JNK3 Is Required for the Cytoprotective Effect of Exendin 4.

Preservation of beta cell against apoptosis is one of the therapeutic benefits of the glucagon-like peptide-1 (GLP1) antidiabetic mimetics for preserving the functional beta cell mass exposed to diabetogenic condition including proinflammatory cytokines. The mitogen activated protein kinase 10 also called c-jun amino-terminal kinase 3 (JNK3) plays a protective role in insulin-secreting cells against death caused by cytokines. In this study, we investigated whether the JNK3 expression is associated with the protective effect elicited by the GLP1 mimetic exendin 4. We found an increase in the abundance of JNK3 in isolated human islets and INS-1E cells cultured with exendin 4. Induction of JNK3 by exendin 4 was associated with an increased survival of INS-1E cells. Silencing of JNK3 prevented the cytoprotective effect of exendin 4 against apoptosis elicited by culture condition and cytokines. These results emphasize the requirement of JNK3 in the antiapoptotic effects of exendin 4

Adaptive changes of human islets to an obesogenic environment in the mouse

Routing protocols in wireless sensor networks (WSN) face two main challenges: first, the challenging environments in which WSNs are deployed negatively affect the quality of the routing process. Therefore, routing protocols for WSNs should recognize and react to node failures and packet losses. Second, sensor nodes are battery-powered, which makes power a scarce resource. Routing protocols should optimize power consumption to prolong the lifetime of the WSN. In this paper, we present a new adaptive routing protocol for WSNs, we call it M^2RC. M^2RC has two phases: mesh establishment phase and data forwarding phase. In the first phase, M^2RC establishes the routing state to enable multipath data forwarding. In the second phase, M^2RC forwards data packets from the source to the sink. Targeting hop-by-hop reliability, an M^2RC forwarding node waits for an acknowledgement (ACK) that its packets were correctly received at the next neighbor. Based on this feedback, an M^2RC node applies multiplicative-increase/additive-decrease (MIAD) to control the number of neighbors targeted by its packet broadcast. We simulated M^2RC in the ns-2 simulator and compared it to GRAB, Max-power, and Min-power routing schemes. Our simulations show that M^2RC achieves the highest throughput with at least 10-30% less consumed power per delivered report in scenarios where a certain number of nodes unexpectedly fail.National Science Foundation (ITR ANI-0205294, EIA-0202067, ANI-0095988, ANI-9986397

Endoplasmic Reticulum Stress Links Oxidative Stress to Impaired Pancreatic Beta-Cell Function Caused by Human Oxidized LDL.

Elevated plasma concentration of the pro-atherogenic oxidized low density lipoprotein cholesterol (LDL) triggers adverse effects in pancreatic beta-cells and is associated with type 2 diabetes. Here, we investigated whether the endoplasmic reticulum (ER) stress is a key player coupling oxidative stress to beta-cell dysfunction and death elicited by human oxidized LDL. We found that human oxidized LDL activates ER stress as evidenced by the activation of the inositol requiring 1α, and the elevated expression of both DDIT3 (also called CHOP) and DNAJC3 (also called P58IPK) ER stress markers in isolated human islets and the mouse insulin secreting MIN6 cells. Silencing of Chop and inhibition of ER stress markers by the chemical chaperone phenyl butyric acid (PBA) prevented cell death caused by oxidized LDL. Finally, we found that oxidative stress accounts for activation of ER stress markers induced by oxidized LDL. Induction of Chop/CHOP and p58IPK/P58IPK by oxidized LDL was mimicked by hydrogen peroxide and was blocked by co-treatment with the N-acetylcystein antioxidant. As a conclusion, the harmful effects of oxidized LDL in beta-cells requires ER stress activation in a manner that involves oxidative stress. This mechanism may account for impaired beta-cell function in diabetes and can be reversed by antioxidant treatment

Endothelium-Derived Netrin-4 Supports Pancreatic Epithelial Cell Adhesion and Differentiation through Integrins α2β1 and α3β1

BACKGROUND: Netrins have been extensively studied in the developing central nervous system as pathfinding guidance cues, and more recently in non-neural tissues where they mediate cell adhesion, migration and differentiation. Netrin-4, a distant relative of Netrins 1-3, has been proposed to affect cell fate determination in developing epithelia, though receptors mediating these functions have yet to be identified. METHODOLOGY/PRINCIPAL FINDINGS: Using human embryonic pancreatic cells as a model of developing epithelium, here we report that Netrin-4 is abundantly expressed in vascular endothelial cells and pancreatic ductal cells, and supports epithelial cell adhesion through integrins α2β1 and α3β1. Interestingly, we find that Netrin-4 recognition by embryonic pancreatic cells through integrins α2β1 and α3β1 promotes insulin and glucagon gene expression. In addition, full genome microarray analysis revealed that fetal pancreatic cell adhesion to Netrin-4 causes a prominent down-regulation of cyclins and up-regulation of negative regulators of the cell cycle. Consistent with these results, a number of other genes whose activities have been linked to developmental decisions and/or cellular differentiation are up-regulated. CONCLUSIONS/SIGNIFICANCE: Given the recognized function of blood vessels in epithelial tissue morphogenesis, our results provide a mechanism by which endothelial-derived Netrin-4 may function as a pro-differentiation cue for adjacent developing pancreatic cell populations expressing adhesion receptors α2β1 and α3β1 integrins

Expression of peroxisome proliferator-activated receptor γ (PPARγ) in normal human pancreatic islet cells

International audienceAims/hypothesis: Thiazolidinediones are reported to improve pancreatic islet morphology and beta-cell function in rodents, supporting the hypothesis of a direct action of thiazolidinediones on endocrine islet cells. In this study we examined the expression of the peroxisome proliferator-activated receptor gamma, a nuclear receptor that is activated by naturally occurring fatty acids and synthetic thiazolidinediones, in normal human endocrine pancreatic cells.Methods: Human islets were isolated from pancreata harvested in ten brain-dead lean non-diabetic adult donors. We analysed the gene and protein expression of the human peroxisome proliferator-activated receptor gamma and evaluated the effects of peroxisome proliferator-activated receptor gamma agonist on insulin secretion in human islet preparations.Results: The RT-PCR carried out on total RNA from four distinct human islet preparations demonstrated the presence of peroxisome proliferator-activated receptor gamma mRNA. Western blot analysis showed the consistent expression of peroxisome proliferator-activated receptor gamma protein. Peroxisome proliferator-activated receptor gamma was shown to be present in all three endocrine cell types studied (alpha, beta and delta cells) by immunohistochemistry.Conclusion/interpretation: We found that peroxisome proliferator-activated receptor gamma is highly expressed in human islet endocrine cells, both at the mRNA and protein levels. These results support the hypothesis of a direct influence of peroxisome proliferator-activated receptor gamma agonist on human pancreatic endocrine cells

Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in normal human pancreatic islet cells

AIMS/HYPOTHESIS: Thiazolidinediones are reported to improve pancreatic islet morphology and beta-cell function in rodents, supporting the hypothesis of a direct action of thiazolidinediones on endocrine islet cells. In this study we examined the expression of the peroxisome proliferator-activated receptor gamma, a nuclear receptor that is activated by naturally occurring fatty acids and synthetic thiazolidinediones, in normal human endocrine pancreatic cells. METHODS: Human islets were isolated from pancreata harvested in ten brain-dead lean non-diabetic adult donors. We analysed the gene and protein expression of the human peroxisome proliferator-activated receptor gamma and evaluated the effects of peroxisome proliferator-activated receptor gamma agonist on insulin secretion in human islet preparations. RESULTS: The RT-PCR carried out on total RNA from four distinct human islet preparations demonstrated the presence of peroxisome proliferator-activated receptor gamma mRNA. Western blot analysis showed the consistent expression of peroxisome proliferator-activated receptor gamma protein. Peroxisome proliferator-activated receptor gamma was shown to be present in all three endocrine cell types studied (alpha, beta and delta cells) by immunohistochemistry. CONCLUSION/INTERPRETATION: We found that peroxisome proliferator-activated receptor gamma is highly expressed in human islet endocrine cells, both at the mRNA and protein levels. These results support the hypothesis of a direct influence of peroxisome proliferator-activated receptor gamma agonist on human pancreatic endocrine cells