyte stimulating hormone (α-MSH) in target areas, hyperphagia, and attenuated white adipose tissue (WAT) lipolysis resulting in obesity. Pharmacological blockade of mitochondrial Ca2+ influx restores α-MSH and the lipolytic program, while improving the metabolic defects of mutant mice. Chemogenetic manipulation of POMC neurons confirms a role in lipolysis control. Our results unveil a novel axis that connects OPA1 in POMC neurons with mitochondrial cristae, Ca2+ homeostasis, and WAT lipolysis in the regulation of energy balance.

Gsα-dependent signaling is required for postnatal establishment of a functional ß-cell mass.

OBJECTIVE: Early postnatal life is a critical period for the establishment of the functional ß-cell mass that will sustain whole-body glucose homeostasis during the lifetime. ß cells are formed from progenitors during embryonic development but undergo significant expansion in quantity and attain functional maturity after birth. The signals and pathways involved in these processes are not fully elucidated. Cyclic adenosine monophosphate (cAMP) is an intracellular signaling molecule that is known to regulate insulin secretion, gene expression, proliferation, and survival of adult ß cells. The heterotrimeric G protein Gs stimulates the cAMP-dependent pathway by activating adenylyl cyclase. In this study, we sought to explore the role of Gs-dependent signaling in postnatal ß-cell development. METHODS: To study Gs-dependent signaling, we generated conditional knockout mice in which the α subunit of the Gs protein (Gsα) was ablated from ß-cells using the Cre deleter line Ins1Cre. Mice were characterized in terms of glucose homeostasis, including in vivo glucose tolerance, glucose-induced insulin secretion, and insulin sensitivity. ß-cell mass was studied using histomorphometric analysis and optical projection tomography. ß-cell proliferation was studied by ki67 and phospho-histone H3 immunostatining, and apoptosis was assessed by TUNEL assay. Gene expression was determined in isolated islets and sorted ß cells by qPCR. Intracellular cAMP was studied in isolated islets using HTRF-based technology. The activation status of the cAMP and insulin-signaling pathways was determined by immunoblot analysis of the relevant components of these pathways in isolated islets. In vitro proliferation of dissociated islet cells was assessed by BrdU incorporation. RESULTS: Elimination of Gsα in ß cells led to reduced ß-cell mass, deficient insulin secretion, and severe glucose intolerance. These defects were evident by weaning and were associated with decreased proliferation and inadequate expression of key ß-cell identity and maturation genes in postnatal ß-cells. Additionally, loss of Gsα caused a broad multilevel disruption of the insulin transduction pathway that resulted in the specific abrogation of the islet proliferative response to insulin. CONCLUSION: We conclude that Gsα is required for ß-cell growth and maturation in the early postnatal stage and propose that this is partly mediated via its crosstalk with insulin signaling. Our findings disclose a tight connection between these two pathways in postnatal ß cells, which may have implications for using cAMP-raising agents to promote ß-cell regeneration and maturation in diabetes.

Endogenous cortisol excess confers a unique lipid signature and metabolic network.

Chronic cortisol excess induces several alterations on protein, lipid and carbohydrate metabolism resembling those found in the metabolic syndrome. However, patients exposed to prolonged high levels of cortisol in Cushing syndrome (CS) present exceeding cardiometabolic alterations not reflected by conventional biomarkers. Using 3 ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS) platforms, we aimed to characterise the serum metabolome of 25 patients with active endogenous CS and 25 control subjects matched by propensity score (sex, BMI, diabetes mellitus type 2 (T2D), high blood pressure (HBP) and dyslipidaemia) to search for potential disease-specific biomarkers and pathways associated to the clinical comorbidities. A total of 93 metabolites were significantly altered in patients with CS. Increased levels of sulfur amino acids (AA), triacylglycerols, glycerophospholipids, ceramides and cholesteryl esters were observed. Contrarily, concentrations of essential and non-essential AA, polyunsaturated fatty acids, conjugated bile acids and second messenger glycerolipids were decreased. Twenty-four-hour urinary free cortisol (24h-UFC) independently determined the concentration of 21 lipids and 4 AA. A metabolic signature composed by 10 AA and 10 lipid metabolites presented an AUC-ROC of 95% for the classification of CS patients. Through differential network analysis, 152 aberrant associations between metabolites involved in the Lands cycle and Kennedy pathway were identified. Our data indicates that chronic hypercortisolemia confers a unique lipidomic signature and several alterations in numerous AA even when compared to patients with similar metabolic comorbidities providing novel insights of the increased cardiometabolic burden of CS. KEY MESSAGES: • Cortisol excess induces metabolic alterations beyond conventional biomarkers. • The hypercortisolism extent determines the concentration of 21 lipids and 5 aa. • Cortisol excess confers a unique metabolic signature of 20 metabolites. • Kennedy and Lands cycle are profoundly disturbed by cortisol excess.

Wisp1 is a circulating factor that stimulates proliferation of adult mouse and human beta cells.

Expanding the mass of pancreatic insulin-producing beta cells through re-activation of beta cell replication has been proposed as a therapy to prevent or delay the appearance of diabetes. Pancreatic beta cells exhibit an age-dependent decrease in their proliferative activity, partly related to changes in the systemic environment. Here we report the identification of CCN4/Wisp1 as a circulating factor more abundant in pre-weaning than in adult mice. We show that Wisp1 promotes endogenous and transplanted adult beta cell proliferation in vivo. We validate these findings using isolated mouse and human islets and find that the beta cell trophic effect of Wisp1 is dependent on Akt signaling. In summary, our study reveals the role of Wisp1 as an inducer of beta cell replication, supporting the idea that the use of young blood factors may be a useful strategy to expand adult beta cell mass.

Incidence and regression of metabolic syndrome in a representative sample of the Spanish population: results of the cohort di@bet.es study.

INTRODUCTION: Metabolic syndrome (MetS) is an important predictor of cardiovascular mortality. Identification of occurrence and regression trends of MetS could permit elaboration of preventive strategies with new targets. The objective of this study was to analyze the occurrence and regression rates of MetS and its associated factors in the representative cohort of Spain of the di@bet.es study. RESEARCH DESIGN AND METHODS: The di@bet.es study is a prospective cohort where 5072 people representative of the Spanish population over 18 years of age were randomly selected between 2009 and 2010. Follow-up was a median of 7.5 (IQR 7.2-7.9) years, with 2408 (47%) participating subjects. A total of 1881 (78%) subjects had all the pertinent data available and were included in this study. RESULTS: Of the 1146 subjects without baseline criteria for MetS, 294 (25.7%) developed MetS during follow-up, while of the 735 patients with prior MetS, 148 (20.1%) presented regression. Adjusted MetS incidence per 1000 person-years was 38 (95% CI 32 to 44), while regression incidence was 36 (95% CI 31 to 41). Regression rate was independently higher than incidence rate in the following: women, subjects aged 18-45, university-degree holders, patients without central obesity, without hypertension, as well as those with body mass index of <25 kg/m2. Lower progression and higher regression rates were observed with an adapted 14-point Mediterranean Diet adherence screener questionnaire score of >11 in both groups and with >500 and>2000 MET-min/week of physical activity, respectively. CONCLUSIONS: This study provides MetS incidence and regression rates, and identifies the target population for intervention strategies in Spain and possibly in other countries.

Gut microbiota imbalances in Tunisian participants with type 1 and type 2 diabetes mellitus.

Gut microbiota plays an important role in the regulation of the immune system and host's metabolism. We aimed to characterize the gut microbiota of Tunisian participants with and without diabetes.We enrolled ten participants with type 1 diabetes mellitus (T1DM), ten patients with type 2 diabetes mellitus (T2DM), and 11 subjects without diabetes. Bacteria was quantified in fecal samples by quantitative PCR (qPCR). Statistical tests and multivariate analysis were performed using RStudio program.Results showed that the proportions of Firmicutes, Akkermansia muciniphila, and Faecalibacterium prausnitzii (P≤0.041), as well as, the ratio Firmicutes/Bacteroidetes decreased in participants with T1DM compared with those without diabetes (p = 0.036). Participants with T2DM presented a reduction in the amounts of A. muciniphila and F. prausnitzii compared with those without diabetes (P≤0.036). Furthermore, A. muciniphila is negatively correlated with glucose level (P=0.022) and glycated hemoglobin (HbA1c) (P=0.035). Multivariate analysis revealed that participants with diabetes formed a cluster apart compared with those without diabetes.In conclusion the gut bacteria of Tunisian participants with diabetes was altered. The gut bacterial profile, especially the distribution of A muciniphila in participants with diabetes was affected by glycemic dysregulation. The investigation of the gut microbiota may help clinicians to improve diagnosis and treatment of diabetes and its complications.

Targeting pancreatic islet PTP1B improves islet graft revascularization and transplant outcomes.

Deficient vascularization is a major driver of early islet graft loss and one of the primary reasons for the failure of islet transplantation as a viable treatment for type 1 diabetes. This study identifies the protein tyrosine phosphatase 1B (PTP1B) as a potential modulator of islet graft revascularization. We demonstrate that grafts of pancreatic islets lacking PTP1B exhibit increased revascularization, which is accompanied by improved graft survival and function, and recovery of normoglycemia and glucose tolerance in diabetic mice transplanted with PTP1B-deficient islets. Mechanistically, we show that the absence of PTP1B leads to activation of hypoxia-inducible factor 1α-independent peroxisome proliferator-activated receptor γ coactivator 1α/estrogen-related receptor α signaling and enhanced expression and production of vascular endothelial growth factor A (VEGF-A) by ß cells. These observations were reproduced in human islets. Together, these findings reveal that PTP1B regulates islet VEGF-A production and suggest that this phosphatase could be targeted to improve islet transplantation outcomes.

Ambient temperature and prevalence of diabetes and insulin resistance in the Spanish population: Di@bet.es study.

Objective The activity of brown adipose tissue is sensitive to changes in ambient temperature. A lower exposure to cold could result in an increased risk of developing diabetes at population level, although this factor has not yet been sufficiently studied. Design We studied 5072 subjects, participants in a national, cross-sectional population-based study representative of the Spanish adult population (Di@bet.es study). All subjects underwent a clinical, demographic and lifestyle survey, a physical examination and blood sampling (75 g oral glucose tolerance test). Insulin resistance was estimated with the homeostasis model assessment (HOMA-IR). The mean annual temperature (°C) in each individual municipality was collected from the Spanish National Meteorology Agency. Results Linear regression analysis showed a significant positive association between mean annual temperature and fasting plasma glucose (ß: 0.087, P < 0.001), 2 h plasma glucose (ß: 0.049, P = 0.008) and HOMA-IR (ß: 0.046, P = 0.008) in multivariate adjusted models. Logistic regression analyses controlled by multiple socio-demographic variables, lifestyle, adiposity (BMI) and geographical elevation showed increasing odds ratios for prediabetes (WHO 1999), ORs 1, 1.26 (0.95-1.66), 1.08 (0.81-1.44) and 1.37 (1.01-1.85) P for trend = 0.086, diabetes (WHO 1999) ORs 1, 1.05 (0.79-1.39), 1.20 (0.91-1.59) and 1.39 (1.02-1.90) P = 0.037, and insulin resistance (HOMA-IR ≥75th percentile of the non-diabetic population): ORs 1, 1.03 (0.82-1.30), 1.22 (0.96-1.55), 1.26 (0.98-1.63) (P for trend = 0.046) as the mean annual temperature (into quartiles) rose. Conclusions Our study reports an association between ambient temperature and the prevalence of dysglycemia and insulin resistance in Spanish adults, consistent with the hypothesis that a lower exposure to cold could be associated with a higher risk of metabolic derangements.

The Mitochondria-Targeted Antioxidant MitoQ Modulates Mitochondrial Function and Endoplasmic Reticulum Stress in Pancreatic ß Cells Exposed to Hyperglycaemia.

BACKGROUND/AIMS: Mitochondria-targeted antioxidants such as mitoquinone (MitoQ) have demonstrated protective effects against oxidative damage in several diseases. The increase in reactive oxygen species (ROS) production during glucose metabolism in ß cells can be exacerbated under hyperglycaemic conditions such as type 2 diabetes (T2D), thus contributing to ß cell function impairment. In the present work, we aimed to evaluate the effect of MitoQ on insulin secretion, oxidative stress, endoplasmic reticulum (ER) stress and nuclear factor kappa B (NFκB) signalling in a pancreatic ß cell line under normoglycaemic (NG, 11.1 mM glucose), hyperglycaemic (HG, 25 mM glucose) and lipidic (palmitic acid (PA), 0.5mM) conditions. METHODS: We incubated the pancreatic ß cell line INS-1E with or without MitoQ (0.5µM) under NG, HG and PA conditions. We then assessed the following parameters: glucose-induced insulin secretion, O2 consumption (with a Clark-type electrode); mitochondrial function, oxidative stress parameters and calcium levels (by fluorescence microscopy); ER stress markers and NFκB-p65 protein levels (by western blotting). RESULTS: MitoQ increased insulin secretion and prevented the enhancement of ROS production and O2 consumption and decrease in GSH levels that are characteristic under HG conditions. MitoQ also reduced protein levels of ER stress markers (GRP78 and P-eIF2α) and the proinflammatory nuclear transcription factor NFκB-p65, both of which increased under HG. MitoQ did not significantly alter ER stress markers under lipidic conditions. CONCLUSION: Our findings suggest that treatment with MitoQ modulates mitochondrial function, which in turn ameliorates endoplasmic reticulum stress and NFκB activation, thereby representing potential benefits for pancreatic ß cell function.

Fine-scale haplotype mapping of MUT, AACS, SLC6A15 and PRKCA genes indicates association with insulin resistance of metabolic syndrome and relationship with branched chain amino acid metabolism or regulation.

Branched chain amino acids (BCAA) are essential elements of the human diet, which display increased plasma levels in obesity and regained particular interest as potential biomarkers for development of diabetes. To define determinants of insulin resistance (IR) we investigated 73 genes involved in BCAA metabolism or regulation by fine-scale haplotype mapping in two European populations with metabolic syndrome. French and Romanians (n = 465) were genotyped for SNPs (Affymetrix) and enriched by imputation (BEAGLE 4.1) at 1000 genome project density. Initial association hits detected by sliding window were refined (HAPLOVIEW 3.1 and PHASE 2.1) and correlated to homeostasis model assessment (HOMAIR) index, in vivo insulin sensitivity (SI) and BCAA plasma levels (ANOVA). Four genomic regions were associated with IR located downstream of MUT, AACS, SLC6A15 and PRKCA genes (P between 9.3 and 3.7 x 10-5). Inferred haplotypes up to 13 SNPs length were associated with IR (e.g. MUT gene with P < 4.9 x 10-5; Bonferroni 1.3 x 10-3) and synergistic to HOMAIR. SNPs in the same regions were also associated with one order of magnitude lower P values (e.g. rs20167284 in the MUT gene with P < 1.27 x 10-4) and replicated in Mediterranean samples (n = 832). In French, influential haplotypes (OR > 2.0) were correlated with in vivo insulin sensitivity (1/SI) except for SLC6A15 gene. Association of these genes with BCAA levels was variable, but influential haplotypes confirmed implication of MUT from BCAA metabolism as well as a role of regulatory genes (AACS and PRKCA) and suggested potential changes in transcriptional activity. These data drive attention towards new regulatory regions involved in IR in relation with BCAA and show the ability of haplotypes in phased DNA to detect signals complimentary to SNPs, which may be useful in designing genetic markers for clinical applications in ethnic populations.

Branched-Chain Amino Acid Database Integrated in MEDIPAD Software as a Tool for Nutritional Investigation of Mediterranean Populations.

Branched-chained amino acids (BCAA) are essential dietary components for humans and can act as potential biomarkers for diabetes development. To efficiently estimate dietary intake, we developed a BCAA database for 1331 food items found in the French Centre d'Information sur la Qualité des Aliments (CIQUAL) food table by compiling BCAA content from international tables, published measurements, or by food similarity as well as by calculating 267 items from Greek, Turkish, Romanian, and Moroccan mixed dishes. The database embedded in MEDIPAD software capable of registering 24 h of dietary recalls (24HDR) with clinical and genetic data was evaluated based on archived 24HDR of the Saint Pierre Institute (France) from 2957 subjects, which indicated a BCAA content up to 4.2 g/100 g of food and differences among normal weight and obese subjects across BCAA quartiles. We also evaluated the database of 119 interviews of Romanians, Turkish and Albanians in Greece (27⁻65 years) during the MEDIGENE program, which indicated mean BCAA intake of 13.84 and 12.91 g/day in males and females, respectively, comparable to other studies. The MEDIPAD is user-friendly, multilingual, and secure software and with the BCAA database is suitable for conducting nutritional assessment in the Mediterranean area with particular facilities for food administration.

The Antidiabetic Agent Sodium Tungstate Induces Abnormal Glycogen Accumulation in Renal Proximal Tubules from Diabetic IRS2-Knockout Mice.

The kidney is an insulin-sensitive organ involved in glucose homeostasis. One major effect of insulin is to induce glycogen storage in the liver and muscle. However, no significant glycogen stores are detected in normal kidneys, but diabetic subjects present a characteristic renal histopathological feature resulting from extensive glycogen deposition mostly in nonproximal tubules. The mechanism of renal glycogen accumulation is yet poorly understood. Here, we studied in situ glycogen accumulation in the kidney from diabetic IRS2-knockout mice and the effect of the insulin-mimetic agent sodium tungstate (NaW). IRS2-knockout mice displayed hyperglycemia and hyperinsulinemia. NaW only normalized glycemia. There was no evident morphological difference between kidneys from untreated wild-type (WT), NaW-treated WT, and untreated IRS2-knockout mice. However, NaW-treated IRS2-knockout mice showed tubular alterations resembling clear cells in the cortex, but not in the outer medulla, that were correlated with glycogen accumulation. Immunohistochemical detection of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase, mostly expressed by renal proximal tubules, showed that altered tubules were of proximal origin. Our preliminary study suggests that IRS2 differentially regulates glycogen accumulation in renal tubules and that NaW treatment in the context of IRS2 ablation induces abnormal glycogen accumulation in cortical proximal tubules.

Validación española de la Escala de Adicción a Videojuegos para Adolescentes (GASA) / Spanish validation of Game Addiction Scale for Adolescents (GASA)

OBJETIVO: El objetivo es adaptar y validar la escala Game Addiction Scale for Adolescents (GASA) a población juvenil española. DISEÑO: Estudio de adaptación cultural y validación. Emplazamiento: Centros de educación secundaria seleccionados por conveniencia. PARTICIPANTES: Se realizan dos estudios independientes con 466 jóvenes de 15,27 años (13-18, DT: 1,83) 48,7%♀ y 556 de 21,24 años (19-26; DT: 1,86) 44,1%♀. Mediciones: Adicción a los videojuegos (GASA); Conducta de juego (Cuestionario de hábitos de uso de videojuegos), Impulsividad. (Escala de Impulsividad de Plutchik) y Presión de grupo (cuestionario ad hoc). RESULTADOS: La versión española de GASA ha mostrado buena fiabilidad y una estructura factorial fiel a la de la escala original. En cuanto a la validez de criterio, las puntuaciones de GASA son significativamente diferentes en función de 4 criterios asociados al juego problemático: intensidad y frecuencia de juego, impulsividad y presión de grupo. CONCLUSIONES: Los resultados muestran que la versión adaptada de GASA es una medida adecuada y válida para la evaluación de la conducta problemática de videojuegos

OBJECTIVE: The aim of this study is to adapt and validate the Game Addiction Scale for Adolescents (GASA) to the Spanish youth population. DESIGN: Cultural adaptation and validation study. SETTING: Secondary Education centres. PARTICIPANTS: Two independent studies were conducted on a group of 466 young people with a mean age of 15.27 years (13-18, SD: 1.83) and 48.7% ♀ and on another group of 566, with a mean age of 21.24 years (19-26; SD: 1.86) 44.1% ♀. Measurements: Addiction to video games (GASA); Game behavior (Game habits usage questionnaire), Impulsiveness (Plutchik Impulsiveness Scale) and Group Pressure (Ad hoc questionnaire). RESULTS: The Spanish version of GASA has shown good reliability and true to the original scale factor structure. As regards criterion validity, GASA scores are significantly different according to four criteria related to problem gambling: Game intensity and frequency, impulsiveness, and peer pressure. CONCLUSIONS: The results show that the adapted version GASA is adequate and a valid tool for assessing problematic gaming behavior

Modulation of the endocrine transcriptional program by targeting histone modifiers of the H3K27me3 mark.

Posttranscriptional modifications of histones constitute an epigenetic mechanism that is closely linked to both gene silencing and activation events. Trimethylation of Histone3 at lysine 27 (H3K27me3) is a repressive mark that associates with developmental gene regulation during differentiation programs. In the developing pancreas, expression of the transcription factor Neurogenin3 in multipotent progenitors initiates endocrine differentiation that culminates in the generation of all pancreatic islet cell lineages, including insulin-producing beta cells. Previously, we showed that Neurogenin3 promoted the removal of H3K27me3 marks at target gene promoters in vitro, suggesting a functional connection between this factor and regulators of this chromatin mark. In the present study, we aimed to specifically evaluate whether targeting the activity of these histone modifiers can be used to modulate pancreatic endocrine differentiation. Our data show that chemical inhibition of the H3K27me3 demethylases Jmjd3/Utx blunts Neurogenin3-dependent gene activation in vitro. Conversely, inhibition of the H3K27me3 methyltransferase Ezh2 enhances both the transactivation ability of Neurogenin3 in cultured cells and the formation of insulin-producing cells during directed differentiation from pluripotent cells. These results can help improve current protocols aimed at generating insulin-producing cells for beta cell replacement therapy in diabetes.

[Spanish validation of Game Addiction Scale for Adolescents (GASA)]. / Validación española de la Escala de Adicción a Videojuegos para Adolescentes (GASA).

OBJECTIVE: The aim of this study is to adapt and validate the Game Addiction Scale for Adolescents (GASA) to the Spanish youth population. DESIGN: Cultural adaptation and validation study. SETTING: Secondary Education centres. PARTICIPANTS: Two independent studies were conducted on a group of 466 young people with a mean age of 15.27 years (13-18, SD: 1.83) and 48.7% ♀ and on another group of 566, with a mean age of 21.24 years (19-26; SD: 1.86) 44.1% ♀. MEASUREMENTS: Addiction to video games (GASA); Game behavior (Game habits usage questionnaire), Impulsiveness (Plutchik Impulsiveness Scale) and Group Pressure (Ad hoc questionnaire). RESULTS: The Spanish version of GASA has shown good reliability and true to the original scale factor structure. As regards criterion validity, GASA scores are significantly different according to four criteria related to problem gambling: Game intensity and frequency, impulsiveness, and peer pressure. CONCLUSIONS: The results show that the adapted version GASA is adequate and a valid tool for assessing problematic gaming behaviour.