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)

NOD/Lt mice harboring a hybrid rat insulin-promoter/SV40 large T-antigen gene spontaneously develop beta-cell adenomas. NIT-1 is a pancreatic beta-cell line established from one of these transgenic mice. Immunocytochemical staining of passage 18 cells showed most contained insulin, with less than 5% containing glucagon, and none containing pancreatic polypeptide or somatostatin. Glucagon content radioimmunoassayed in cell extracts was only 0.27% of the insulin content. Two-hour insulin secretion at 16.5 mM glucose was 638 ng/10(6) cells (41% of intracellular content) compared to only 1.3 ng glucagon (32% of intracellular content). Stimulated insulin secretion was consistently observed in response to 11 and 16.5 mM glucose between passages 11 and 19. At passage 19, both theophylline and tolbutamide stimulated insulin secretion at 5.5 mM glucose. Northern-blot analysis confirmed high levels of insulin mRNA but only trace glucagon mRNA and undetectable somatostatin mRNA. Interferon-gamma (IFN-gamma)-induced MHC class I RNA expression was correlated with markedly increased antigen expression at the cell surface. Similarly, a MHC-linked "occult" class I-like antigen detected by Cr release assay only after exposure of standard NOD/Lt islet cells to IFN-gamma was strongly induced by IFN-gamma in NIT-1 cells. Cell surface MHC class II antigen was not constitutively expressed on NIT-1 cells and could not be detected after IFN-gamma incubation, despite demonstration of IFN-gamma-induced Aa, Ab, and Li invariant-chain RNA transcripts. Similarly IFN-gamma induction of intercellular adhesion molecule 1 (Icam-1) transcripts was not accompanied by demonstrable cell surface expression of ICAM-1 antigen.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:NIT-1, a pancreatic beta-cell line established from a transgenic NOD/Lt mouse. 164 94

The amounts of insulin, glucagon and somatostatin in the pancreas of NOD mice were determined and the results were compared with those of normal ICR-strain mice, and plasma antibodies to Coxsackie B-3 and reovirus types 1, 2 and 3 were measured. In the pancreas of NOD mice with fasting plasma glucose (FPG) less than 140 mg/100 ml, the insulin content of the male mice was similar to that of the normal controls, ranging to 3.55 +/- 0.31 U/g wet weight of pancreas, but it was already significantly decreased to 0.85 +/- 0.52 U/g in the female mice. In the NOD mice with FPG more than 201 mg/100 ml, it was 0.002 +/- 0.001 U/g. The glucagon content of the pancreas was 7.76 +/- 0.89 micrograms/g in the normal controls and it was decreased slightly in the NOD mice, but the values among the NOD mice were not significantly different. Pancreas somatostatin showed a tendency to be higher in the NOD mice with FPG more than 201 mg/100 ml. Histologically cell infiltration into the pancreatic islets was conspicuous in the hyperglycemic NOD mice, but it was found even in the normoglycemic NOD. Plasma antibodies to Coxsackie B-3 Virus and reovirus types 1, 2 and 3 were not detected at any stage of FPG.
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PMID:Insulin, glucagon and somatostatin content of the non-obese diabetic (NOD) mouse pancreas and plasma virus antibodies to Coxsackie B- and reoviruses. 286 17

Currently there is debate regarding the capacity of pancreatic islets to regenerate in adult animals. Because pancreatic endocrine cells are thought to arise from duct cells, we examined the pancreatic ductal epithelium of the diabetic NOD mouse for evidence of islet neogenesis. We have evidence of duct proliferation as well as ductal cell differentiation, as suggested by bromodeoxyuridine-labeling and the presence of glucagon-containing cells within these ducts. In addition, the ductal epithelia in diabetic NOD mice expressed the neuroendocrine markers neuropeptide Y and tyrosine hydroxylase. These ducts also expressed the homeobox gene product, insulin promoter factor 1. Ductal cell proliferation and expression of these markers was not observed in transgenic NOD mice (NOD-E), which do not develop clinical or histopathological symptoms of IDDM. This suggests that the observed ductal cell proliferation and differentiation was a direct result of beta-cell destruction and insulin insufficiency in these adult diabetic mice, which further suggests that these events are recapitulating islet ontogeny observed during embryogenesis. It is possible that comparable processes occur in the human diabetic pancreas.
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PMID:alpha-Cell neogenesis in an animal model of IDDM. 907 99

Pancreatic islets of Langerhans exhibit an architecture and cellular organization ideal for rapid, yet finely controlled, responses to changes in blood glucose levels. In type I, insulin-dependent diabetes (IDD), this organization is lost as a result of the progressive autoimmune response which selectively destroys the insulin-producing pancreatic beta cells. Since beta cells are perceived as end-stage differentiated cells having limited capacity for regeneration in situ, individuals with IDD resulting from beta cell loss or dysfunction require life-long insulin therapy. Efforts to produce islet neogenesis or initiate islet growth in vitro from either fetal or adult tissue have had minimal success. We now report that pancreatic-derived, pluripotent islet-producing stem cells (IPSCs), isolated from prediabetic mice, can be grown in long-term cultures and differentiated into immature functional islet-like structures containing cells which express low levels of insulin, glucagon and/or somatostatin. When such in vitro grown islets were implanted into clinically diabetic NOD mice, the implanted mice were successfully weaned from insulin long-term (>50 days) without ill effects. The implanted mice maintained blood glucose levels just above euglycemic (180-220 mg/dl) and showed no signs of disease. Thus, this technical breakthrough provides new therapeutic approaches to diabetes as an alternative to insulin therapy.
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PMID:In vitro-generation of islets in long-term cultures of pluripotent stem cells from adult mouse pancreas. 923 Mar 48

Although organ-specific stem cells possess plasticity that permit differentiation along new lineages, production of endocrine pancreas and insulin-secreting beta cells from adult nonpancreatic stem cells has not been demonstrated. We present evidence that highly purified adult rat hepatic oval "stem" cells, which are capable of differentiation to hepatocytes and bile duct epithelium, can trans-differentiate into pancreatic endocrine hormone-producing cells when cultured in a high-glucose environment. These differentiated cells can self-assemble to form three-dimensional islet cell-like clusters that express pancreatic islet cell differentiation-related transcripts detectable by reverse transcription-PCR/nested PCR (e.g., PDX-1, PAX-4, PAX-6, Nkx2.2 and Nkx6.1, insulin I, insulin II, glucose transporter 2, and glucagon) and islet-specific hormones detectable by immunocytochemistry (e.g., insulin, glucagon, and pancreatic polypeptide). In addition, these cells concomitantly lose expression of the hepatocyte protein Hep-par. When stimulated with glucose, these cells synthesize and secrete insulin, a response enhanced by nicotinamide. In a pilot study, the oval cell-derived islet cell-like clusters displayed the ability to reverse hyperglycemia in a diabetic NOD-scid mouse. These results indicate that primary adult liver stem cells can differentiate in a nonlineage-restricted manner. Trans-differentiation into endocrine pancreas could have significant implications for future therapies of diabetes.
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PMID:In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells. 1204 52

During insulin-dependent diabetes mellitus, immune cells which infiltrate pancreatic islets mediate beta cell destruction over a prolonged asymptomatic prediabetic period. The molecular mechanisms of beta cell death in vivo remain unresolved. At least two major molecular processes of destruction have been proposed. One involves the Fas-FasL (Fas-Fas ligand) system and the other, the perforin pathway. Here, dual-label immunohistochemistry was employed to examine the intra-islet expression, distribution and cellular sources of Fas and FasL in the NOD mouse, during spontaneous diabetes (days 21, 40 and 90) and following acceleration of diabetes with cyclophosphamide (days 0, 4, 7, 11 and 14 after cyclophosphamide administration). The expression of the proteins was correlated with advancing disease. FasL was expressed constitutively in most beta cells but not in glucagon or somatostatin cells or islet inflammatory cells and paralleled the loss of insulin immunolabelling with advancing disease. It was also expressed in beta cells of non-diabetes prone CD-1 and C57BL/6 mice from a young age (day 21). Strong immunolabelling for Fas was first observed in extra-islet macrophages and those close to the islet in NOD and non-diabetes-prone mice. During spontaneous and cyclophosphamide diabetes, it was observed in a higher proportion of islet infiltrating macrophages than CD4 and CD8 T cells, concomitant with advancing insulitis. In cyclophosphamide-treated mice, the proportion of Fas-positive intra-islet CD4 and CD8 T cells at day 14 (with and without diabetes) was considerably higher than at days 0, 4, 7 and 11. At days 11 and 14, a proportion of Fas-positive intra-islet macrophages co-expressed interleukin-1beta and inducible nitric oxide synthase. Fas was not detectable in beta cells and other islet endocrine cells during spontaneous and cyclophosphamide induced diabetes. Our results show constitutive expression of FasL in beta cells in the NOD mouse and predominant expression of Fas in intra-islet macrophages and to a lesser extent in T cells prior to diabetes onset. Interleukin-1beta in intra-islet macrophages may induce Fas and inducible nitric oxide synthase expression in an autocrine and paracrine manner and mediate beta cell destruction or even death of some macrophages and T cells. However, other mechanisms of beta cell destruction during spontaneous and cyclophosphamide-accelerated diabetes and independent of Fas-FasL, require examination.
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PMID:Fas and Fas ligand immunolocalization in pancreatic islets of NOD mice during spontaneous and cyclophosphamide-accelerated diabetes. 1236 94

During insulin-dependent diabetes mellitus, beta cell destruction may involve activation of the Fas-Fas ligand (Fas-FasL) system. Here, we employed dual-label immunohistochemistry to examine the intra-islet expression, distribution, and cellular sources of Fas and FasL in the NOD mouse. Pancreatic tissues were studied during spontaneous diabetes (days 21, 40, and 90) and following acceleration of diabetes with cyclophosphamide (days 0, 4, 7, 11, and 14 after cyclophosphamide administration). Our results show that FasL was expressed constitutively in most beta cells of NOD mice and in nondiabetes-prone mice, but not in glucagon or somatostatin cells or in islet inflammatory cells. It paralleled the loss of insulin immunolabeling with advancing disease. Immunolabeling for Fas was first observed in extra-islet macrophages and those close to the islet in NOD and nondiabetes-prone mice. During spontaneous and cyclophosphamide diabetes, it was observed in a higher proportion of islet infiltrating macrophages than in CD4 and CD8 cells. In the cyclophosphamide group, Fas expression in intra-islet CD4 and CD8 cells showed an increase close to the onset of diabetes. At days 11 and 14, several intra-islet macrophages with immunolabeling for Fas also coexpressed interleukin-1beta and inducible nitric oxide synthase. Fas was not detected in beta cells and other endocrine cells during spontaneous and cyclophosphamide diabetes. We show constitutive expression of FasL in beta cells in the NOD mouse and predominant expression of Fas in intra-islet macrophages and to a lesser extent in T cells prior to diabetes onset. The role of Fas-FasL in beta cell destruction in the NOD mouse requires further clarification.
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PMID:Fas and Fas ligand immunoexpression in pancreatic islets of NOD mice during spontaneous and cyclophosphamide-accelerated diabetes. 1467 52

Genetic and environmental factors are decisive in the etiology of type 1 diabetes. Viruses have been proposed as a triggering environmental event and some evidences have been reported: type I IFNs exist in the pancreata of diabetic patients and transgenic mice expressing these cytokines in beta cells develop diabetes. To determine the role of IFNbeta in diabetes, we studied transgenic mice expressing human IFNbeta in the beta cells. Autoimmune features were found: MHC class I islet hyperexpression, T and B cells infiltrating the islets and transfer of the disease by lymphocytes. Moreover, the expression of beta(2)-microglobulin, preproinsulin, and glucagon in the thymus was not altered by IFNbeta, thus suggesting that the disease is caused by a local effect of IFNbeta, strong enough to break the peripheral tolerance to beta cells. This is the first report of the generation of NOD (a model of spontaneous autoimmune diabetes) and nonobese-resistant (its homologous resistant) transgenic mice expressing a type I IFN in the islets: transgenic NOD and nonobese-resistant mice developed accelerated autoimmune diabetes with a high incidence of the disease. These results indicate that the antiviral cytokine IFNbeta breaks peripheral tolerance to beta cells, influences the insulitis progression and contributes to autoimmunity in diabetes and nondiabetes- prone mice.
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PMID:IFN beta accelerates autoimmune type 1 diabetes in nonobese diabetic mice and breaks the tolerance to beta cells in nondiabetes-prone mice. 1555 58

We generated the homozygous transgenic mice with expression of the active form of TGF-beta1 by the glucagon promoter (homozygous NOD-TGF-beta1). The homozygous NOD-TGF-beta1 showed severe diabetes in 84.6%, impaired glucose tolerance, and low serum insulin levels. The final size of endocrine and whole pancreas decreased, respectively, to 6 and 34%, compared to wild-type mice. The homozygous N(2) backcross to C57BL/6 (B6-TGF-beta1) showed no diabetes, but impaired glucose tolerance and low serum insulin levels. In homozygous NOD-TGF-beta1, the expression of p15(INK4b) was induced by 3.4-fold in pancreatic islets than that in wild-type mice. Based on these, we conclude first that excessive paracrine TGF-beta1 signaling in islets results in endocrine and exocrine pancreatic hypoplasia, second that TGF-beta1decrease the final size of endocrine and exocrine pancreas presumably through regulating cell cycle via p15(INK4b) at least in endocrine pancreas, and third that hypoplastic action of TGF-beta1 of pancreatic islets is independent of the genetic background.
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PMID:Hypoplasia of endocrine and exocrine pancreas in homozygous transgenic TGF-beta1. 1560 41

The cyclophosphamide model of accelerated diabetes in the NOD mouse is a useful model of insulin-dependent diabetes mellitus (IDDM). Knowledge on the progressive destruction of beta cells and the fate of other islet endocrine cell-types in this model is sparse. We employed immunohistochemistry and histochemistry, to study temporal changes in islet cell populations, insulitis and glucose transporter-2 expression during cyclophosphamide administration. Cyclophosphamide was administered to day 95 female NOD mice and the pancreas studied at days 0 ( = day 95), 4, 7, 11 and 14 after treatment and in age-matched control mice. At day 0, a majority of the endocrine cells were insulin-positive. Glucagon and somatostatin cells were mostly in the islet periphery and also internally. In the cyclophosphamide group, insulitis was moderate at day 0, declined at day 4 but increased progressively from day 7. The extent of insulitis in treated mice which were diabetes-free at day 14 was comparable to age-matched control mice. From day 11, the marked increase in insulitis correlated with a reciprocal decline in the extent of insulin immunostained islet area. At day 14, the mean insulin area per islet was markedly less in diabetic mice than in age-matched non-diabetic treated and controls. At diabetes, some islets showed co-expression of glucagon and insulin. Our studies suggest that the mean number of glucagon or somatostatin cells per islet does not vary during the study. Glucose transporter-2 immunolabelling was restricted to beta cells but declined in those adjacent to immune cells. We conclude that in the cyclophosphamide model, there is specific and augmented destruction of beta cells immediately prior to diabetes onset. We speculate that the selective loss of glucose transporter-2 shown in this study suggests the existence of a deleterious gradient close to the immune cell and beta cell surface boundary.
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PMID:Histopathological changes in insulin, glucagon and somatostatin cells in the islets of NOD mice during cyclophosphamide-accelerated diabetes: a combined immunohistochemical and histochemical study. 1620 Apr 62


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