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

Islet transplantation in Type I diabetes mellitus is appealing because of its potential for curing the disease, its relative simplicity and the potential for immunomodification of the graft so that immunosuppression may be avoided. Transplantation of isolated islets is widely used in experimental animals but has had little impact clinically. In contrast, vascularised pancreas grafts in patients are increasingly successful and this success will inevitably result in an even greater shortage of donor organs for islet isolation. Islet grafts can cure diabetes in animal models and prevent the development of diabetic complications, and in some situations even allografts can be accepted and function without immunosuppression. In contrast, vascularised grafts require a major operative procedure and continuing immunosuppression. Recurrence of autoimmune disease in the grafted islets may also be a problem. The shortage of donor tissue may be overcome by the use of xenogeneic islets, perhaps from the pig pancreas. The induction of immunological tolerance has been reported for pig islet xenografts in mice, and xenogeneic islets also appear to be relatively resistant to disease recurrence in a murine model of spontaneous autoimmune diabetes. Thus, vascularised pancreas allografts may be most suitable for and perhaps be restricted to patients who also need a renal transplant and immunosuppression for this, while isolated islet grafts of perhaps xenogeneic origin may become a more suitable treatment for patients early in the course of their disease if adequate immunosuppressive protocols, ideally resulting in immunological tolerance, can be developed.
 ...
PMID:Islet transplantation in Type-I diabetes: current state and prospects. 179 66

The juvenile form of diabetes, type-I diabetes mellitus, is, to our knowledge of today, an autoimmune disease with the hallmark of selective destruction of the insulin-producing beta cells in the endocrine pancreas. The slow, progressive process is in strong contrast with the sudden onset of clinical disease. The identification of target antigens has implications for both, better diagnostic at an earlier time as well as for new forms of therapy such as induction of tolerance or T-cell vaccination. Next to the direct products of the beta cell, insulin and proinsulin, two antigens of 38 resp. 64 kD molecular weight, have been identified. Other possible antigens include carboxypeptidase H and a heat-shock protein of 65 kD. The identity of the antigen recognized by islet-cell antibodies, the most frequently used marker for type-I diabetes mellitus, remains a subject of discussion.
 ...
PMID:[Autoantigens in type-I diabetes]. 180 31

It has been demonstrated, in certain autoimmune disease models, that pathogenic T cells express antigen receptors of limited diversity. It has been suggested that the T cells responsible for the pathogenesis of type I diabetes mellitus might similarly demonstrate restricted T cell receptor (TCR) usage. Recently, attempts have been made to identify the V beta subset(s) that initiates and/or perpetuates the antiislet response in a mouse model of spontaneous autoimmune diabetes (non-obese diabetic [NOD] mice). In studies reported here, we have bred NOD mice to a mouse strain that congenitally lacks approximately one-half of the conventional TCR V beta alleles. Included in this deletion are TCR V beta gene products previously implicated as being involved in the pathogenesis of NOD disease. By studying second backcross-intercross animals, we were able to demonstrate that this deletion of TCR V beta gene segments did not prevent the development of insulitis or diabetes.
 ...
PMID:Genetic dissection of T cell receptor V beta gene requirements for spontaneous murine diabetes. 183 91

The presence of specific antibodies at the time of clinical diagnosis, together with genetic susceptibility and animal models of spontaneous diabetes obtained by immunological destruction of insulin-secreting cells, suggests that insulin-dependent (type I) diabetes is an autoimmune disease. Prospective studies conducted among first-degree relatives of type I diabetes patients or in the general population have identified 3 types of markers appearing during subclinical destruction of islet cells, or pre-diabetes, which can be used to detect subjects at high risk. These are: high-titer anti-islet antibodies (ICA), anti-insulin autoantibodies and early insulin response to intravenous hyperglycaemia. Owing to the great heterogeneity of metabolic profiles, immunological markers alone cannot predict the time when insulin-dependence will occur. The psychological impact of these studies is such that they should be carried out only in specialized centres. Identifying pre-diabetes is important for the prevention of the disease. Until immunomodulators devoid of side-effects are available, pre-diabetes is a good period to train the patients and start insulin therapy when it becomes necessary.
 ...
PMID:[Predicting insulin-dependent diabetes. Study of risk markers]. 183 28

Diabetes in NOD mice is an autoimmune disease which is characterized by the infiltration of islets of Langerhans by large numbers of T cells. Some of these infiltrating T cells are clearly islet-cells-specific; however, many or most of these T cells could be attracted nonspecificity into these lesions. To study NOD pancreas-infiltrating T cells, we fused these cells with BW5147 to make T cell hybridomas. Ninety-four pancreas-derived T hybrids were analyzed of which 12 responded specifically to islet cells by secreting IL-2. Only CD3+, CD4+ hybrids responded to islet cells in our assay, and a large proportion of these hybrids were islet-cell reactive. T cell receptor (TCR) V beta element usage was heterogeneous in islet-reactive hybridomas.
 ...
PMID:Analysis of pancreas-infiltrating T cells in diabetic NOD mice: fusion with BW5147 yields a high frequency of islet-reactive hybridomas. 183 36

Effective fuel metabolism is dependent on balances among exogenous and endogenous fuel availability, the glucagon/insulin ratio, and tissue insulin sensitivity. Diabetes mellitus results when imbalances occur. The resultant metabolic derangement is accompanied by abnormalities in carbohydrate, protein, and fat metabolism. The two most common forms of diabetes are insulin dependent (IDDM) and noninsulin dependent (NIDDM). IDDM is an autoimmune disease, characterized by insulinopenia and ketosis. NIDDM is related to impaired insulin secretion, defective tissue sensitivity, and abnormalities in glucose transporter proteins. This article describes normal fuel metabolism and traces the abnormal metabolic processes that lead to both IDDM and NIDDM.
 ...
PMID:Normal fuel metabolism and alterations in diabetes mellitus. 184 Sep 66

The non-obese diabetic (NOD) mouse develops spontaneous insulin-dependent diabetes mellitus. Converging lines of evidence indicate that the disease is of autoimmune origin and is primarily mediated by T cells. It thus appeared interesting to study the morphology of the thymic microenvironment in order to determine whether the architecture and/or the cellular components of the organ are altered. In the NOD mouse, significant aspects of involution were observed as early as the first month of life, forming a heterogeneous pattern with non-involuted areas. With time, these involuted aspects increased in surface and severity. In non-involuted zones vacuolization of epithelial cells was noted, as well as infiltration by plasma cells and the presence of numerous macrophages with high phagocytic activity. Involuted areas, forming a cellular layer as if cells had lost their limiting membranes, were crossed by a great number of cystic cavities bordered by epithelial cells and cells containing granulations. Their lumens contained lymphocytes and a few macrophages. These observations, which are reminiscent of similar reports made in other autoimmune mouse strains, may be related to the functional thymic abnormality thought to participate in the pathogenesis of autoimmune disease.
 ...
PMID:Thymus reticulum of autoimmune mice. 3. Ultrastructural study of NOD (non-obese diabetic) mouse thymus. 184 56

The non-obese diabetic mouse (NOD mouse) is widely used as a model of organ-specific autoimmunity because it develops specific autoimmune destruction of pancreatic beta cells mediated by T cells and culminating in insulin-dependent diabetes mellitus. Here, we report that the NOD mouse also develops Coombs'-positive hemolytic anemia, a B cell-mediated autoimmune disease. Aged NOD mice were found to have splenomegaly and jaundice predominantly due to raised unconjugated serum bilirubin. Their hematocrits were markedly lowered, and there was a reciprocal increase in the reticulocyte count. Red blood cells (RBC) from anemic mice showed a normal lytic response to hypotonicity. RBC from non-anemic mice had normal half lives in non-anemic, non-diabetic NOD mice by 51Cr labeling but, dramatically shortened half lives in anemic mice. Similar results were obtained with RBC from anemic mice. Hemolysis could be transferred with serum from anemic mice resulting in reticulocytosis. The antibody-mediated nature of the anemia was confirmed with the direct Coombs' test. Anemia was found only in mice aged greater than 200 days and was more common in diabetic (4/8) than non-diabetic (1/16) mice at 300 days. However, by 550 days, 14/17 non-diabetic mice were affected.
 ...
PMID:Hemolytic anemia in non-obese diabetic mice. 188 56

Glutamic acid decarboxylase (GAD; glutamate decarboxylase, L-glutamate 1-carboxy-lyase, EC 4.1.1.15), which catalyzes formation of gamma-aminobutyric acid from L-glutamic acid, is detectable in different isoforms with distinct electrophoretic and kinetic characteristics. GAD has also been implicated as an autoantigen in the vastly differing autoimmune disease stiff-man syndrome and insulin-dependent diabetes mellitus. Despite the differing GAD isoforms, only one type of GAD cDNA (GAD-1), localized to a syntenic region of chromosome 2, has been isolated from rat, mouse, and cat. Using sequence information from GAD-1 to screen a human pancreatic islet cDNA library, we describe the isolation of an additional GAD cDNA (GAD-2), which was mapped to the short arm of human chromosome 10. Genomic Southern blotting with GAD-2 demonstrated a hybridization pattern different from that detected by GAD-1. GAD-2 recognizes a 5.6-kilobase transcript in both islets and brain, in contrast to GAD-1, which detects a 3.7-kilobase transcript in brain only. The deduced 585-amino acid sequence coded for by GAD-2 shows less than 65% identity to previously published, highly conserved GAD-1 brain sequences, which show greater than 96% deduced amino acid sequence homology among the three species. The function of this additional islet GAD isoform and its importance as an autoantigen in insulin-dependent diabetes remain to be determined.
 ...
PMID:Cloning and primary structure of a human islet isoform of glutamic acid decarboxylase from chromosome 10. 192 93

Autoimmune diseases result from the activation of self-reactive T cells induced by autoantigens or by foreign antigens cross-reactive with an autoantigen. A striking characteristic of autoimmune diseases is the increased frequency of certain HLA alleles in affected individuals. Moreover, as demonstrated for example in rheumatoid arthritis and insulin-dependent diabetes mellitus, class II alleles positively associated with autoimmune diseases share amino acid residues in the hypervariable HLA regions involved in peptide binding. Therefore, it is likely that disease-associated HLA class II molecules have the capacity to bind the autoantigen and present it to T cells, thereby inducing and maintaining, under appropriate conditions, the autoimmune disease. The data reviewed here demonstrate MHC-selective inhibition of antigen-induced T cell responses in vivo by parenterally administered soluble, MHC-binding peptide competitors, under conditions in which the competitor is not immunogenic. This suggests the feasibility of a therapeutic approach based on MHC blockade in the treatment of HLA-linked autoimmune diseases.
 ...
PMID:Inhibition of T cell activation by blockade of MHC class II molecules. 193 5


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>