Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The specific performance of the adult hepatic parenchymal cell is maintained and controlled by factors deriving from the stromal bed; the chemical nature of these factors is unknown. This study aimed to develop a serum-free hierarchical hepatocyte-nonparenchymal (stromal) cell coculture system. Hepatic stromal cells proliferated on crosslinked collagen in serum-free medium with epidermal growth factor, basic fibroblast growth factor, and hepatocyte-conditioned medium; cell type composition changed during the 2-wk culture period. During the first wk, the culture consisted of proliferating sinusoidal endothelial cells with well-preserved sieve plates, proliferating hepatic stellate cells, and partially activated Kupffer cells. The number of endothelial cells declined thereafter; stellate cells and Kupffer cells became the prominent cell types after 8 d. Hepatocytes were seeded onto stromal cells precultured for 4-14 d; they adhered to stellate and Kupffer cells, but spared the islands of endothelial cells. Stellate cells spread out on top of the hepatocytes; Kupffer cell extensions established multiple contacts to hepatocytes and stellate cells. Hepatocyte viability was maintained by coculture; the positive influence of stromal cell signals on hepatocyte differentiation became evident after 48 h; a strong improvement of cell responsiveness toward hormones could be observed in cocultured hepatocytes. Hierarchial hepatocyte coculture enhanced the glucagon-dependent increases in phosphoenolpyruvate carboxykinase activity and messenger ribonucleic acid (mRNA) content three- and twofold, respectively; glucagon-activated urea production was elevated twofold. Coculturing also stimulated glycogen deposition; basal synthesis was increased by 30% and the responsiveness toward insulin and glucose was elevated by 100 and 55%, respectively. The insulin-dependent rise in the glucokinase mRNA content was increased twofold in cocultured hepatocytes. It can be concluded that long-term signals from stromal cells maintain hepatocyte differentiation. This coculture model should, therefore, provide the technical basis for the investigation of stroma-derived differentiation factors.
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PMID:Elevated expression of hormone-regulated rat hepatocyte functions in a new serum-free hepatocyte-stromal cell coculture model. 1114 49

The endocrine cells of the rat pancreatic islets of Langerhans, including insulin-producing beta-cells, turn over every 40-50 days by processes of apoptosis and the proliferation and differentiation of new islet cells (neogenesis) from progenitor epithelial cells located in the pancreatic ducts. However, the administration to rats of islet trophic factors such as glucose or glucagon-like peptide 1 for 48 h results in a doubling of islet cell mass, suggesting that islet progenitor cells may reside within the islets themselves. Here we show that rat and human pancreatic islets contain a heretofore unrecognized distinct population of cells that express the neural stem cell-specific marker nestin. Nestin-positive cells within pancreatic islets express neither the hormones insulin, glucagon, somatostatin, or pancreatic polypeptide nor the markers of vascular endothelium or neurons, such as collagen IV and galanin. Focal regions of nestin-positive cells are also identified in large, small, and centrolobular ducts of the rat pancreas. Nestin-positive cells in the islets and in pancreatic ducts are distinct from ductal epithelium because they do not express the ductal marker cytokeratin 19 (CK19). After their isolation, these nestin-positive cells have an unusually extended proliferative capacity when cultured in vitro (approximately 8 months), can be cloned repeatedly, and appear to be multipotential. Upon confluence, they are able to differentiate into cells that express liver and exocrine pancreas markers, such as alpha-fetoprotein and pancreatic amylase, and display a ductal/endocrine phenotype with expression of CK19, neural-specific cell adhesion molecule, insulin, glucagon, and the pancreas/duodenum specific homeodomain transcription factor, IDX-1. We propose that these nestin-positive islet-derived progenitor (NIP) cells are a distinct population of cells that reside within pancreatic islets and may participate in the neogenesis of islet endocrine cells. The NIP cells that also reside in the pancreatic ducts may be contributors to the established location of islet progenitor cells. The identification of NIP cells within the pancreatic islets themselves suggest possibilities for treatment of diabetes, whereby NIP cells isolated from pancreas biopsies could be expanded ex vivo and transplanted into the donor/recipient.
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PMID:Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. 1124 71

Thus far, histopathological changes in the pancreatic islets of Zucker Diabetic Fatty (ZDF) rats, an animal model of type 2 diabetes mellitus (or non-insulin-dependent diabetes mellitus), have only been studied in male rats and in 18-weeks old rats or younger. In this study, we have examined in both male and female ZDF rats the histopathological changes longitudinally, from 6 to 32 weeks of age. We studied islet architecture and cellular distribution of the various islet hormones both in ZDF and control rats. In the ZDF rats, aging was initially associated with an enlargement of the islets. From 18 weeks onwards, no further enlargement was noted but islet boundaries became increasingly irregular, leading to the appearance of projections of endocrine cells into the surrounding exocrine tissue. At the islet boundaries as well as within the islets progressive fibrosis was observed with increasing amounts of collagen and reticular fibers. In the islets, staining intensity of both insulin and islet amyloid polypeptide (IAPP) increased slightly till 10 weeks of age and thereafter decreased rapidly. In contrast, the staining intensities of glucagon, somatostatin, and pancreatic polypeptide (PP) did not change. Even at the age of 32 weeks, just the beta-cells and not the other endocrine islet cells appear to be affected. In control rats, aging evoked only minor changes. Thus, we observed that during prolonged development of diabetes mellitus in both male and female ZDF rats histopathological changes in the pancreatic islets became progressively more severe, eventually leading to disintegration of the islets.
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PMID:Progressive histopathological changes in pancreatic islets of Zucker Diabetic Fatty rats. 1150 51

It is currently believed that pancreatic progenitor or stem cells exist in the ductal cell population and that these cells have the ability to be grown and differentiated into endocrine cells for the treatment of diabetes. In this study, we have examined this potential in IMPAN (Immortalized Pancreatic) cells. These cells are derived from the adult H-2K(b)-tsA58 transgenic mouse. We observed an increased mRNA expression of insulin, proendocrine gene neurogenin 3, and beta-cell transcription factor Pdx1 when the cells were grown on bovine collagen I gels. The induction profile of these three genes was similar under the tested conditions. No glucagon or other endocrine-specific transcription factors were detectable. Application of GIP, GLP-1 derivative NN2211, and activin-A/betacellulin to IMPAN cells in normal culture did not lead to endocrine differentiation. In conclusion, it appears that the ability of IMPAN cells to mature to endocrine cells is limited.
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PMID:IMPAN cells: a pancreatic model for differentiation into endocrine cells. 1169 65

To provide a global analysis of genes involved in the inflammatory process in joints of DBA/1J mice suffering from collagen induced arthritis (CIA) we used oligonucleotide microarrays representing approximately 11,000 genes to determine the gene expression profile of the inflamed paws at peak of disease, and compared them to normal tissue. Peak of disease was determined from clinical evaluation of disease and histopathology of joints. Of the 11,000 genes assayed, 223 showed differential expression of four fold or more (187 upregulated and 36 downregulated). Ninety-five of the genes observed had well-characterized full length sequences in databases, and 128 were unknown (Ests). Inflammation resulted in a profile of increased gene expression of matrix metalloproteinases, immune-related, extra-cellular matrix and cell adhesion molecules, as well as molecules involved in cell division and transcription; differential regulation of molecules involved in signal transduction, protein synthesis and metabolism. Of the 55 genes with known chromosomal locations nine mapped to previously identified QTL, contributing to susceptibility or severity of CIA, i.e. MHC class I, II, Basigin, FAP, Cathepsin K, CD 53, RAF1, glucagon, and retinal taurine transporter. The profile of gene expression supports current theoretical models of disease progression and might open new perspectives for both diagnosis and treatment of arthritis.
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PMID:Gene-expression profile of collagen-induced arthritis. 1190 48

The PICM-19 fetal liver cell line was isolated from the primary culture and spontaneous differentiation of pig epiblast cells, i.e. embryonic stem cells. PICM-19 cells were induced to differentiate into mostly ductular formations by culturing at pH 7.6-7.8. The ductules were functionally assayed by treatment with cAMP inducing agents and bioactive peptides reported to influence the secretory activity of liver bile ductules. The secretory response of the cells was assessed by qualitative or quantitative measurement of the cross-sectional area of the ductal lumens and the appearance of biliary canaliculi in between PICM-19 cells that had formed monolayers instead of ducts. Forskolin (10 microM) and 8-bromoadenosine 3':5'-cyclic monophosphate (bcAMP; 2 mM) stimulated fluid transport and expansion of ductal structures in 15-20 min and stimulated the appearance and expansion of biliary canaliculi in 30-60 min. Cholera toxin (50 ng/ml) stimulates fluid transport in both ductules and canaliculi in 1-2 h, while 8-bromoguanosine 3':5'-cyclic monophosphate (bcGMP; 2 mM) stimulated only biliary canaliculi in 2 h. Glucagon (1.4 nM) produced a similar response in 5-10 min in ductal structures only, but the response was transitory and was almost completely reversed within 30 min. Secretin (100 pM) and vasoactive intestinal peptide (75 pM) produced a sustained response with maximal ductal lumen expansion occurring in 5-10 min and neither had an immediate effect on canaliculi. Somatostatin (0.5 microM) and gastrin (1 microM) caused marked reduction or disappearance of ductal lumens in 30-60 min, but was ineffective in reversing secretin (100 nM)-induced duct distension. Application of the adrenergic agonists, epinephrine, isoproterenol, and phenylephrine (100 microM), resulted in the complete shrinkage of ductal lumens in 20-30 min. A shift to pH 7.0-7.2 resulted in almost complete reduction of ductal lumens, while a shift to pH 7.8-8.0 resulted in expansion, although not full expansion, of the ductal lumens. PICM-19 bile duct cultures were positive for cytokeratin-7, aquaporin-1 and aquaporin-9 by Western blot analysis. The amounts of these proteins increased in the cultures as differentiation proceeded over time. Transmission electron microscopy revealed that the ductal structures were usually sandwiched between SIM mouse, thioguanine- and ouabain-resistant (STO) feeder cells that had produced a collagen matrix. Also, the ductular PICM-19 cells possessed cilia, probably occurring as a single cilium in each cell, that projected into the lumens of the ducts. The results indicated that the in vitro-produced ductal structures of the PICM-19 cell line are a functional model for biliary epithelium.
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PMID:The PICM-19 cell line as an in vitro model of liver bile ductules: effects of cAMP inducers, biopeptides and pH. 1209 33

The purpose of this study was to investigate the effect of culture microenvironment on the cell death of isolated rat pancreatic islets. After isolation by the conventional collagenase digestion technique, the islets were cultured in a hydrogel of collagen type I mixed with collagen type III, type IV, and laminin. Irrespective of the type of mixture, islet cell death was significantly suppressed by their co-culture with the collagen hydrogel mixtures, although no change in islet morphology was observed. Co-culture with the collagen mixtures had no influence on the expressed mRNA level of insulin, glucagon, and somatostatin of the islets, or the islet secretion of hepatocyte growth factor (HGF), interleukin (IL)-1alpha, and IL-1beta. These findings suggest that three-dimensional culture in the collagen hydrogel and the mixture of laminin is able to maintain the cell viability of islets.
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PMID:Co-culture of extracellular matrix suppresses the cell death of rat pancreatic islets. 1218 60

Small hepatocytes (SHs), which are known to be hepatic progenitor cells, were isolated from an adult rat liver. SHs in a colony sometimes change their shape from small to large and from flat to rising/piled-up. The aim of the present study is to clarify whether the alteration of cell shape is correlated with the maturation of SHs and whether extracellular matrix (ECM) can induce the morphological changes of SHs. We used liver-enriched transcription factors (LETFs) such as hepatocyte nuclear factor (HNF) 4 alpha, HNF6, CCAAT/enhancer binding proteins (C/EBP) alpha, and C/EBP beta, tryptophan 2,3-dioxygenase (TO), and serine dehydratase (SDH) as markers of hepatic maturation. To enrich the number of SH colonies, the colonies were isolated from dishes and replated. Replated colonies proliferated and the average number of cells per colony was about five times larger at day 9 than at day 1. When the cells were treated with laminin, type IV collagen, a mixture of laminin and type IV collagen, Matrigel or collagen gel (CG), only the cells treated with Matrigel dramatically changed their shape within several days and had reduced growth activity, whereas the cells treated with other ECM did not. HNF4 alpha, HNF6, C/EBP alpha, C/EBP beta, and TO were well expressed in the cells treated with Matrigel. Furthermore, addition of both glucagon and dexamethasone dramatically induced the expression of SDH mRNA and protein in the cells treated with Matrigel. In conclusion, morphological changes of SHs may be correlated with hepatic maturation and basement membrane (BM)-like structure may induce the morphological changes of SHs.
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PMID:Morphological changes induced by extracellular matrix are correlated with maturation of rat small hepatocytes. 1221 Jul 18

Serine:pyruvate/alanine:glyoxylate aminotransferase (SPT/AGT) is largely located in mitochondria in carnivores, whereas it is entirely found within peroxisomes in herbivores and humans. In rat liver, SPT/AGT is found in both of these organelles, and only the mitochondrial enzyme is markedly induced by glucagon. Although SPT/AGT is a bifunctional enzyme involved in the metabolism of both L-serine and glyoxylate, its contribution to L-serine metabolism is independent of mitochondrial or peroxisomal localization (Xue HH et al., J Biol Chem 274: 16028-16033, 1999). Therefore, the species-specific and food habit-dependent organelle distribution might be required for proper metabolism of glyoxylate at the subcellular site of its formation. Glyoxylate formation from glycolate and that from L-hydroxyproline have been shown to occur in peroxisomes and mitochondria, respectively. The present study found that urinary excretion of oxalate was markedly increased when a large dose of L-hydroxyproline or glycolate was administered to rats. Oxalate formation from L-hydroxyproline but not that from glycolate was significantly reduced when mitochondrial SPT/AGT had been induced by glucagon. The hydroxyproline content of collagen is 10 to 13%, and collagen accounts for about 30% of total animal protein; therefore, these results suggest that an important role of mitochondrial SPT/AGT in carnivores is to convert L-hydroxyproline-derived glyoxylate into glycine in situ, preventing undesirable overflow into the production of oxalate.
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PMID:Control of oxalate formation from L-hydroxyproline in liver mitochondria. 1266 Mar 28

We have previously shown that a subcutaneous injection of glucagon-like peptide-2 (GLP-2) at 9 a.m. in fasting postmenopausal women results in a dose-dependent decrease in the serum concentration of fragments derived from the degradation of the C-terminal telopeptide region of collagen type I (s-CTX), a marker of bone resorption. In contrast, GLP-2 was found to have a neutral effect on bone formation, as assessed by serum osteocalcin. Since increased s-CTX levels are normally observed at night, we conducted bedtime studies in healthy postmenopausal women. The objective was to study the effect of GLP-2 injection on bone turnover given at bedtime. A total of 81 postmenopausal women were included in two randomised placebo-controlled studies. In conclusion, we found a dose-related reduction of s-CTX after injection of GLP-2 (P < 0.05) and osteocalcin levels was increased as compared to placebo (P = 0.07) by the treatment, suggestive of a stimulative effect on bone formation. An area under the curve (AUC0-10 h) analysis for s-CTX after GLP-2 injection confirmed the dose-related decrease as compared to placebo (P < 0.05).
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PMID:Reduction of nocturnal rise in bone resorption by subcutaneous GLP-2. 1475 71


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