Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two lysosomal glycohydrolases, beta-galactosidase and beta-N-hexosaminidase which have been associated with kidney disease were measured in the urine of 110 youngsters with juvenile diabetes mellitus. The mean enzyme excretions in the diabetic group were intermediate between those of normal youngsters and those with active renal disease. Three youngsters with known kidney disease had elevations comparable to others in the diabetic group but no direct correlation could be shown between enzyme elevations and proteinuria or Addis count abnormalities. Positive correlations were seen between enzyme levels and indices of metabolic balance including blood sugar, cholesterol and triglycerides but not with urine sugar or ketones. Duration and estimated stage and control of diabetes also correlated with the urinary enzymes. These preliminary studies are consistent with the possibility that the excretion of these enzymes reflects the ongoing renal damage which occurs in most juvenile diabetics.
 ...
PMID:Urinary acidic glycohydrolases as an index of kidney damage in juvenile diabetes mellitus. 11 9

A human insulinoma cDNA library was constructed in the expression plasmid vector pUEX1. The clone pUEX1Ins12 was selected by means of hybridization with an insulin probe. It codes for full size amino acid sequence preproinsulin. The bacterial strain pUEX3Ins8 producing proinsulin as beta-galactosidase fusion protein was obtained for the use of recombinant protein as an antigen in an ELISA to detect serum antibodies in subjects with IDDM. Recombinant clones containing the middle, N- and C-terminal domains of the GAD65, the major autoantigen in IDDM, were constructed in pVEX1. These clones may become important tools to study the nature of GAD autoreactivity in IDDM. The clone pHICEO.9 was selected from the human insulinoma cDNA library by immunoscreening with total human insulinoma protein antibodies. This clone expresses the C-terminal fragment of human cholesterol esterase/lipase containing its antigenic determinant and can be used for blood lipase determination. Four clones containing cDNA inserts (0.47-1.42 kb) without any significant homologies to the known sequences in the Gene Bank were obtained by means of statistic selection.
 ...
PMID:[Study on structural gene expression in human insulinoma]. 774 51

Activity of lysosomal enzymes was studied in 68 patients with Types 1 and 2 diabetes mellitus concurrent with diffuse thyroid enlargement. A decrease in activities of beta-galactosidase and DNAase and activation of cathepsins were detected in the leukocytes fraction from patients with Types 1 or 2 diabetes mellitus, thus demonstrating that metabolic impairments occurred in diabetes mellitus. These patterns were improved after intensive insulin therapy. Hyperfunction of the thyroid gland in patients with moderate Type 1 diabetes mellitus normalizes the activity of lysosomal enzymes.
 ...
PMID:[Activity of lysosomal enzymes in diabetes mellitus patients along with diffuse enlargement of the thyroid gland]. 851 85

The establishment of gene delivery systems that result in efficient transfection of the pancreatic beta-cells may generate an important tool for the study of IDDM and may also represent one critical step toward a clinical application of gene transfer for the prevention or early treatment of the disease. Using the reporter gene vectors pCAT and pCMV beta-gal, we have investigated the efficiency of transfection mediated by calcium phosphate precipitation, the monocationic liposome Lipofectin, the polycationic liposome Lipofectamine, and adenovirus-polylysine (AdpL) DNA complexes in human, mouse, rat, and fetal porcine islet cells. In all species studied, calcium phosphate-mediated transfection resulted in lower chloramphenicol acetyl transferase (CAT) activities than the other methods. Intact human, mouse, and rat islets were poorly transfected by Lipofectin, Lipofectamine, and AdpL. When dispersed by trypsin treatment, however, human, mouse, rat, and fetal pig islect cells were efficiently transfected by Lipofectamine. Moreover, transfection of dispersed human and mouse islet cells using AdpL, also resulted in high CAT activities. The percentage of cells staining positively for beta-galactosidase after transfection with Lipofectamine was 49% for mouse, 56% for rat, and 57% for dispersed human islet cells. Transfection of human islet cells using AdpL, however, yielded 70% beta-gal-positive cells. Fluorescence-activated cell sorting-purified rat islet alpha- and beta-cells were transfected with similar efficiency using Lipofectamine. CAT expression in human islet cells transfected with either Lipofectamine or AdpL reached a peak value after 5-7 days, followed by a gradual decline. It is concluded that transfection with AdpL or Lipofectamine are both efficient means to achieve transient expression of gene constructs in human and mouse islet cells, while for rat and fetal porcine islet cells, Lipofectamine is the most efficient of the agents investigated in this study.
 ...
PMID:Efficient gene transfer to dispersed human pancreatic islet cells in vitro using adenovirus-polylysine/DNA complexes or polycationic liposomes. 877 22

Apoptosis has been identified as a mechanism of pancreatic islet beta-cell death in autoimmune diabetes. Proinflammatory cytokines are candidate mediators of beta-cell death in autoimmune diabetes, and these cytokines can induce beta-cell death by apoptosis. In the present study, we examined whether transfection of human islet beta-cells with an anti-apoptotic gene, bcl-2, can prevent cytokine-induced beta-cell destruction. Human islet beta-cells were transfected by a replication-defective herpes simplex virus (HSV) amplicon vector that expressed the bcl-2 gene (HSVbcl-2) and, as a control, the same HSV vector that expressed a beta-galactosidase reporter gene (HSVlac). Two-color immunohistochemical staining revealed that 95+/-3% of beta-cells transfected with HSVbcl-2 expressed Bcl-2 protein compared with 14+/-3% of beta-cells transfected with HSVlac and 19+/-4% of nontransfected beta-cells. The bcl-2-transfected beta-cells were fully protected from impaired insulin secretion and destruction resulting from incubation for 5 days with the cytokine combination of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma. In addition, the bcl-2-transfected islet cells were significantly protected from cytokine-induced lipid peroxidation and DNA fragmentation. These results demonstrate that cytokine-induced beta-cell dysfunction and death involve mechanisms subject to regulation by an anti-apoptotic protein, Bcl-2. Therefore, bcl-2 gene therapy has the potential to protect human beta-cells in pancreatic islets, or islet grafts, from immune-mediated damage in type 1 diabetes.
 ...
PMID:Transfection of human pancreatic islets with an anti-apoptotic gene (bcl-2) protects beta-cells from cytokine-induced destruction. 1034 8

Interleukin-1beta is a potent pro-inflammatory cytokine that has been shown to inhibit islet beta cell function as well as to activate Fas-mediated apoptosis in a nitric oxide-dependent manner. Furthermore, this cytokine is effective in recruiting lymphocytes that mediate beta cell destruction in IDDM onset. The insulin-like growth factor I (IGF-I) has been shown to block IL-1beta actions in vitro. We hypothesized that gene transfer of the insulin-like growth factor I to intact human islets could prevent IL-1beta-induced beta cell dysfunction and sensitization to Fas-triggered apoptosis activation. Intact human islets were infected with adenoviral vectors encoding IGF-I as well as beta-galactosidase and enhanced green fluorescent protein as controls. Adenoviral gene transfer of human IGF-I prevented IL-1beta-mediated nitric oxide production from human islets in vitro as well as the suppression of beta cell function as determined by glucose-stimulated insulin production. Moreover, IGF-I gene transfer prevented IL-1beta-induced, Fas-mediated apoptosis. These results suggest that locally produced IGF-I from cultured islets may be beneficial in maintaining beta cell function and promoting islet survival before and following islet transplantation as a potential therapy for type I diabetes.
 ...
PMID:Prevention of beta cell dysfunction and apoptosis activation in human islets by adenoviral gene transfer of the insulin-like growth factor I. 1117 13

The thymus expresses proinsulin, among many other tissue-specific antigens, and the inheritance of genetically determined low thymic proinsulin expression has been associated with impaired proinsulin-specific autoreactive T-cell tolerance and type 1 diabetes susceptibility. The cellular and molecular biology of proinsulin expression in the thymus remains unknown, and contradictory reports exist regarding the identity of proinsulin-producing cells. Using knock-in mice expressing beta-galactosidase (beta-Gal) under the control of an endogenous insulin promoter, we found that thymic proinsulin and beta-Gal transcripts were detectable at high levels in purified thymic epithelial cells. Immunohistochemical analysis of beta-Gal activity showed that most proinsulin expression can be accounted for by rare medullary epithelial cells of the Hassall's corpuscles. Moreover, flow cytometry analyses of beta-Gal-positive cells showed that only 1-3% of all epithelial cells express proinsulin, and this technique will now provide us with a method for isolating the proinsulin-producing cells in mouse thymus.
 ...
PMID:Proinsulin expression by Hassall's corpuscles in the mouse thymus. 1474 85

We have previously reported the discovery of an islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) that is predominantly expressed in islet beta-cells. IGRP has recently been identified as a major autoantigen in a mouse model of type 1 diabetes. The analysis of IGRP-chloramphenicol acetyltransferase (CAT) fusion gene expression in transiently transfected islet-derived hamster insulinoma tumor and betaTC-3 cells revealed that the promoter region located between -306 and +3 confers high-level reporter gene expression. To determine whether this same promoter region is sufficient to confer islet beta-cell-specific gene expression in vivo, it was ligated to a beta-galactosidase reporter gene, and transgenic mice expressing the resulting fusion gene were generated. In two independent founder lines, this -306 to +3 promoter region was sufficient to drive beta-galactosidase expression in newborn mouse islets, predominantly in beta-cells, which was initiated during the expected time in development, around embryonic day 12.5. However, unlike the endogenous IGRP gene, beta-galactosidase expression was also detected in the cerebellum. Moreover, beta-galactosidase expression was almost completely absent in adult mouse islets, suggesting that cis-acting elements elsewhere in the IGRP gene are required for determining appropriate IGRP tissue-specific expression and for the maintenance of IGRP gene expression in adult mice.
 ...
PMID:The proximal islet-specific glucose-6-phosphatase catalytic subunit-related protein autoantigen promoter is sufficient to initiate but not maintain transgene expression in mouse islets in vivo. 1522 Jan 99

Plasmid-DNA gene-gun immunization may be an efficient approach for investigating the role of skin dendritic cells (DCs) in type 1 diabetes (T1D) pathogenesis and the significance of the presentation of peptides that mimic autoantigenic epitopes in aggravating or modulating the autoimmune reaction. Gene-gun immunization has been described as producing long-lasting immune responses elicited by skin DCs, especially Langerhans cells (LCs). Therefore, we tested the immune response and diabetes modulation in nonobese diabetic (NOD) mice and in control BALB/c mice, by gene-gun administration of plasmid-DNA encoding (1) human 65 kDa glutamic acid decarboxylase (hGAD65) mimicking the crucial mouse autoantigen GAD65 (similarity of 95.7%) or (2) beta-galactosidase (betaGAL) as a negative control. Expression of GAD and betaGAL in skin of pc-GAD- and pc-LacZ-injected mice, respectively, was confirmed. It was surprising that both pc-LacZ-injected BALB/c and NOD mice exhibited a betaGAL-specific Th1 immune response: spleen cells of pc-LacZ mice proliferated specifically to betaGAL (P < 10(-4)) and secreted significant amounts of IFNgamma (P < 10(-4)). pc-LacZ mice also developed a betaGAL-specific Th1-related (IgG2a/2c) and Th2-related (IgG1) humoral response. Although pc-GAD BALB/c mice showed Th2-related GAD-specific IgG1 production and a significant secretion of IL4 (P < .03), pc-GAD NOD mice did not generate either an antibody response or a T cell response specific to GAD. Moreover, gene-gun immunization encoding hGAD65 did not clearly modulate diabetes onset in NOD mice. This absence of detectable GAD-specific response may implicate skin DC deficiencies in NOD mice. The gene-gun technique could thus provide an interesting model for studying skin DC abnormalities in NOD mice and their potential implication of presenting mimetic peptides that modulate the autoimmune response in T1D.
 ...
PMID:Gene-gun biolistic immunization encoding glutamic acid decarboxylase: a model for studying Langerhans cell abnormalities and mimicry in the nonobese diabetic mouse. 1612 2

Type 1 diabetes results from insulin deficiency caused by destruction of pancreatic beta cells. Glucagon-like peptide (GLP)-1 stimulates beta cell growth and differentiation. To determine whether continuous expression of GLP-1 in vivo can regenerate beta cells and remit type 1 diabetes in mice for a prolonged time, we constructed an adenoviral vector containing the cytomegalovirus promoter/enhancer and albumin leader sequence followed by GLP-1 cDNA (rAd-GLP-1). A single administration of rAd-GLP-1 via the tail vein into streptozotocin (STZ)-induced diabetic non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice resulted in remission of diabetes within 10 days; normoglycemia remained until the experiment was terminated. The number of insulin-positive cells in the pancreas and insulin secretion significantly increased in rAd-GLP-1-treated mice compared with STZ-induced diabetic mice treated with rAd-beta-galactosidase. Glucose tolerance tests in mice that achieved normoglycemia after treatment with rAd-GLP-1 showed that the kinetics of glucose clearance was similar to normal NOD/SCID mice. Treatment of autoimmune diabetic mice with rAd-GLP-1 restored normoglycemia, which was maintained for 1 year when mice were also treated with an immunoregulator to halt the autoimmune response to beta cells. We suggest that regeneration of insulin-producing cells by GLP-1 gene therapy may be a potential method for prolonged control of type 1 diabetes in humans.
 ...
PMID:Prolonged remission of diabetes by regeneration of beta cells in diabetic mice treated with recombinant adenoviral vector expressing glucagon-like peptide-1. 1716 79


1