Feeding a Protective Hydrolysed Casein Diet to Young Diabetes-prone BB Rats Affects Oxidation of L[U−C14] glutamine in Islets and Peyer's Patches, Reduces Abnormally High Mitotic Activity in Mesenteric Lymph Nodes, Enhances Islet Insulin and Tends to Normalize NO Production

The present studies were undertaken to examine concomitant diet-induced changes in pancreatic islets and cells of the gut immune system of diabetes-prone BB rats in the period before classic insulitis. Diabetes-prone (BBdp) and control non-diabetes prone (BBc) BB rats were fed for ~ 17 days either a mainly plant-based standard laboratory rodent diet associated with high diabetes frequency, NIH-07 (NIH) or a protective semipurified diet with hydrolyzed casein (HC) as the amino acid source. By about 7 weeks of age, NIH-fed BBdp rats had lower plasma insulin and insulin/glucose ratio, lower insulin content of isolated islets, lower basal levels of NO but higher responsiveness of NO production to IL-1β in cultured islets, and higher Con A response and biosynthetic activities in mesenteric lymphocytes than control rats fed the same diet. In control rats, the HC diet caused only minor changes in most variables, except for a decrease in oxidation of L-[U−C14]glutamine in Peyer's patch (PP) cells and an increase in protein biosynthesis in mesenteric lymphocytes. In BBdp rats, however, the HC diet increased plasma insulin concentration, islet insulin/ protein ratio, and tended to normalize the basal and IL-1β-stimulated NO production by cultured islets. The HC diet decreased oxidation of L-[U−C14]glutamine in BBdp pancreatic islets, whereas oxidation of L-[U−C14]glutamine in PP cells was increased, and the basal [Methyl-H3] thymidine incorporation in mesenteric lymphocytes was decreased. These findings are compatible with the view that alteration of nutrient catabolism in islet cells as well as key cells of the gut immune system, particularly changes in mitotic and biosynthetic activities in mesenteric lymphocytes, as well as basal and IL-1β stimulated NO production, participate in the sequence of events leading to autoimmune diabetes in BB rats. Thus, the protection afforded by feeding a hydrolysed casein-based diet derives from alterations in both the target islet tissue and key cells of the gut immune system in this animal model of type 1 diabetes

Glucagon-Like Peptide-1 Agonists Protect Pancreatic β-Cells From Lipotoxic Endoplasmic Reticulum Stress Through Upregulation of BiP and JunB

Chronic exposure of pancreatic beta-cells to saturated free fatty acids (FFAs) causes endoplasmic reticulum (ER) stress and apoptosis and may contribute to beta-cell loss in type 2 diabetes. Here, we evaluated the molecular mechanisms involved in the protection of beta-cells from lipotoxic ER stress by glucagon-like peptide (GLP)-1 agonists utilized in the treatment of type 2 diabetes.info:eu-repo/semantics/publishe

Cytokines Interleukin-1β and Tumor Necrosis Factor-α Regulate Different Transcriptional and Alternative Splicing Networks in Primary β-Cells

OBJECTIVE: Cytokines contribute to pancreatic beta-cell death in type 1 diabetes. This effect is mediated by complex gene networks that remain to be characterized. We presently utilized array analysis to define the global expression pattern of genes, including spliced variants, modified by the cytokines interleukin (IL)-1beta + interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha + IFN-gamma in primary rat beta-cells. RESEARCH DESIGN AND METHODS: Fluorescence-activated cell sorter-purified rat beta-cells were exposed to IL-1beta + IFN-gamma or TNF-alpha + IFN-gamma for 6 or 24 h, and global gene expression was analyzed by microarray. Key results were confirmed by RT-PCR, and small-interfering RNAs were used to investigate the mechanistic role of novel and relevant transcription factors identified by pathway analysis. RESULTS Nearly 16,000 transcripts were detected as present in beta-cells, with temporal differences in the number of genes modulated by IL-1beta + IFNgamma or TNF-alpha + IFN-gamma. These cytokine combinations induced differential expression of inflammatory response genes, which is related to differential induction of IFN regulatory factor-7. Both treatments decreased the expression of genes involved in the maintenance of beta-cell phenotype and growth/regeneration. Cytokines induced hypoxia-inducible factor-alpha, which in this context has a proapoptotic role. Cytokines also modified the expression of >20 genes involved in RNA splicing, and exon array analysis showed cytokine-induced changes in alternative splicing of >50% of the cytokine-modified genes. CONCLUSIONS: The present study doubles the number of known genes expressed in primary beta-cells, modified or not by cytokines, and indicates the biological role for several novel cytokine-modified pathways in beta-cells. It also shows that cytokines modify alternative splicing in beta-cells, opening a new avenue of research for the field.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Actions métabolique et insulinotrope d'esters de nutriments

Doctorat en Sciencesinfo:eu-repo/semantics/nonPublishe

Effects of succinate dimethyl ester on the metabolic and hormonal response to exercise in fed and starved rats.

This study aims at investigating the possible beneficial effect of succinic acid dimethyl ester (SAD), injected intraperitoneally (5.0 micromol/g body wt.), upon the metabolic and hormonal response to a 60 min exercise in both fed and overnight starved rats. In fed rats, the injection of SAD minimized the fall in plasma D-glucose concentration, and the increase in plasma lactate, beta-hydroxybutyrate, free fatty acid and glycerol concentrations, otherwise provoked by exercise. SAD, however, failed to prevent the decrease in plasma insulin concentration and liver glycogen content caused by exercise. Starved rats displayed lower plasma D-glucose and insulin concentrations and higher plasma beta-hydroxybutyrate and free fatty acid concentrations than fed rats. The body weight, liver weight and paraovarian fat weight, as well as the glycogen content of both liver and heart were also decreased in the starved rats. In the latter animals, the injection of SAD again opposed the exercise-induced increase in plasma beta-hydroxybutyrate, free fatty acid and glycerol concentrations, and again failed to prevent the more modest decreases in plasma insulin concentration and liver glycogen content caused by exercise in the starved, as distinct from fed rats. These findings suggest that, independently of any obvious change in plasma insulin concentration, SAD minimizes the exercise-induced mobilization and enhanced utilization of endogenous nutrients, especially fatty acids and glycerol produced by hydrolysis of triglycerides in adipose tissue, presumably through its capacity to act as an oxidizable nutrient in various cell types and as a gluconeogenic precursor in hepatocytes.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Nutritional value of succinic acid monoethyl ester in starvation.

Rats were fasted for 48 h, but infused with either NaCl or the sodium salt of monoethyl succinic acid (EMS), both delivered at a rate of 80 mumol/g body weight per day. The infusion of EMS, as compared to NaCl, failed to affect paraovarian adipose tissue or liver weight, liver or muscle glycogen, and insulinemia. It accentuated the starvation-induced fall in body weight, and decreased both liver and muscle protein content. Nevertheless, the succinate ester increased plasma D-glucose concentration, delayed the rise in ketonemia, maintained a higher glucokinase/hexokinase activity ratio in liver and pancreatic islets, and allowed for a more efficient stimulation of insulin release by D-glucose or 2-ketoisocaproate in isolated pancreatic islets. These findings indicate that monoethyl succinate displays a significant nutritional value when infused in starved rats.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Resistance of the insulinotropic action of alpha-D-glucose and beta-L-glucose pentaacetates to cholera and pertussis toxins.

The pentaacetate esters of alpha-D-glucose and beta-L-glucose were recently reported to stimulate insulin release. The possible participation of G-protein-coupled receptors to the insulinotropic action of these esters was investigated in rat pancreatic islets either preincubated with cholera toxin or obtained from animals injected with pertussis toxin. Neither procedure affected adversely the secretory response to the esters in islets incubated in the presence of L-leucine. Thus, in both situations, alpha-D-glucose pentaacetate and, to a lesser extent, beta-L-glucose pentaacetate augmented insulin release evoked by the branched-chain amino acid, whilst beta-L-galactose pentaacetate failed to do so. These findings suggest that G-proteins sensitive to either cholera or pertussis toxins are not involved in one of the two modalities by which these esters are thought to stimulate insulin secretion, namely that independent of the catabolic fate of their hexose moieties.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Stimulation of 45Ca uptake and insulin release by l,l-dimethyl-2-[2-morpholinophenyl]guanidine fumarate in pancreatic islets from Goto-Kakizaki rats

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Effects of neonatal capsaicin upon plasma insulin concentration and insulin secretion by islets of diabetic Goto-Kakizaki rats.

The effects of neonatal capsaicin upon selected metabolic and hormonal variables were investigated in hereditarily diabetic Goto-Kakizaki rats. Capsaicin failed to affect significantly the intake of food and fluid, the gain in body weight, the plasma glucose and insulin concentrations, and the insulin content of isolated pancreatic islets. However, the neonatal injection of capsaicin suppressed the stress-induced decrease in plasma insulin/ glucose ratio, and increased in isolated pancreatic islets the secretory responsiveness of the B-cell to D-glucose, but not carbamylcholine. These findings suggest that C-fibres may participate to the perturbation of glucose homeostasis in the diabetic Goto-Kakizaki rats.info:eu-repo/semantics/publishe

Succinic acid esters as new nutrients

Abstract in :Belgian Chemical Society Symposium on Metabolism impact on drug design and development, p; 36 (1998)info:eu-repo/semantics/nonPublishe