Browsing by Subject "Islets of Langerhans"
Now showing 1 - 8 of 8
- Results Per Page
- Sort Options
Item AMYLIN: a new beta-cell hormone and its potential role in diabetes(1989-12-07) Luskey, Kenneth L.Item Diseases of the pancreatic islets(1976-12-23) Unger, Roger H.Item New Roles of the Transcription Factor NKX6.1 in Beta Cell Biology(2006-05-15) Schisler, Jonathan Cummings; Johnston, Stephen A.Pancreatic islet beta cells play a critical role in the maintenance of metabolic fuel homeostasis. Type 1 diabetes results from autoimmune destruction of the beta cells, whereas type 2 diabetes involves loss of beta cell function, particularly glucose-stimulated insulin secretion (GSIS), and a gradual diminution of beta cell mass. To identify genes that are involved in GSIS and contribute to the mature beta cell phenotype, a panel of beta cell lines with varying capacities for GSIS was employed for a candidate gene screen. Expression of the homeodomain transcription factor Nkx6.1 was found to be positively correlated with the capacity for GSIS in these lines. Although previously identified as an essential factor for beta cell differentiation, little was known about the function of Nkx6.1 in mature beta cells. The purpose of this dissertation research was to investigate the role of Nkx6.1 in the biology of mature beta cells via manipulation of its expression in beta cell lines and primary pancreatic islets and measurement of a variety of functional outcomes. These studies led to identification of three novel roles of Nkx6.1 in the mature beta cell. First, Nkx6.1 was found to suppress expression of the glucagon gene via a direct interaction with its promoter, although the studies also demonstrate a role for Pdx1 and Mafbeta in mediating this suppression. Second, the silencing of Nkx6.1 expression in pancreatic beta cells results in a severe impairment in GSIS, suggesting that Nkx6.1 target genes are critical for robust GSIS. Third, Nkx6.1 is shown to regulate beta cell proliferation, in part via direct interaction with the cyclin B1 gene and stimulation of its expression. Thus, whereas the majority of primary beta cells are quiescent, overexpression of Nkx6.1 is sufficient to initiate DNA synthesis and cell division. Importantly, and different from the common experience, this manipulation also enhances GSIS. These studies suggest that Nkx6.1 should be further investigated as a gene involved in development of diabetes and as a potential new therapeutic target.Item [News](1990-03-14) Harrell, AnnItem 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 Pancreas and islet cell transplantation in diabetes(2003-08-21) Raskin, PhilipItem The Roles of Orphan Nuclear Receptors in the Endocrine Pancreas(2008-09-12) Chuang, Jen-Chieh; Repa, Joyce J.The hormone insulin plays a critical role in carbohydrate metabolism of animals. The production and secretion of insulin by beta-cells of the pancreatic islet need to be tightly regulated to maintain proper blood glucose levels in the circulation. Dysfunction of this important endocrine system is responsible for diabetic mellitus. Over the last several years, research has suggested that the function and integrity of beta-cells can be dramatically affected by exposure to and accumulation of lipids. Several Orphan Nuclear Receptors (ONRs) have been identified and characterized in other cell types as "lipid sensors" that respond to elevated cellular lipid levels to regulate gene expression. Therefore the goal of my thesis research is to evaluate the expression and role of these transcription factors on beta-cell function and glucose metabolism. First, the complement of nuclear hormone receptors in mouse islets, and representative alpha- and beta- cell lines was determined by quantitative real-time PCR. Many nuclear receptors are expressed in the cells of the islet and several show differential expression levels under varying glucose conditions which suggests these nuclear receptors may be important for normal islet cell function. Of particular interest to our group LXRbeta, and to a lesser extent LXRalpha, are present in the beta cell of islets, and respond to synthetic LXR agonists to upregulate previously identified target genes. Exposing isolated mouse islets to the synthetic LXR agonist T1317 results in increased glucose-stimulated insulin secretion (GSIS). Incubation of islets from Lxr-null mice with this ligand has no effect on GSIS thus suggesting the T-compound effect is mediated by LXR. In addition, oral administration of T1317 to wild type, but not Lxr-null mice, altered islet GSIS in vivo and promoted efficient glucose clearance. These results suggest that activation of LXR in islet cells can modify islet function and help to control serum glucose levels. We also identified ChREBP as a novel target gene of LXR in the beta cells of the islet and characterized the importance of the LXR-ChREBP axis in insulin secretion from pancreatic islets. In addition to LXR, HNF4gamma is also an ONR of interest in beta cells. Realtime PCR results suggested that HNF4gamma and HNF4alpha are highly expressed in the pancreatic beta cells. Losing the function of HNF4alpha in beta cells has been shown to cause a rare form of diabetes called MODY1 (maturity-onset diabetes of the young).Item [UT Southwestern Medical Center News](2007-08-28) McKenzie, Aline