Browsing by Subject "Insulin-Secreting Cells"
Now showing 1 - 4 of 4
- Results Per Page
- Sort Options
Item Beta cells and immune cells: breaking the cycle of type 1 diabetes(2022-11-18) Herold, Kevan C.Item MAPK Signaling Pathways in Pancreatic Beta Cells: The Regulation of RAF Activation by Nutrient Stimuli(2011-02-01) Duan, Lingling; Cobb, Melanie H.In pancreatic β cells cells, ERK1 and ERK2 participate in nutrient sensing and their activities rise and fall as a function of glucose concentration over the physiologic range. Glucose metabolism triggers calcium influx and release of calcium from intracellular stores which are required for ERK1/2 activity. Calcium influx also activates the calcium-dependent phosphatase calcineurin, which is required for maximal ERK1/2 activation by glucose. Calcineurin controls insulin gene expression by ERK1/2-dependent and -independent mechanisms. This study showed that in β cells, glucose activates the ERK1/2 cascade primarily through B-Raf. Glucose also enhances dimerization of B-Raf with C-Raf. Furthermore, calcineurin up-regulates B-Raf activity and stabilizes C-Raf/B-Raf in response to glucose. Calcineurin binds to B-Raf in both unstimulated and stimulated cells. B-Raf phospho-T401 is one of the target sites that can be dephosphorylated by calcineurin. This study reveals that cross-talk between Raf and calcineurin is essential for the maximal activation of ERK1/2 in the glucose signaling pathways. [Keywords: TCF; POP-1; Wnt; embryogenesis; C. elegans]Item Novel Roles of Gastrin and Cholecystokinin in Islet Beta Cell Proliferation(2007-06-12) Presley, Brent Kevin; Newgard, Christopher B.Type 1 diabetes and the latter stages of Type 2 diabetes share a common theme: an insufficient beta cell mass to maintain glucose homeostasis. In Type 1 diabetes this deficiency arises from autoimmune destruction of the beta cells. In the latter stages of Type 2 diabetes, there is a precipitous drop in beta cell mass, resulting from the combination of several factors. In the last decade, islet transplantation has re-emerged as a viable option for the treatment of Type 1 diabetes, thanks to greatly improved islet isolation protocols and immunosuppressive regimens. Despite these advancements, the supply of available islet beta cells for transplantation is greatly eclipsed by the demand. Consequently, the identification of genes or external factors that promote beta cell proliferation and survival is a key step toward developing a replenishable population of beta cells that can be used for transplantation for Type 1 diabetes. Additionally, any method discovered to promote beta cell growth or enhance beta cell function is directly applicable in the treatment of Type 2 diabetes. Through a broad-based microarray screen, the preprogastrin gene was found to be differentially expressed in our model of beta cell cytokine resistance, the INS-1res cell lines compared to unselected INS-1 cells. As a result of this finding, preprogastrin was initially evaluated for its involvement in cytokine resistance and beta cell survival. During the course of this analysis, preprogastrin was determined to exhibit significant mitogenic properties when overexpressed in INS-1 cell lines and isolated rat islets. These results led to the discovery that the related protein, preprocholecystokinin, also promotes impressive beta cell growth, in addition to enhanced beta cell function, as measured by improved glucose-stimulated insulin secretion. Several additional experiments suggest that traditional plasma membrane receptors and signaling pathways for gastrin and cholecystokinin do not explain the effect of overexpression of these prohormones on islet replication, including a lack of effect of exogenously added gastrin and cholecystokinin peptides. These results could be attributable to an intracrine mode of signaling that will require further investigation as a possible therapeutic target for the treatment of Type 1 and Type 2 diabetes.Item Regulation of Insulin and CHOP Gene Expression in Pancreatic Beta Cells(2009-01-14) Shao, Chunli; Cobb, Melanie H.Insulin is a major hormone in maintaining glucose homeostasis. It is essential to understand the mechanisms by which insulin gene expression is regulated in pancreatic beta cells. In addition to examining histone modifications on the insulin gene promoter, I focused on the effect of MafA modification on insulin expression. MafA is a transcriptional activator of the insulin gene via binding to the RIPE3b/C1 (rat insulin promoter element 3b) element. Mutagenesis showed that MafA was post-translationally modified by SUMO-1/2 (small ubiquitin-like modifier) mainly at lysine 32. Low glucose starvation or hydrogen peroxide stimulation increased sumoylation of MafA. Forced sumoylation of MafA reduced its transcriptional activity towards the insulin gene promoter and increased its suppression of the CHOP (C/EBP homologous protein) gene promoter. However, sumoylation of MafA did not alter its nuclear localization, protein stability, or apparently its DNA binding to the insulin promoter in beta cells. These studies suggest that MafA sumoylation modulates gene transcription in beta cells. In type I diabetes, beta-cell apoptosis is the major reason for immune-mediated pancreatic beta-cell death. IL-1beta (interleukin 1beta), a proinflammatory cytokine, induces ER (endoplasmic reticulum) stress and activates proapoptotic networks in beta cells, such as NF-kappaB (nuclear factor-kappaB) and JNK (c-Jun N-terminal kinase) signaling pathways. The second project focused on the mechanisms by which JNK and NF-kappaB regulate the expression of CHOP, a mediator of ER stress-induced apoptosis, upon IL-1beta stimulation. Exposure of beta cells to IL-1beta markedly increased CHOP messenger RNA and protein. Electrophoretic mobility shift assays showed that IL-1beta-activated NF-kappaB bound to the CHOP promoter. Furthermore, immunoblot data indicated that expression of c-Jun was strongly increased, and that multiple residues on c-Jun were phosphorylated after IL-1beta treatment. IL-1beta also increased c-Fos expression in beta cells. These data suggest that IL-1beta-induced activation of NF-kappaB and JNK controls CHOP gene expression in pancreatic beta cells, and that IL-1beta influences beta-cell function through a variety of signaling pathways.