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)

Xenotransplantation of pig islets under the kidney capsule (KC) of diabetic rats was performed. Natural preformed ACI rat anti-pig leukocytotoxicity, leukoagglutination and hemagglutination antibody titers ranged from Neat-1: 16, 1:8-1:32 and 1:128-1:256, respectively (n = 14). Normal ACI sera were non-toxic to pig islets during short term incubation. Pig islet xenograft survival times in the nonimmunosuppressed ACI rats, ACI rats immunosuppressed with antithymocyte serum (ATS) or cyclosporin A were 3.8 +/- 0.4 (mean +/- SE; n = 5), 10.4 +/- 0.7 (n = 13) and 6.0 +/- 1.0 (n = 5) days, respectively. Pig islets implanted in the abdominal testis of ACI recipients immunosuppressed with 5 doses ATS survived for a mean of 6.4 +/- 1.0 days (n = 7). The mean K rate following an intravenous glucose tolerance test (IVGTT) in ACI rats 1 week after transplantation with pig islet under the KC was 2.2 +/- 0.4 (n = 10) compared to that of 2.91 +/- 0.30 found in normal control rats (n = 8). Peak insulin at 1 min was 60.1 +/- 3.9 microU/ml (n = 4). Histological and immunohistochemical examination showed that the xenograft from recipients treated with 5 doses of ATS still contained well-preserved islet tissue with many insulin- and glucagon-containing cells on the day of graft removal when blood glucose had returned to hyperglycemic level. Both CD4 and CD8 positive cells were in the vicinity of the graft tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Transplantation of discordant pig islet xenografts in diabetic rats. 157 20

Interactions of pancreatic islets and islet-associated mononuclear cells (IAMCs) from the nonobese diabetic (NOD) mouse were morphologically investigated. To obtain IAMCs, pancreatic islets isolated from adult NOD mice were cultured for 7 days with interleukin 2. Noted by light microscopy, interactions between IAMCs and freshly isolated islets from young NOD mice began 30 min after the initiation of the coculture, and 6 h later, normal cellular array of the islets was lost. By electron microscopy, most IAMCs had low nucleus-cytoplasm ratio, the nucleus was notched and exhibited condensed chromatin along the nuclear membrane, and well-developed Golgi complexes and several mitochondria were distributed in the cytoplasm. These IAMCs adhered to beta-cells, but not to alpha- or delta-cells, with their pseudopods and caused cytolysis of beta-cells. Immunohistochemical study with antibodies specific for pancreatic hormones demonstrated that only cells reacting with anti-insulin antibody were selectively lost as the incubation time proceeded. Electron immunohistochemistry by immunogold technique showed that effector cells in IAMCs reacted with anti-CD8 (Lyt-2) antibody, but not anti-CD4 (L3T4) or anti-asialogangliosideM1 antibody. In addition, the concentration of pancreatic hormones in the culture medium, used as a marker of cytolysis, also demonstrated that insulin was significantly increased after 6 h of culture, whereas glucagon and somatostatin were not. These results suggest that CD8+ cytotoxic T lymphocytes are involved in the selective destruction of pancreatic beta-cells in the NOD mouse.
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PMID:Morphological analysis of selective destruction of pancreatic beta-cells by cytotoxic T lymphocytes in NOD mice. 168 98

Streptozotocin (stz) given in low doses (40 mg/kg body weight) on 5 consecutive days to susceptible strains of mice causes diabetes. Previous studies have shown that the induction of diabetes is associated with inflammatory infiltrates within the pancreatic islets. However, it is unclear whether stz causes limited beta cell destruction followed by insulitis or whether the diabetogen promotes immune cell influx into the pancreatic islets, followed by immune-mediated beta-cell destruction. It is also unclear whether stz given in sub-diabetogenic doses is capable of causing diabetes independent of cell-mediated processes. Here we have examined these possibilities in CB.17 Scid mice which lack functional T and B cells but have immunocompetent macrophages and NK cells. Low dose stz given to Scid mice caused diabetes in approximately 50% of mice of both sexes by 21 days (14/24 males; 10/18 females). Sections of pancreas were examined immunohistochemically for the presence of MAC-1 positive cells (macrophages and natural killer cells) in the exocrine, peri- and intra-islet regions at different time points following the administration of stz. There were no statistically significant differences in the number of immunoreactive cells in the three locations between tissues obtained from stz-injected mice (3, 7, 14 and 21 days after stz injection and at onset of diabetes) and buffer-injected Scid mice. Although diabetic Scid mice showed a reduced number of insulin immunoreactive cells and peri- and intra-islet distributed glucagon cells, no insulitis was seen histochemically. In parallel studies, normal Swiss male mice given stz at a similar dose developed diabetes (10/10) associated with insulitis which consisted predominantly of CD4, CD8 and MAC-1 cells. Balb/c mice given stz similarly, also developed diabetes (5/8) without showing insulitis, although a moderate increase in the number of macrophages were observed within several islets. These studies demonstrate that stz administered in multiple low doses to Scid mice can cause beta cell destruction and diabetes in the absence of immune cell infiltrate within the pancreatic islets.
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PMID:Low dose streptozotocin causes diabetes in severe combined immunodeficient (SCID) mice without immune cell infiltration of the pancreatic islets. 757 72

CD4 and CD8 T cells and macrophages have been implicated as cellular mediators of beta cell destruction in insulin-dependent diabetes mellitus (IDDM). The ratios of the two T cell subsets were, therefore, quantified in nonobese diabetic (NOD) mouse islets prior to IDDM, at the onset of the disease, and following onset by immunohistochemistry. The number of periislet-, intraislet-, and exocrine-located macrophages were also determined during these stages. At all time points studied (day 90, day 250, at diabetes onset, 4-6 weeks after diabetes), CD4 cells were 2.5 times higher than CD8 cells except at day 250, on which the CD4:CD8 ratio was 3.8. At days 90 and 250, islets were heavily infiltrated with both the T cell subsets associated with lower numbers of macrophages. At onset of the disease and after insulin treatment, although the CD4:CD8 ratios were similar, the absolute numbers of the two subsets were reduced-considerably. At these stages a majority of the islets was atrophied, some were still surrounded by T cells and macrophages and were enriched with glucagon cells. CD4 and CD8 cells were also observed in the exocrine region at the two stages. Macrophages located in the periislet areas were significantly higher in number than in the intraislet positions in all study groups (p = 0.001). They also showed a gradual decline from day 90 to clinical diabetes. Periislet-located macrophages were significantly higher at day 90 than after onset and in control Swiss mice (p < 0.05). The numbers of macrophages in the exocrine areas were similar in all groups of NOD mice. In control Swiss mice they were significantly lower in the periislet, intraislet, and exocrine regions.
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PMID:Immunohistochemical analyses of pancreatic macrophages and CD4 and CD8 T cell subsets prior to and following diabetes in the NOD mouse. 766 42

Existance of messenger ribonucleic acids of eleven functionally differentiated proteins in normal human cells and tumor cell lines was investigated using reverse transcription--nested polymerase chain reaction method. Examined gene transcripts were those of progesterone receptor, estrogen receptor, interleukin 2, CD8, parathyroid hormone, cholecystokinin/pancreozymin, glucagon, insulin, adrenocorticotropic hormone, enkephalin and thyroid stimulating hormone. In RT-PCR almost all primers were originally designed and sequences of PCR products were confirmed by the Sanger's method. Investigated cells were normal human peripheral mononuclear cells and their subsets, lymphokine-activated killer cells, gastric mucosal cells, sperm and fifteen established tumor cell lines. All of the examined mRNAs were detected in all of the above cell groups. Therefore, cells of independent tissues or tumors share same kinds of mRNA such as steroid hormone receptors, cytokine, lymphocyte surface molecule and parathyroid, digestive and cerebral hormones. These findings strongly suggest that every cell can express every mRNA. Beneath the cell differentiation there may exist a DNA-->RNA basal constant flow, the arrow of time captured in a cell.
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PMID:Gene transcripts of eleven proteins with specific functions are all detected in human normal cells and tumor cell lines: a possible DNA-->RNA basal constant flow. 872 Oct 92

Expression of gene transcripts for 16 proteins was investigated in a human single lymphocyte using RT-nested PCR method. Examined mRNAs were for IL-2, CD8, progesterone receptor, parathyroid hormone, gastrin, glucagon, cholecystokinin/pancreozymin, insulin, enkephalin, thyroid stimulating hormone, MUC1, MAGE1, pregnancy-specific beta-1 glycoprotein 4, phenylethanolamine-N-methyltransferase, beta B3-crystallin and HOX4A. Most of the proteins were thought to be functionally irrelevant to a lymphocyte. All of them were detected in a lymphocyte without exception. The result suggests that there is a possibility of all mRNA expression in a human single cell.
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PMID:A possibility of all mRNA expression in a human single lymphocyte. 918 70

FK506 a new and potent immunosuppressive agent has been shown to be effective in prolonging pancreatic islet allograft survival. The present study was to determine its efficacy in prolonging pig islet xenotransplantation in two different strains of rat recipients. A total of two dosages of FK506 at 1 or 2 mg/kg per day for 2 weeks and then at weekly intervals were tested as monotherapy for their effect on the survival of renal subcapsular xenografts of purified or impure adult pig islets in inbred ACI and outbred Wistar rats. Histological assessment indicated that FK506 at 2 mg/kg per day significantly prolonged purified pig islet xenograft survival and to 7.5 months in two of three ACI recipients. Monotherapy with a lower dosage of FK506 or transplantation with impure pig islets resulted in increased graft survival time over controls, but less than that with the 2 mg/kg per day FK506. The viable pig islet xenografts showed a normal appearance and were readily identified by immunohistochemical staining for insulin and glucagon and further confirmed by immunohistochemical staining with anti-pig islet specific monoclonal antibody clone P44, developed in our laboratory. Mononuclear cell infiltration, mainly of the CD8-positive T-cell subset, increased with the duration of the graft in the recipient. By 7.5 months the majority of the xenografted islet cells were enclosed by the cellular infiltrate. The in vitro perfusion study of pig islets that had survived for 1 or 2 months in vivo showed that they were responsive to glucose stimulation with increase in insulin secretion into the perfusate. The results demonstrated that FK506 significantly prolonged pig islet survival in two rat strains and suggested that it is an effective immunosuppressant for the xenotransplantation model.
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PMID:Prolongation of pig islet xenograft survival in rats immunosuppressed with FK506. 930 35

Paracrine effect of transforming growth factor-beta1 (TGF-beta1) on autoimmune insulitis and diabetes was studied by transgenic production of the active form of porcine TGF-beta1 (pTGF-beta1) in pancreatic islet (islet) alpha cells in nonobese diabetic (NOD) mice under the control of rat glucagon promoter (RGP) (NOD-RGP-TGF-beta1). None of 27 NOD-RGP-TGF- beta1 mice developed diabetes by 45 wk of age, in contrast to 40 and 71% in male and female nontransgenic mice, respectively. None of the NOD-RGP-TGF-beta1 mice developed diabetes after cyclophosphamide (CY) administration. Adoptive transfer of splenocytes of NOD-RGP-TGF-beta1 mice to neonatal NOD mice did not transfer diabetes after CY administration. Adoptive transfer of three types of diabetogenic lymphocytes to NOD-RGP-TGF-beta1 and nontransgenic mice after CY administration led to the lower incidence of diabetes in NOD-RGP-TGF-beta1 mice versus that in nontransgenic mice: 29 vs. 77% for diabetogenic splenocytes, 25 vs. 75% for islet beta cell-specific Th1 clone cells, and 0 vs. 50% for islet beta cell-specific CD8(+) clone cells, respectively. Based on these, it is concluded that autoimmune diabetes in NOD mice is not a systemic disease and it can be completely prevented by the paracrine TGF-beta1 in the islet compartment through protection against CD4(+) and CD8(+) effector lymphocytes.
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PMID:Abrogation of autoimmune diabetes in nonobese diabetic mice and protection against effector lymphocytes by transgenic paracrine TGF-beta1. 969 Oct 86

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


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