44 research outputs found
Cross-Talk between PPARγ and Insulin Signaling and Modulation of Insulin Sensitivity
PPARγ activation in type 2 diabetic patients results in a marked improvement in insulin and glucose parameters, resulting from an improvement of whole-body insulin sensitivity. Adipose tissue is the major mediator of PPARγ action on insulin sensitivity. PPARγ activation in mature adipocytes induces the expression of a number of genes involved in the insulin signaling cascade, thereby improving insulin sensitivity. PPARγ is the master regulator of adipogenesis, thereby stimulating the production of small insulin-sensitive adipocytes. In addition to its importance in adipogenesis, PPARγ plays an important role in regulating lipid, metabolism in mature adipocytes by increasing fatty acid trapping. Finally, adipose tissue produces several cytokines that regulate energy homeostasis, lipid and glucose metabolism. Disturbances in the production of these factors may contribute to metabolic abnormalities, and PPARγ activation is also associated with beneficial effects on expression and secretion of a whole range of cytokines
Long-term exposure of pancreatic β-cells to palmitate results in SREBP-1C-dependent decreases in GLP-1 receptor signaling via CREB and AKT and insulin secretory response
The effects of prolonged exposure of pancreatic β-cells to high saturated fatty acids on glucagonlike peptide-1 (GLP-1) action were investigated. Murine islets, human pancreatic 1.1B4 cells, and rat INS-1E cells were exposed to palmitate for 24 hours. mRNA and protein expression/phosphorylation were measured by real-time RT-PCR and immunoblotting, respectively. Specific short interfering RNAs were used to knockdown expression of the GLP-1 receptor (Glp1r) and Srebf1. Insulin release was assessed with a specific ELISA. Exposure of murine islets, as well as of human and INS-1E β-cells, to palmitate reduced the ability of exendin-4 to augment insulin mRNA levels, protein content, and release. In addition, palmitate blocked exendin-4-stimulated cAMP-response element-binding protein and v-akt murine thymoma viral oncogene homolog phosphorylation, whereas phosphorylation of MAPK-ERK kinase-1/2 and ERK-1/2 was not altered. Similarly, RNA interference-mediated suppression of Glp1r expression prevented exendin-4-induced cAMP-response element-binding protein and v-akt murine thymoma viral oncogene homolog phosphorylation, but did not impair exendin-4 stimulation of MAPK-ERK kinase-1/2 and ERK-1/2. Both islets from mice fed a high fat diet and human and INS-1E β-cells exposed to palmitate showed reduced GLP-1 receptor and pancreatic duodenal homeobox-1 (PDX-1) and increased sterol regulatory element-binding protein (SREBP-1C) mRNA and protein levels. Furthermore, suppression of SREBP-1C protein expression prevented the reduction of PDX-1 and GLP-1 receptor levels and restored exendin-4 signaling and action. Finally, treatment of INS-1E cells with metformin for 24 h resulted in inhibition of SREBP-1C expression, increased PDX-1 and GLP-1 receptor levels, consequently, enhancement of exendin-4-induced insulin release. Palmitate impairs exendin-4 effects on β-cells by reducing PDX-1 and GLP-1 receptor expression and signaling inaSREBP-1C-dependent manner. Metformin counteracts the impairment of GLP-1 receptor signaling induced by palmitate
TNFα signals via p66Shcto induce E-selectin, promote leukocyte transmigration and enhance permeability in human endothelial cells
Endothelial cells participate in inflammatory events leading to atherogenesis by regulating endothelial cell permeability via the expression of VE-Cadherin and β-catenin and leukocyte recruitment via the expression of E-Selectins and other adhesion molecules. The protein p66Shc acts as a sensor/inducer of oxidative stress and may promote vascular dysfunction. The objective of this study was to investigate the role of p66Shc in tumor necrosis factor TNFα-induced E-Selectin expression and function in human umbilical vein endothelial cells (HUVEC). Exposure of HUVEC to 50 ng/ml TNFα resulted in increased leukocyte transmigration through the endothelial monolayer and E-Selectin expression, in association with augmented phosphorylation of both p66Shc on Ser36 and the stress kinase c-Jun NH2-terminal protein kinase (JNK)-1/2, and higher intracellular reactive oxygen species (ROS) levels. Overexpression of p66 Shc in HUVEC resulted in enhanced p66Shc phosphorylation on Ser36, increased ROS and E-Selectin levels, and amplified endothelial cell permeability and leukocyte transmigration through the HUVEC monolayer. Conversely, overexpression of a phosphorylation-defective p66 Shc protein, in which Ser36 was replaced by Ala, did not augment ROS and E-Selectin levels, nor modify cell permeability or leukocyte transmigration beyond those found in wild-type cells. Moreover, siRNA-mediated silencing of p66Shc resulted in marked reduction of E-Selectin expression and leukocyte transmigration. In conclusion, p66Shc acts as a novel intermediate in the TNFα pathway mediating endothelial dysfunction, and its action requires JNK-dependent phosphorylation of p66 Shc on Ser36. © 2013 Laviola et al
ARIA digital anamorphosis : Digital transformation of health and care in airway diseases from research to practice
Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.Peer reviewe
The p66Shc redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells
The reference site collaborative network of the european innovation partnership on active and healthy ageing
Seventy four Reference Sites of the European Innovation
Partnership on Active and Healthy Ageing (EIP on AHA)
have been recognised by the European Commission in
2016 for their commitment to excellence in investing and
scaling up innovative solutions for active and healthy
ageing. The Reference Site Collaborative Network
(RSCN) brings together the EIP on AHA Reference Sites
awarded by the European Commission, and Candidate
Reference Sites into a single forum. The overarching goals
are to promote cooperation, share and transfer good
practice and solutions in the development and scaling up
of health and care strategies, policies and service delivery
models, while at the same time supporting the action
groups in their work. The RSCN aspires to be recognized
by the EU Commission as the principal forum and
authority representing all EIP on AHA Reference Sites.
The RSCN will contribute to achieve the goals of the EIP
on AHA by improving health and care outcomes for
citizens across Europe, and the development of sustainable
economic growth and the creation of jobs
ARIA digital anamorphosis: Digital transformation of health and care in airway diseases from research to practice
Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed
GLP-1: a new approach for type 2 diabetes therapy
β-cell dysfunction is an early pathophysiological defect in type 2 diabetes mellitus. Conventional secretagogues, although effective in increasing insulin secretion, may be associated with undesirable side effects, including hypoglycemia, abnormalities in cardiovascular responses, and β-cell apoptosis. Glucagon-like peptide(GLP)-1 is an incretin hormone displaying glucose-dependent stimulation of insulin secretion, trophic effects on the pancreatic β-cells, and inhibitory effects on gastrointestinal motility, which has been shown to ameliorate hyperglycemia and reduce glycemic excursions. However, after parenteral administration native GLP-1 is rapidly degraded by plasma dipeptydil peptidase (DPP)-IV. Hence, degradation-resistant, long-acting GLP-1 receptor agonists have been proposed as novel agents for diabetes therapy. Alternatively, inhibitionof DPP-IV-mediated GLP-1 degradation represents another approach for exploiting GLP-1 beneficial effects on metabolic control. This review will summarize the biological effects of GLP-1, the general features of GLP-1 mimetics and DPP-IV inhibitors, and the promising results of recently published clinical trials testing these compounds for the treatment of type 2 diabetes. © 2006 Elsevier Ireland Ltd. All rights reserved