Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To compare the clinical usefulness of commercial radioimmunoassay (RIA) kits based on recombinant and pig brain GAD, we measured glutamic acid decarboxylase autoantibody (GADAb) titers in 125 non-obese (body mass index < 24) Japanese diabetics without insulin therapy using two commercial RIA kits based on recombinant human (rh) GAD65 (GADAb Cosmic) and purified pig brain native GAD (RIP Anti-GAD Hoechst). The frequencies of GADAb positivity using these two RIA kits (normal ranges; < 1.3 and < 4.0 U/ml, respectively) were about 4.8 (6/125) and 3.2% (4/125), respectively. The six patients found to be positive with RIA using GADAb Cosmic demonstrated significantly higher prevalence of NIDDM in their parents (P = 0.04), lower beta-cell function estimated by intravenous glucagon loading tests (P = 0.03) and higher prevalence of progression to insulin therapy (P = 0.0001). Five of these six patients slowly progressed to insulin-requiring status within 34 +/- 11 months of follow-up evaluation, and one of these five patients progressed to a completely insulin-dependent status within 30 months from the onset of diabetes. Of these six patients, two demonstrated chronic pancreatitis, three had chronic thyroiditis, and five showed HLA DR4. Interestingly, two of the six patients demonstrated very low GADAb titers (2.3 and 2.9 U/ml), while RIP Anti-GAD Hoechst showed no positivity with the same sera. Based on the binding study after pre-incubation of unlabeled GADs, these low titrated GADAb were elucidated to be true specific reactions to rh GAD65 alone. Moreover, one of the two patients with chronic thyroiditis and HLA DR4 slowly progressed to insulin-requiring status over a period of 45 months. These findings suggest that the measurement of GADAb using a commercial assay kit with rh GAD65 may be more useful to detect non-insulin-dependent type I diabetics among non-obese patients than using a commercial kit with purified pig brain native GAD, especially among those with low GADAb titers.
Diabetes Res Clin Pract 1998 Jul
PMID:Antibodies to glutamic acid decarboxylase (GAD) in non-obese Japanese diabetics without insulin therapy: a comparison of two commercial RIA kits based on recombinant and pig brain GAD. 976 69

Activation of autoreactive T cells can lead to autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM). The initiation and maintenance of IDDM by dendritic cells (DC), the most potent professional antigen-presenting cells, were investigated in transgenic mice expressing the lymphocytic choriomeningitis virus glycoprotein (LCMV-GP) under the control of the rat insulin promoter (RIP-GP mice). We show that after adoptive transfer of DC constitutively expressing the immunodominant cytotoxic T lymphocyte (CTL) epitope of the LCMV-GP, RIP-GP mice developed autoimmune diabetes. Kinetic and functional studies of DC-activated CTL revealed that development of IDDM was dependent on dose and timing of antigenic stimulation. Strikingly, repeated CTL activation by DC led to severe destructive mononuclear infiltration of the pancreatic islets but also to de novo formation of islet-associated organized lymphoid structures in the pancreatic parenchyma. In addition, repetitive DC immunization induced IDDM with lymphoid neogenesis also in perforin-deficient RIP-GP mice, illustrating that CD8(+) T cell-dependent inflammatory mechanisms independent of perforin could induce IDDM. Thus, DC presenting self-antigens not only are potent inducers of autoreactive T cells, but also help to maintain a peripheral immune response locally; therefore, the induction of autoimmunity against previously ignored autoantigens represents a potential hazard, particularly in DC-based antitumor therapies.
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PMID:Dendritic cells induce autoimmune diabetes and maintain disease via de novo formation of local lymphoid tissue. 978 26

Pancreatic islets of Langerhans are composed of four major endocrine cell types with a smaller number of nonendocrine cells. To study the molecular constituents and function of just one subpopulation of islet cells, it is necessary to sort them from the other cell types. While rat beta-cells can be sorted by autofluorescence-activated flow cytometry, this has not proved possible on a routine and reproducible basis for human beta-cells. In the present study, we have selectively labeled human beta-cells with green fluorescent protein (GFP), allowing for their sorting by flow cytometry. Human islet cells were infected with replication-defective (attenuated) recombinant adenovirus expressing GFP driven by the rat insulin I promoter (Ad-RIP-GFP) for targeted expression in beta-cells, or beta-galactosidase driven by the promiscuous cytomegalovirus (CMV) promoter (Ad-CMV-beta-gal) as control. Whereas the majority of islet cells can be infected by adenovirus, as shown by control infection with Ad-CMV-beta-gal, increased fluorescence after infection with Ad-RIP-GFP was limited to insulin-containing beta-cells. Infection of islet cells with Ad-RIP-GFP resulted reproducibly in the appearance of a population of intensely fluorescent cells, when analyzed by flow cytometry. These cells were sorted using a fluorescence-activated cell sorter (FACS) and shown by immunofluorescence to consist of >95% beta-cells. The targeted expression of GFP thus allows for preparation of human beta-cells purified close to homogeneity. This method should be readily applicable in any laboratory with FACS capability.
Diabetes 1998 Dec
PMID:Sorting human beta-cells consequent to targeted expression of green fluorescent protein. 983 34

Insulin replacement by injection is clearly not a cure for Insulin Dependent Diabetes Mellitus (IDDM). Replacement of the destroyed islets by pancreas or islet allograft transplantation can achieve the good metabolic control required to prevent diabetic complications, but tissue supply is limited. The problem of islet supply to treat the 1 million IDDM patients in the USA could be overcome by using immortalized islet beta-cells as a donor source. However, before either allogeneic or xenogeneic immortalized beta-cells are used, some major problems have to be overcome: control of immortalized cell growth, allograft or xenograft rejection and recurrence of autoimmunity. To tackle these problems we have used a cell impermeable immunoisolation device containing mouse insulinoma cells. Transplantation of devices with insulinomas from NOD mice carrying the Rat-insulin promoter regulated SV40 T-Antigen transgene (RIP-TAg), normalized the blood glucose levels of diabetic NOD mice. Insulinomas from allogeneic CBA/NOD-RIP-TAg mice were also capable of normalizing diabetic NOD mice. Not only were non-fasting blood glucoses normalized but when given an intraperitoneal injection of glucose, the corrected mice had a near normal clearance of glucose from the blood. When the devices were removed from normalized mice they became diabetic again, demonstrating that the immunoisolation device was capable of protecting against both alloimmune and autoimmune destruction. The results with allogeneic mouse beta-cells suggest the possibility that immortalized human beta-cells could be an effective source of tissue to correct diabetes in IDDM patients without the use of immunosuppression.
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PMID:Correction of diabetic nod mice with insulinomas implanted within Baxter immunoisolation devices. 993 Sep 67

Type 2 diabetes is characterized by islet amyloid deposits, which are primarily composed of the amyloidogenic human form of islet amyloid polypeptide (IAPP, amylin). The mechanism of islet amyloido-genesis is not known, but other products (e.g., apolipoprotein E and perlecan) contained within islet amyloid may be necessary. Because rodent IAPP does not form islet amyloid, the currently available beta-cell lines are not useful for studying processes involved in amyloid formation. To develop a suitable in vitro cell system for the study of islet amyloid formation, we generated two new beta-cell lines that express the amyloidogenic human IAPP. We did this by crossbreeding human IAPP transgenic mice with RIP-Tag mice that develop islet tumors and then culturing one of these islet tumors from two separate offspring of this cross. The resultant 2350-2C0 and 2511 cell lines produce human as well as mouse IAPP-like immunoreactivity (IAPP-LI) and immunoreactive insulin (IRI). Incubation of both these cell lines with 16.7 mmol/l glucose resulted in a two- to fourfold increase in human IAPP-LI, mouse IAPP-LI, and IRI secretion compared with 1.67 mmol/l glucose and the combination of 16.7 mmol/l glucose and 10 mmol/l arginine, 0.1 mmol/l 3-isobutyl-1-methylxanthine (IBMX), and 5 micromol/l carbachol induced a >50-fold increase in the release of these peptides. The omission of calcium from the above secretagogue cocktail reduced secretion of all three peptides to only two- to sixfold higher than the 16.7 mmol/l glucose condition. Perifusion with 16.7 mmol/l glucose plus 0.1 mmol/l IBMX caused a biphasic secretion of human IAPP-LI and mouse IAPP-LI, as well as IRI, in both cell lines, with the peak of the first phase being five- to sixfold higher than the prestimulated 1.67 mmol/l glucose condition. Immunoelectron microscopic inspection of both 2350-2C0 and 2511 cells after 7 days of culture did not reveal the presence of amyloid fibrils, suggesting the need for other critical components. We conclude that we have established two novel beta-cell lines that produce and secrete human IAPP in a regulated manner. These cell lines will be a useful tool to investigate the secretion of human IAPP as well as the necessity of other components for islet amyloid formation.
Diabetes 1999 Oct
PMID:Two novel immortal pancreatic beta-cell lines expressing and secreting human islet amyloid polypeptide do not spontaneously develop islet amyloid. 1051 60

Apoptosis, the process of programmed cell death, plays a critical role in many normal and pathological (disease) processes. In normal tissues, apoptosis functions in the homeostatic maintenance of proper tissue and organ size by eliminating aged cells to offset the birth of new cells that arise by mitosis. In disease, apoptosis can affect the pathological process is two disparate ways. There are diseases that have too much apoptosis such as autoimmune diabetes and Alzheimer's, or those that have too little apoptosis, such as cancer. This review will focus on the latter and, more specifically, detail and summarize some important lessons learned about apoptosis and cancer from studying a transgenic mouse model of islet cell carcinoma, RIP-Tag, as outlined below.
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PMID:Tumor cells utilize multiple pathways to down-modulate apoptosis. Lessons from a mouse model of islet cell carcinogenesis. 1066 71

Type 1 diabetes is a T cell-mediated autoimmune disease where a number of islet beta-cell target autoantigens have been characterized on the basis of reactivity with autoantibodies. Nevertheless, there remains uncertainty of the nature of another group of autoantigens associated with the secretory granule fraction of islet beta-cells that appear to be targeted predominantly by autoreactive T cells. We have previously characterized CD4+, HLA-DR-restricted T cell lines from new onset type 1 diabetic patients that are specific for the secretory granule fraction of rat tumour insulinoma, RIN. The T cell line from the first patient, HS, proliferates in response to crude microsomal membranes prepared from a recently established, pure human islet beta-cell line NES2Y. In addition, the HS line also responds to secretory granule fractions prepared from a murine tumour insulinoma grown in RIP-Tag mice, showing the recognition of species-conserved antigen(s) in beta-cells. Using partially matched antigen-presenting cells, the HS T cells and another line derived from a second patient, MR, were shown to be restricted by disease-associated DRB1*0101 and DRB1*0404 alleles, respectively. Neither the HS or MR T cell lines proliferate in response to a large panel of candidate islet cell antigens, including insulin, proinsulin, glutamic acid decarboxylase, the protein tyrosine phosphatase IA-2/phogrin, imogen-38, ICA69 or hsp60. Our data provide compelling evidence of the presence of a group of antigens associated with the secretory granule fraction of islet beta-cells recognized by the T cell lines, whose definition may contribute to our knowledge of disease induction as well as to diagnosis.
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PMID:Evidence for recognition of novel islet T cell antigens by granule-specific T cell lines from new onset type 1 diabetic patients. 1088 45

Although transgenic mice expressing murine B7-1 (mCD80) on their pancreatic beta cells under the rat insulin-1 promoter (RIP-mCD80(+) mice) rarely develop spontaneous beta cell destruction and diabetes, we have previously reported the transgene-dependent induction of profound insulitis and lethal diabetes following multiple low dose injections of the beta cell toxin streptozotocin (MLDS) in RIP-mCD80(+) mice. Here, we have further characterized this MLDS-induced diabetes model using the RIP-mCD80(+) mice and now demonstrate that disease is critically dependent on T cell signaling via CD28. Thus, although naive RIP-mCD80(+) and nontransgenic littermates have comparable gross beta cell mass, and immediately following MLDS induction the mice display similar degrees of insulitis and decrements in the beta cell mass, only transgenic mice continued to destroy their beta cells and develop insulin-dependent diabetes mellitus. Strikingly, MLDS-induced diabetes was completely prevented in CD28-deficient mice (RIP-mCD80(+)CD28(-/-)) due to abrogation of leukocytes infiltrating their pancreatic islets. We further characterized MLDS-induced diabetes in the RIP-mCD80(+) mice by demonstrating that the MLDS-induced lymphocytic islet infiltrate contained a substantial frequency of autoantigen-specific, IFN-gamma-secreting, CD8(+) T cells. We conclude that MLDS-induced beta cell destruction and subsequent insulin-dependent diabetes mellitus in RIP-mCD80(+) mice is T cell-mediated as it involves both Ag-specific recognition of self-target molecules in the inflamed pancreatic islet (signal 1) and is CD28 costimulation dependent (signal 2).
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PMID:Low dose streptozotocin-induced diabetes in rat insulin promoter-mCD80-transgenic mice is T cell autoantigen-specific and CD28 dependent. 1116 Mar 14

MHC class II molecules are critical determinants of genetic susceptibility to human type 1 diabetes. In patients, the most common haplotype contains the DRA1*0101-DRB1*0401 (DR4) and DQA1*0301-DQB1*0302 (DQ8) loci. To assess directly the relative roles of HLA-DQ8 and DR4 for diabetes development in vivo, we generated C57BL/6 transgenic mice that lack endogenous mouse MHC class II molecules but express HLA-DQ8 and/or DR4. Neither HLA-DQ nor HLA-DR transgenic mice developed insulitis or spontaneous diabetes. However, when they were crossed to transgenic mice (C57BL/6) expressing the B7.1 costimulatory molecules on pancreatic beta cells that do not normally develop diabetes, T cells from these double transgenic mice were no longer tolerant to islet autoantigens. The majority of DQ8/RIP-B7 mice developed spontaneous diabetes, whereas only 25% of DR4/RIP-B7 mice did so. Interestingly, when DQ8 and DR4 were coexpressed (DQ8DR4/RIP-B7), only 23% of these mice developed diabetes, an incidence indistinguishable from the DR4/RIP-B7 mice. T cells from both DR4/RIP-B7 and DQ8DR4/RIP-B7 mice, unlike those from DQ8/RIP-B7 mice, exhibited a Th2-like phenotype. Thus, the expression of DR4 appeared to downregulate DQ8-restricted autoreactive T cells in DQ8DR4/RIP-B7 mice. Our data suggest that although both DQ8 and DR4 can promote spontaneous diabetes in mice with a non-autoimmune-prone genetic background, the diabetogenic effect of the DQ8 allele is much greater, whereas DR4 expression downregulates the diabetogenic effect of DQ8, perhaps by enhancing Th2-like immune responses.
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PMID:The regulatory role of DR4 in a spontaneous diabetes DQ8 transgenic model. 1128 96

The early three (E3) region of the adenovirus (Ad) encodes a number of immunomodulatory proteins that interfere with class I major histocompatibility-mediated antigen presentation and confer resistance to cytokine-induced apoptosis in cells infected by the virus. Transgenic expression of Ad E3 genes under the rat insulin II promoter (RIP-E3) in beta-cells in nonobese diabetic (NOD) mice decreases the incidence and delays the onset of autoimmune diabetes. The immune effector cells of RIP-E3/NOD mice maintain the ability to infiltrate the islets and transfer diabetes into NOD-scid recipients, although at a significantly reduced rate compared with wild-type littermates. The islets of RIP-E3/ NOD mice can be destroyed by adoptive transfer of splenocytes from wild-type NOD mice; however, the time to onset of hyperglycemia is delayed significantly, and 40% of these recipients were not diabetic at the end of the experiment. These findings suggest that expression of E3 genes in beta-cells affects both the activation of immune effector cells and the intrinsic resistance of beta-cells to autoimmune destruction.
Diabetes 2001 May
PMID:Adenovirus early region 3(E3) immunomodulatory genes decrease the incidence of autoimmune diabetes in NOD mice. 1133 41


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