Islet adaptive changes to fructose-induced insulin resistance: β-cell mass, glucokinase, glucose metabolism, and insulin secretion

β-Cell mass, hexokinase/glucokinase (HK/GK) activity, glucose metabolism and insulin secretion were studied in the islets of rats with fructose-induced insulin resistance (IR). Normal male Wistar rats were fed a standard commercial diet and water without (control, C) or with 10% fructose-rich diet (FRD) for 3 weeks. Blood glucose (strips), triglyceride (commercial kit), and insulin (RIA) levels were measured at the time of death. Glucose-induced insulin release, glucose metabolism (14CO2 and 3H2O production from D-[U-14C]- and D-[5-3H]-glucose) and HK/GK activity (G-6-P production), transcription (RTPCR), protein expression (Western blot), and cellular compartmentalization were measured in isolated islets (collagenase digestion). FRD rats presented normoglycemia but impaired glucose tolerance, hypertriglyceridemia, hyperinsulinemia, and increased HOMA-IR index. In these rats, β-cell mass decreased significantly by 33%, with a 44% increase in the percentage of apoptotic cells. Glucose-induced insulin release and islet glucose metabolism were higher in FRD rats. While GK activity (total and cytosolic fraction) and protein expression were significantly higher in FRD islets, HK showed no change in any of these parameters. Our results demonstrate that the changes induced by dietary-induced IR upon β-cell function and mass are strongly conditional on the nutrient model used. In our model (intact animals with impaired glucose tolerance), GK activity increases through mechanisms previously shown only in vitro or under highly hyperglycemic conditions. Such an increase plays a pivotal role in the adaptive increased release of insulin in response to IR, even in the presence of marked β-cell mass reduction.Centro de Endocrinología Experimental y Aplicad

Islet adaptive changes to fructose-induced insulin resistance: β-cell mass, glucokinase, glucose metabolism, and insulin secretion

β-Cell mass, hexokinase/glucokinase (HK/GK) activity, glucose metabolism and insulin secretion were studied in the islets of rats with fructose-induced insulin resistance (IR). Normal male Wistar rats were fed a standard commercial diet and water without (control, C) or with 10% fructose-rich diet (FRD) for 3 weeks. Blood glucose (strips), triglyceride (commercial kit), and insulin (RIA) levels were measured at the time of death. Glucose-induced insulin release, glucose metabolism (14CO2 and 3H2O production from D-[U-14C]- and D-[5-3H]-glucose) and HK/GK activity (G-6-P production), transcription (RTPCR), protein expression (Western blot), and cellular compartmentalization were measured in isolated islets (collagenase digestion). FRD rats presented normoglycemia but impaired glucose tolerance, hypertriglyceridemia, hyperinsulinemia, and increased HOMA-IR index. In these rats, β-cell mass decreased significantly by 33%, with a 44% increase in the percentage of apoptotic cells. Glucose-induced insulin release and islet glucose metabolism were higher in FRD rats. While GK activity (total and cytosolic fraction) and protein expression were significantly higher in FRD islets, HK showed no change in any of these parameters. Our results demonstrate that the changes induced by dietary-induced IR upon β-cell function and mass are strongly conditional on the nutrient model used. In our model (intact animals with impaired glucose tolerance), GK activity increases through mechanisms previously shown only in vitro or under highly hyperglycemic conditions. Such an increase plays a pivotal role in the adaptive increased release of insulin in response to IR, even in the presence of marked β-cell mass reduction.Centro de Endocrinología Experimental y Aplicad

Ontogénesis y evolución de la masa de células INGAP (Islet Neogenesis Associated Protein) positivas en el período intrauterino y en adultos con insulinorresistencia fisiológica (ratas preñadas)

Objetivos: Estudiar la cronología de aparición de células INGAP positivas en fetos de ratas normales y la evolución simultánea de su masa y la de las células β en ratas preñadas y su presencia en el páncreas de rata.Facultad de Ciencias Médica

Posible efecto de los canabinoides endógenos y el rimonabant sobre la insulinorresistencia y la función de las células β

El propósito del trabajo es estudiar el posible papel regulador del sistema canabinoide sobre la secreción de insulina y los cambios endocrino-metabólicos inducidos en ratas normales por una dieta rica en fructosa (DRF).Facultad de Ciencias Médicas (FCM

Rol de la actvidad del NADPH oxidasa insular sobre los cambios en la secreción de insulina inducidos por una dieta rica en fructuosa

La dieta rica en fructosa (DRF) induce estrés oxidativo (EO), insulinorresistencia, tolerancia a la glucosa alterada y disminución de la masa de células β. Previamente ha sido demostrada la presencia de NADPHoxidasa (NOXi) a nivel insular; por otro lado, su actividad varía en función de diferentes estímulos de la secreción de insulina. Hasta el momento se desconoce el rol de la NOXi sobre los cambios inducidos por DRF en la función insular.Facultad de Ciencias Médica

Machine learning algorithms identified relevant SNPs for milk fat content in cattle

In recent years, machine learning methods have been shown to be efficient in identifying a subset of single nucleotide polymorphisms (SNP) underlying a trait of interest. The aim of this study was the construction of predictive models using machine learning algorithms, for the identification of loci that best explain the variance in milk fat production of dairy cattle. Further objectives involve determining the genes flanking relevant SNPs and retrieving the pathways, biological processes, or molecular functions overrepresented by them. Fat production values adjusted for fixed effects (FPadj) and estimated breeding values for milk fat production (EBVFP) were used as phenotypes and SNPs as predictor variables. The models constructed for EBVFP performed better and yield considerably less relevant SNPs than models for FPadj. Among the genes flanking relevant SNPs, signaling transduction pathways and gated channel activities were detected as overrepresented. The loci obtained for EBVFP matched better with previously reported relevant loci for milk fat content than those obtained for FPadj. Based on the better performance showed by the models trained for EBVFP and their agreement with previous reported results for the trait studied, we conclude that the relationship among individuals should be accounted for in the phenotype used.Sociedad Argentina de Informática e Investigación Operativ

Efecto de sitagliptina y exendina-4 sobre la función insular en ratas con insulinorresistencia inducida por fructosa

Objetivos: estudiar el efecto de la sitagliptina (inhibidor de DPP-4) y de exendina-4 (agonista del receptor de GLP-1) en ratas alimentadas con una dieta estándar sin (C) o con el agregado de fructosa al 10% en el agua de bebida (F), sobre la función insular.Facultad de Ciencias Médica

Genome-wide scan for commons SNPs affecting bovine leukemia virus infection level in dairy cattle

Abstract Background Bovine leukemia virus (BLV) infection is omnipresent in dairy herds causing direct economic losses due to trade restrictions and lymphosarcoma-related deaths. Milk production drops and increase in the culling rate are also relevant and usually neglected. The BLV provirus persists throughout a lifetime and an inter-individual variation is observed in the level of infection (LI) in vivo. High LI is strongly correlated with disease progression and BLV transmission among herd mates. In a context of high prevalence, classical control strategies are economically prohibitive. Alternatively, host genomics studies aiming to dissect loci associated with LI are potentially useful tools for genetic selection programs tending to abrogate the viral spreading. The LI was measured through the proviral load (PVL) set–point and white blood cells (WBC) counts. The goals of this work were to gain insight into the contribution of SNPs (bovine 50KSNP panel) on LI variability and to identify genomics regions underlying this trait. Results We quantified anti–p24 response and total leukocytes count in peripheral blood from 1800 cows and used these to select 800 individuals with extreme phenotypes in WBCs and PVL. Two case-control genomic association studies using linear mixed models (LMMs) considering population stratification were performed. The proportion of the variance captured by all QC-passed SNPs represented 0.63 (SE ± 0.14) of the phenotypic variance for PVL and 0.56 (SE ± 0.15) for WBCs. Overall, significant associations (Bonferroni’s corrected -log10p > 5.94) were shared for both phenotypes by 24 SNPs within the Bovine MHC. Founder haplotypes were used to measure the linkage disequilibrium (LD) extent (r2 = 0.22 ± 0.27 at inter-SNP distance of 25−50 kb). The SNPs and LD blocks indicated genes potentially associated with LI in infected cows: i.e. relevant immune response related genes (DQA1, DRB3, BOLA-A, LTA, LTB, TNF, IER3, GRP111, CRISP1), several genes involved in cell cytoskeletal reorganization (CD2AP, PKHD1, FLOT1, TUBB5) and modelling of the extracellular matrix (TRAM2, TNXB). Host transcription factors (TFs) were also highlighted (TFAP2D; ABT1, GCM1, PRRC2A). Conclusions Data obtained represent a step forward to understand the biology of BLV–bovine interaction, and provide genetic information potentially applicable to selective breeding programs