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Insulinotropic hormone glucagon-like peptide-1 differentiation of human pancreatic islet-derived progenitor cells into insulin-producing cells 总被引:28,自引:0,他引:28
Glucagon-like peptide-1 (GLP-1) is an intestinal incretin hormone, derived from the processing of proglucagon, that exerts insulinotropic actions on insulin-producing pancreatic islet beta-cells. Recently GLP-1 was shown to stimulate the growth and differentiation (neogenesis) of beta-cells and appears to do so by inducing the expression of the homeodomain protein IDX-1 (islet duodenum homeobox-1; also known as PDX-1, pancreatic and duodenal homeobox gene; and as IPF-1, insulin promoter factor), which is required for pancreas development and the expression of beta-cell-specific genes. Earlier we identified multipotential progenitor cells in the islet and ducts of the pancreas, termed nestin-positive islet-derived progenitor cells (NIPs). Here we report the expression of functional GLP-1 receptors on NIPs and that GLP-1 stimulates the differentiation of NIPs into insulin-producing cells. Furthermore, confluent NIP cultures express the proglucagon gene and secrete GLP-1. These findings suggest a model of islet development in which pancreatic progenitor cells express both GLP-1 receptors and proglucagon with the formation of GLP-1. Locally produced GLP-1 may act as an autocrine/paracrine developmental morphogen on receptors on NIPs, resulting in the activation of IDX-1 and the expression of the proinsulin gene conferring a beta-cell phenotype. GLP-1 may be an important morphogen both for the embryonic development of the pancreas and for the neogenesis of beta-cells in the islets of the adult pancreas. 相似文献
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PDX:PBX complexes are required for normal proliferation of pancreatic cells during development 总被引:22,自引:0,他引:22 下载免费PDF全文
Dutta S Gannon M Peers B Wright C Bonner-Weir S Montminy M 《Proceedings of the National Academy of Sciences of the United States of America》2001,98(3):1065-1070
The homeobox factor PDX-1 is a key regulator of pancreatic morphogenesis and glucose homeostasis; targeted disruption of the PDX-1 gene leads to pancreatic agenesis in pdx-1(-/-) homozygotes. Pdx-1 heterozygotes develop normally, but they display glucose intolerance in adulthood. Like certain other homeobox proteins, PDX-1 contains a consensus FPWMK motif that promotes heterodimer formation with the ubiquitous homeodomain protein PBX. To evaluate the importance of PDX-1:PBX complexes in pancreatic morphogenesis and glucose homeostasis, we expressed either wild-type or PBX interaction defective PDX-1 transgenes under control of the PDX-1 promoter. Both wild-type and mutant PDX-1 transgenes corrected glucose intolerance in pdx-1 heterozygotes. The wild-type PDX-1 transgene rescued the development of all pancreatic lineages in pdx-1(-/-) animals, and these mice survived to adulthood. In contrast, pancreata from pdx-1(-/-) mice expressing the mutant PDX-1 transgene were hypoplastic, and these mice died within 3 weeks of birth from pancreatic insufficiency. All pancreatic cell types were observed in pdx-1(-/-) mice expressing the mutant PDX-1 transgene; but the islets were smaller, and increased numbers of islet hormone-positive cells were noted within the ductal epithelium. These results indicate that PDX-1:PBX complexes are dispensable for glucose homeostasis and for differentiation of stem cells into ductal, endocrine, and acinar lineages; but they are essential for expansion of these populations during development. 相似文献
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Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1) 下载免费PDF全文
Wideman RD Yu IL Webber TD Verchere CB Johnson JD Cheung AT Kieffer TJ 《Proceedings of the National Academy of Sciences of the United States of America》2006,103(36):13468-13473
Glucagon-like peptide 1 (GLP-1) is a hormone that has received significant attention as a therapy for diabetes because of its ability to stimulate insulin biosynthesis and release and to promote growth and survival of insulin-producing beta cells. While GLP-1 is produced from the proglucagon precursor by means of prohormone convertase (PC) 1/3 activity in enteroendocrine L cells, the same precursor is differentially processed by PC2 in pancreatic islet alpha cells to release glucagon, leaving GLP-1 trapped within a larger fragment with no known function. We hypothesized that we could induce GLP-1 production directly within pancreatic islets by means of delivery of PC1/3 and, further, that this intervention would improve the viability and function of islets. Here, we show that adenovirus-mediated expression of PC1/3 in alpha cells increases islet GLP-1 secretion, resulting in improved glucose-stimulated insulin secretion and enhanced survival in response to cytokine treatment. PC1/3 expression in alpha cells also improved performance after islet transplantation in a mouse model of type 1 diabetes, possibly by enhancing nuclear Pdx1 and insulin content of islet beta cells. These results demonstrate a unique strategy for liberating GLP-1 from directly within the target organ and highlight the potential for up-regulating islet GLP-1 production as a means of treating diabetes. 相似文献
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Proglucagon is processed to glucagon by prohormone convertase PC2 in alpha TC1-6 cells. 总被引:8,自引:0,他引:8 下载免费PDF全文
Y Rouillé G Westermark S K Martin D F Steiner 《Proceedings of the National Academy of Sciences of the United States of America》1994,91(8):3242-3246
Proglucagon is processed differentially in the pancreatic alpha cells and the intestinal L cells to yield either glucagon or glucagon-like peptide 1, respectively, structurally related hormones with opposing metabolic actions. Here, we have studied the processing of proglucagon in alpha TC1-6 cells, an islet-cell line transformed by simian virus 40 large tumor (T) antigen, a model of the pancreatic alpha cell. We found that these cells process proglucagon at certain dibasic cleavage sites to release glucagon and only small amounts of glucagon-like peptide 1, as demonstrated by both continuous and pulse-chase labeling experiments. Both normal islet alpha cells and alpha TC1-6 cells were shown to express the prohormone convertase PC2 at high levels, but not the related protease PC3. Expression of PC2 antisense RNA in alpha TC1-6 cells inhibited both PC2 production and proglucagon processing concomitantly. We conclude that PC2 is the key endoprotease responsible for proglucagon processing in cells with the alpha-cell phenotype. 相似文献
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Profound defects in pancreatic beta-cell function in mice with combined heterozygous mutations in Pdx-1, Hnf-1alpha, and Hnf-3beta 总被引:2,自引:0,他引:2 下载免费PDF全文
Shih DQ Heimesaat M Kuwajima S Stein R Wright CV Stoffel M 《Proceedings of the National Academy of Sciences of the United States of America》2002,99(6):3818-3823
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Pancreatic duodenal homeobox-1 and islet neogenesis-associated protein: a possible combined marker of activateable pancreatic cell precursors 总被引:6,自引:0,他引:6
Gagliardino JJ Del Zotto H Massa L Flores LE Borelli MI 《The Journal of endocrinology》2003,177(2):249-259
The aim of this work was to study the possible relationship between pancreatic duodenal homeobox-1 (Pdx-1) and islet neogenesis-associated protein (INGAP) during induced islet neogenesis. Pregnant hamsters were fed with (S) and without (C) sucrose, and glycemia, insulin secretion in vitro, and pancreas immunomorphometric parameters were measured in their 7-day-old offspring. S offspring had significantly lower glycemic levels than C animals. Insulin release in response to increasing glucose concentrations in the incubation medium (2-16 mM glucose) did not increase in pancreata from either C or S offspring. However, pancreata from S offspring released more insulin than those from C animals. In S offspring, beta-cell mass, beta-cell replication rate and islet neogenesis increased significantly, with a simultaneous decrease in beta-cell apoptotic rate. INGAP- and Pdx-1-positive cell mass also increased in the islets and among acinar and duct cells. We found two subpopulations of Pdx-1 cells: INGAP-positive and INGAP-negative. Pdx-1/INGAP-positive cells did not stain with insulin, glucagon, somatostatin, pancreatic polypeptide, or neurogenin 3 antibodies. The increment of Pdx-1/INGAP-positive cells represented the major contribution to the Pdx-1 cell mass increase. Such increments varied among pancreas subsectors: ductal>insular>extrainsular. Our results suggested that INGAP participates in the regulation of islet neogenesis, and Pdx-1/INGAP-positive cells represent a new stem cell subpopulation at an early stage of development, highly activateable in neogenesis. 相似文献
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MIN6 cells retains glucose-stimulated insulin secretion (GSIS) as isolated islets. We comprehensively evaluated the gene expression and production of other islet hormones in MIN6 cells. Islet hormones were demonstrated by immunohistochemical staining and measured by ELISA. The gene expression profiles of MIN6 cells were compared with those in the mouse islets obtained by the laser capture micro-dissection (LCM). MIN6 cells excreted insulin, glucagon, somatostatin and ghrelin. They expressed mRNAs of insulin I and II, proglucagon, somatostatin, pancreatic polypeptide (PP) and ghrelin which were shown in the mouse pancreatic islet core and periphery obtained by LCM. A variety of genes closely related to the islet hormone producing cells were expressed in MIN6. Confocal laser scanning microscopy revealed that MIN6 cells included not only insulin positive cells but also insulin and glucagon or somatostin double positive cells. Glucagon, somatostatin and ghrelin were detectable in the culture medium. The present study clearly demonstrated that MIN6 produce pancreatic endocrine cells. It would be possible to use this cell line as a model to research the development, cell differentiation and function of pancreatic islets. 相似文献
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