A long non-coding RNA that harbors a SNP associated with type 2 diabetes regulates the expression of TGM2 gene in pancreatic beta cells

IntroductionMost of the disease-associated single nucleotide polymorphisms (SNPs) lie in non- coding regions of the human genome. Many of these variants have been predicted to impact the expression and function of long non-coding RNAs (lncRNA), but the contribution of these molecules to the development of complex diseases remains to be clarified. MethodsHere, we performed a genetic association study between a SNP located in a lncRNA known as LncTGM2 and the risk of developing type 2 diabetes (T2D), and analyzed its implication in disease pathogenesis at pancreatic beta cell level. Genetic association study was performed on human samples linking the rs2076380 polymorphism with T2D and glycemic traits. The pancreatic beta cell line EndoC-bH1 was employed for functional studies based on LncTGM2 silencing and overexpression experiments. Human pancreatic islets were used for eQTL analysis. ResultsWe have identified a genetic association between LncTGM2 and T2D risk. Functional characterization of the LncTGM2 revealed its implication in the transcriptional regulation of TGM2, coding for a transglutaminase. The T2Dassociated risk allele in LncTGM2 disrupts the secondary structure of this lncRNA, affecting its stability and the expression of TGM2 in pancreatic beta cells. Diminished LncTGM2 in human beta cells impairs glucose-stimulated insulin release. ConclusionsThese findings provide novel information on the molecular mechanisms by which T2D-associated SNPs in lncRNAs may contribute to disease, paving the way for the development of new therapies based on the modulation of lncRNAs.This work was supported by grants from the Ministerio de Ciencia, Innovación y Universidades (PID2019-104475GA-I00 to I.S, and PGC2018-097573-A-I00 to AC-R) and the European Foundation for the Study of Diabetes (EFSD) - EFSD/JDRF/Lilly Programme on Type 1 Diabetes Research to IS. FO (MS19/00109) is recipient of the Miguel Servet scheme, and AL (FI19/00045) was supported by the Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia, Innovación y Universidades, Gobierno de España (ES). HR-M (PRE2019-089350) is supported by predoctoral grant from the Ministerio de Ciencia, Innovacion y Universidades, Gobierno de España (ES) IG-M, MS-C, JM-S and AO-G were supported by Predoctoral Fellowship Grants from the UPV/EHU (Universidad del Pais Vasco/EuskalHerrikoUnibertsitatea) and the Basque Department of Education. MC is supported by the Fonds National de la RechercheScientifique (FNRS), the Francophone Foundation for Diabetes Research (sponsored by the French Diabetes Federation, Abbott, Eli Lilly, Merck Sharp & Dohme, and Novo Nordisk) and FF and MC by the EFSD/BoehringerIngelheim European Research Programme on Multi-System Challenges in Diabetes. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication

Craniopharyngioma in the elderly: a multicenter and nationwide study in Spain

[Abstract] Background: Craniopharyngioma (CP) is a rare tumor in the elderly whose clinical features and prognosis are not well known in this population. Aim: To evaluate the clinicopathological features and therapeutic outcomes of CP diagnosed in the elderly. Patients and Methods: This was a retrospective, multicenter, national study of CP patients diagnosed over the age of 65 years and surgically treated. Results: From a total of 384 adult CP patients, we selected 53 (13.8%) patients (27 women [50.9%], mean age 72.3 ± 5.1 years [range 65–83 years]) diagnosed after the age of 65 years. The most common clinical symptoms were visual field defects (71.2%) followed by headache (45.3%). The maximum tumor diameter was 2.9 ± 1.1 cm. In most patients, the tumor was suprasellar (96.2%) and mixed (solid-cystic) (58.5%). The surgical approach most commonly used was transcranial surgery (52.8%), and more than half of the patients (54.7%) underwent subtotal resection (STR). Adamantinomatous CP and papillary CP were present in 51 and 45.1%, respectively, with mixed forms in the remaining. Surgery was accompanied by an improvement in visual field defects and in headaches; however, pituitary hormonal hypofunction increased, mainly at the expense of an increase in the prevalence of diabetes insipidus (DI) (from 3.9 to 69.2%). Near-total resection (NTR) was associated with a higher prevalence of DI compared with subtotal resection (87.5 vs. 53.6%, p = 0.008). Patients were followed for 46.7 ± 40.8 months. The mortality rate was 39.6% with a median survival time of 88 (95% CI: 57–118) months. DI at last visit was associated with a lower survival. Conclusion: CP diagnosed in the elderly shows a similar distribution by sex and histologic forms than that diagnosed at younger ages. At presentation, visual field alterations and headaches are the main clinical symptoms which improve substantially with surgery. However, surgery, mainly NTR, is accompanied by worsening of pituitary function, especially DI, which seems to be a predictor of mortality in this population

Diferencias de género en la mortalidad de personas con diabetes tipo 2: Estudio Asturias 2018.

To investigate the influence of gender on mortality according to the presence or absence of type 2 diabetes mellitus (DM2) and other cardiovascular risk factors in the Asturias Study cohort. The Asturias Study (started in 1998) is an observational, prospective cohort study of a representative sample of a population of Asturias aged 30-75 years. The population was divided into groups according to the presence or absence of DM2 and according to gender to assess control of cardiovascular risk factors. In addition, aware of the vital status of the cohort 18 years after the beginning of the study, we analyzed differences in causes of mortality according to the previous categories. In 1998, 1034 people started the study, 561 women (54.25%) and 473 men (45.75%). Of these, 131 (12.66%) had diabetes (75 men and 56 women). The women with T2D presented a hazard ratio (HR) for total mortality of 1.64 (95% confidence interval [95%CI]: .97-2.77), which was 1.63 (95%CI: 1.07-2.50) for the men and, for cardiovascular mortality, 3.06 (95%CI: 1.44-6.47) for the females, versus 1.49 (95%CI: 0.64-3.46) for the males. The mortality rate for people with T2D of both sexes was higher than for people without T2D. Women with T2D have a risk more than three times higher than women without diabetes of dying from cardiovascular causes. We should implement treatment strategies in women with this condition

miR-24-3p and Body Mass Index as Type 2 Diabetes Risk Factors in Spanish Women 15 Years after Gestational Diabetes Mellitus Diagnosis

Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance that is diagnosed for the first time during pregnancy. The objective of this study is to know the glucose tolerance status after 15 years of pregnancy in patients diagnosed with gestational diabetes and to assess the long-term effect of GDM on the circulating miRNA profile of these women. To answer these, 30 randomly selected women diagnosed with GDM during 2005–2006 were included in the study, and glucose tolerance was measured using the National Diabetes Data Group criteria. Additionally, four miRNAs (hsa-miR-1-3p, hsa-miR-24-3p, hsa-miR-329-3p, hsa-miR-543) were selected for their analysis in the plasma of women 15 years after the diagnosis of GDM. In our study we discovered that, fifteen years after the diagnosis of GDM, 50% of women have some degree of glucose intolerance directly related to body weight and body mass index during pregnancy. Dysglycemic women also showed a significantly increased level of circulating hsa-miR-24-3p. Thus, we can conclude that initial weight and BMI, together with circulating expression levels of hsa-miR-24-3p, could be good predictors of the future development of dysglycemia in women with a previous diagnosis of GDM

Metformin and Glucose Concentration as Limiting Factors in Retinal Pigment Epithelial Cell Viability and Proliferation

Metformin is a well-established drug for the treatment of type 2 diabetes; however, the mechanism of action has not been well described and many aspects of how it truly acts are still unknown. Moreover, regarding in vitro experiments, the glycaemic status when metformin is used is generally not considered, which, added to the suprapharmacological drug concentrations that are commonly employed in research, has resulted in gaps of its mechanism of action. The aim of this study was to determine how glucose and metformin concentrations influence cell culture. Considering that diabetic retinopathy is one of the most common complications of diabetes, a retinal pigment epithelial cell line was selected, and cell viability and proliferation rates were measured at different glucose and metformin concentrations. As expected, glucose concentration by itself positively influenced cell proliferation rates. When the metformin was considered, results were conditioned, as well, by metformin concentration. This conditioning resulted in cell death when high concentrations of metformin were used under physiological concentrations of glucose, while this did not happen when clinically relevant concentrations of metformin were used independently of glucose status. Our study shows the importance of in vitro cell growth conditions when drug effects such as metformin’s are being analysed

Circulating miRNA expression in long-standing type 1 diabetes mellitus

Abstract Type 1 diabetes is a chronic autoimmune disease which results in inefficient regulation of glucose homeostasis and can lead to different vascular comorbidities through life. In this study we aimed to analyse the circulating miRNA expression profile of patients with type 1 diabetes, and with no other associated pathology. For this, fasting plasma was obtained from 85 subjects. Next generation sequencing analysis was firstly performed to identify miRNAs that were differentially expressed between groups (20 patients vs. 10 controls). hsa-miR-1-3p, hsa-miR-200b-3p, hsa-miR-9-5p, and hsa-miR-1200 expression was also measured by Taqman RT-PCR to validate the observed changes (34 patients vs. 21 controls). Finally, through a bioinformatic approach, the main pathways affected by the target genes of these miRNAs were studied. Among the studied miRNAs, hsa-miR-1-3p expression was found significantly increased in patients with type 1 diabetes compared to controls, and positively correlated with glycated haemoglobin levels. Additionally, by using a bioinformatic approach, we could observe that changes in hsa-miR-1-3p directly affect genes involved in vascular development and cardiovascular pathologies. Our results suggest that, circulating hsa-miR-1-3p in plasma, together with glycaemic control, could be used as prognostic biomarkers in type 1 diabetes, helping to prevent the development of vascular complications in these patients

Sézary syndrome patient-derived models allow drug selection for personalized therapy

Current therapeutic approaches for Sézary syndrome (SS) do not achieve a significant improvement in long-term survival of patients, and they are mainly focused on reducing blood tumor burden to improve quality of life. Eradication of SS is hindered by its genetic and molecular heterogeneity. Determining effective and personalized treatments for SS is urgently needed. The present work compiles the current methods for SS patient-derived xenograft (PDX) generation and management to provide new perspectives on treatment for patients with SS. Mononuclear cells were recovered by Ficoll gradient separation from fresh peripheral blood of patients with SS (N = 11). A selected panel of 26 compounds that are inhibitors of the main signaling pathways driving SS pathogenesis, including NF-kB, MAPK, histone deacetylase, mammalian target of rapamycin, or JAK/STAT, was used for in vitro drug sensitivity testing. SS cell viability was evaluated by using the CellTiter-Glo_3D Cell Viability Assay and flow cytometry analysis. We validated one positive hit using SS patient-derived Sézary cells xenotransplanted (PDX) into NOD-SCID-γ mice. In vitro data indicated that primary malignant SS cells all display different sensitivities against specific pathway inhibitors. In vivo validation using SS PDX mostly reproduced the responses to the histone deacetylase inhibitor panobinostat that were observed in vitro. Our investigations revealed the possibility of using high-throughput in vitro testing followed by PDX in vivo validation for selective targeting of SS tumor cells in a patient-specific manner