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)

Following the onset of diabetes mellitus (DM) in the NOD mouse, diabetic dams have many offspring with severe anomalies, especially with visceroatrial heterotaxy syndrome. The purpose of the present study is to analyze this syndrome with special reference to atrial situs. The fetuses from a colony of NOD mice in our laboratory were divided into two study groups: Group A included fetuses from dams before the onset of DM and group B included fetuses from dams with overt DM before day 8 of pregnancy. The fetuses which had cardiac anomalies with viscero-atrial heterotaxy were classified into four subtypes according to the atrial morphology, i.e., "incomplete situs solitus" (or solitus-like), "incomplete situs inversus" (inversus-like), right isomerism, and left isomerism. Group A (671 fetuses) included only one case with right isomerism (0.15%) and four cases with left isomerism (0.6%). Group B (158 fetuses) had 57 fetuses with heterotaxy syndrome (36.1%), including 20 cases with solitus-like, 6 with inversus-like, 30 with right isomerism, and one with left isomerism. A tendency for right isomerism to occur was found in fetuses with solitus-like and inversus-like anomalies. These results show that the maternal DM in this mouse had an influence upon the morphological mechanism determining right isomerism of visceroatrial heterotaxy syndrome. Thus this syndrome in the NOD mouse is equivalent to asplenia in humans, and it may be useful in elucidating the mechanism of the human syndrome.
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PMID:Visceroatrial heterotaxy syndrome in the NOD mouse with special reference to atrial situs. 195 68

The aim of this study was to investigate whether neonatal glucose treatment influences the incidence of diabetes in NOD mice. Thirty-nine NOD mice (19 males, 20 females) were treated with 8 g glucose/kg BW/day administered by subcutaneous injections twice a day for the first six days of life. Thirty-six untreated NOD mice (20 males, 16 females) served as a control group. In the glucose-treated group, 33% became diabetic compared with 58% in the control group (X2 = 5.3, p = 0.021). Among the glucose-treated males, 16% became diabetic compared with 50% of the untreated males (X2 = 5.5, p = 0.019), whereas 50% of the glucose-treated females became diabetic compared with 69% of the untreated females (X2 = 1.1, NS). We conclude that neonatal glucose treatment can reduce the diabetes incidence in NOD mice. These results could have implications for the prevention of type 1 diabetes mellitus in humans.
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PMID:Reduction of diabetes incidence in NOD mice by neonatal glucose treatment. 195 55

It is generally held that one of the recessive genes controlling diabetes in the NOD mouse is linked to the major histocompatibility complex (MHC). Unique substitution of Asp57 with Ser in the A beta chain is considered to make the A beta gene the MHC-linked susceptibility gene. We therefore analysed the nucleotide sequences of the A beta second exon in ILI, CTS, and NON mice, which are nondiabetic inbred strains but are derived from the same Jcl-ICR mice as the NOD mouse. The DNA sequence analyses revealed that the A beta second exon sequences in the ILI and CTS mice, but not in the NON mouse, are identical to that of the NOD mouse. Possible roles of Ser57 of the A beta chain in the nondiabetic sister strains are discussed.
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PMID:The unique nucleotide sequence of the A beta gene in the NOD mouse is shared with its nondiabetic sister strains, the ILI and the CTS mouse. 196 45

Islet transplants for large numbers of patients with diabetes will require xenografts. Microencapsulation is an appealing method for islet xenografting. However, graft function has been limited by a cellular reaction, particularly intense in spontaneously diabetic, NOD mice. The purpose of this study was to elucidate the mechanism of this reaction. Poly-1-lysine-alginate microcapsules containing 4000-12,000 dog or 1800-2000 rat islets were xenografted intraperitoneally into streptozotocin (SZN)-diabetic C57BL/6J and NOD mice, with or without recipient treatment with GK 1.5 (anti-CD4 monoclonal antibody) (20-30 microliters i.p. every 5 days, begun on day -7. Grafts were considered technically successful if random blood glucose (BG) was normalized (less than 150 mg/dl) within 36 hr. Graft failure was defined as BG greater than 250 mg/dl. Dog and rat islets in microcapsules normalized BG in both SZN and NOD mice within 24 hr routinely. Empty microcapsules and GK 1.5 treatments alone did not affect BG. NODs destroyed both microencapsulated dog and rat islets more rapidly than did SZN-diabetic mice (P less than .01). Graft biopsies showed an intense cellular reaction, composed of lymphocytes, macrophages and giant cells, and no viable islets. GK 1.5 treatment significantly prolonged both dog-to-NOD and rat-to-NOD grafts (P less than 0.01). Biopsies of long-term functioning grafts (on days 65-85) demonstrated viable islets and no cellular reaction around microcapsules; 1/4 rat and 1/8 dog islet xenografts continued to function indefinitely in NOD recipients, even after cessation of GK 1.5 therapy. Prediabetic NODs receiving encapsulated dog or rat islets mounted a moderate cellular reaction to grafts. Empty microcapsules excited no cellular reaction in diabetic or prediabetic NODs. We conclude that the NOD reaction to microencapsulated xenogeneic islets is helper T cell-dependent, and that the target of this reaction is not the microcapsule itself, but the donor cells within.
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PMID:The role of CD4+ helper T cells in the destruction of microencapsulated islet xenografts in nod mice. 196 98

The NOD mouse is characterized by the development of spontaneous autoimmune diabetes which begins with a peri-islet lymphocyte infiltration of the pancreas around 6 weeks of age and progresses to overt diabetes in 50-60% of females from about 12 weeks. Although infiltration occurs around islets in males, the incidence of overt diabetes is much less (about 1%) and suggests that there may be more effective regulatory circuits in these animals. This possibility was examined by using splenocytes from young males to reconstitute irradiated male recipients 6 d before the transfer of diabetogenic spleen cells from spontaneously diabetic females. Those animals which were not reconstituted with male spleen cells developed diabetes 3-5 weeks later, whereas the majority of the reconstituted mice remained normoglycaemic. Characterization of the protective population demonstrated a role for CD4+ T cells. An additional observation was that splenocytes from young normal males also contained a population of non-T cells which could advance the diabetogenic transfer of disease by at least a week.
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PMID:The transfer of autoimmune diabetes in NOD mice can be inhibited or accelerated by distinct cell populations present in normal splenocytes taken from young males. 197 Nov 73

An early molecular event in the evolution of insulin-dependent diabetes in humans and NOD mice appears to involve the interaction of MHC class II molecules, beta-cell autoantigen-derived peptides, and receptor molecules of helper T lymphocytes. To examine the influence of T-lymphocyte-receptor beta-genes on the development of beta-cell autoimmunity, (NOD x NZW)F1 x NOD backcrossed (BC) mice were studied for the development of insulitis, because insulitis is the pathognomonic histological lesion of autoimmune diabetes. Heterozygosity for H-2nod was permissive for the development of pancreatic interstitial inflammation and peri-islet insulitis, whereas homozygosity for H-2nod was highly associated with insulitis. However, (NOD x NZW)F1 x NOD BC mice developed insulitis regardless of homozygosity or heterozygosity for T-lymphocyte receptor beta nod. Therefore, in our study, T-lymphocyte receptor beta nod did not function as an autosomal-recessive beta-cell autoimmunity gene.
Diabetes 1990 Aug
PMID:Immunogenetic analysis of beta-cell autoimmunity in NOD mice. Relationship of insulitis to T-lymphocyte-receptor beta nod and A beta nod genes. 197 74

BDC-6.9 is a CD4-positive T-cell clone, specific for NOD islets, which was isolated from the spleen and lymph nodes of a diabetic NOD mouse. The cells were transplanted in a blood clot adjacent to established NOD islet grafts in diabetic (CBA X NOD)F1 recipients. The BDC-6.9 cells initiated extensive damage to the islet grafts, while a non-islet specific clone transplanted adjacent to grafted islets caused no noticeable damage. In addition, the BDC-6.9 cells initiated similar destruction when injected intraperitoneally, suggesting that they may have some migratory capacity. By introducing these islet-reactive cells into the (CBA X NOD)F1, a non-diabetes prone environment, we hope to clarify the role of the islet-specific CD4 cell as related to islet destruction in vivo.
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PMID:In vivo activity of an islet-reactive T-cell clone. 197 4

Type 1 (insulin-dependent) diabetes mellitus results from an autoimmune disease which is directed to insulin-secreting islet cells. In man, it is closely associated to definite major histocompatibility complex alleles. The islets are infiltrated by inflammatory cells (insulitis). Anti-islet cell autoantibodies are present in most patients and represent a valuable marker for the autoimmune reaction. The major role of autoreactive T lymphocytes has been demonstrated in animal models of spontaneous insulin-dependent diabetes (the BB rat and the NOD mouse). Such pathophysiological concepts already have clinical applications. The presence of anti-islet cell antibodies identifies patients with type 1 diabetes of slow onset who initially present with non-insulin dependent diabetes. In the same respect it is now feasible to predict the possible occurrence of diabetes in 'at risk' subjects (such as siblings of a diabetic patient) on the basis of HLA typing and the presence of markers of anti-beta cell immunity. Lastly, both in animal models and in human diabetes, it has been demonstrated that immune intervention can alter the course of anti-islet autoimmunity. From these results one may hope in the future to get preventive treatment of type 1 diabetes before the onset of metabolic disturbances.
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PMID:[Type 1 diabetes mellitus, autoimmune disease: physiopathologic aspects and practical applications]. 206 84

The development of IDDM results from the destruction of pancreatic beta cells. Genetic factors, various immune system alterations, and environmental factors have been studied as the possible causes of IDDM. The concordance rate for developing IDDM between monozygotic twins approaches 50%, suggesting that genetic factors are necessary, but nongenetic factors such as various immune system alterations and environmental factors also influence the clinical expression of genetic susceptibility. Environmental factors (e.g., viruses, chemicals, and diet) affecting the induction of diabetes may act as primary injurious agents which damage pancreatic beta cells or as triggering agents of autoimmunity. Certain viruses including EMC-D and Mengo virus 2T can directly infect pancreatic beta cells and replicate in the cells. The replication of viruses in the beta cells results in the destruction of the cells within 3 days, and the infected mice develop a diabeteslike syndrome in 3-4 days without the involvement of autoimmunity. In contrast, rubella virus appears to be somewhat weakly associated with autoimmune IDDM in hamsters. In addition, endogenous retrovirus expressed in pancreatic beta cells is clearly associated with the development of insulitis and diabetes in NOD mice. In man, there appears to be no correlation between the detection of islet cell autoantibodies and anti-Coxsackie B viral antibodies in newly diagnosed IDDM. In contrast, persistent infection of CMV and rubella virus appears to be associated with the presence of autoantibodies in newly diagnosed IDDM patients. It is particularly noteworthy that human CMV can induce islet cell autoantibodies that react specifically with a 38 kDa islet cell protein which may represent islet cell-specific antigens in a proportion of CMV-associated IDDM cases. These observations suggest that the association of diabetes with Coxsackie B viruses might be due to cytolytic infection of the beta cells with no link to autoimmunity, while both rubella virus and CMV are probably associated with autoimmune IDDM. A number of structurally diverse chemicals including alloxan, streptozotocin, chlorozotocin, Vacor, and cyproheptadine are diabetogenic mainly in rodents and sometimes in man. Possible mechanisms for beta cell destruction by these chemicals include (a) generation of oxygen free radicals and alteration of endogenous scavengers of these reactive species; (b) breakage of DNA and a consequent increase in the activity of poly-ADP-ribose synthetase, an enzyme depleting nicotinamide adenine dinucleotide in beta cells; and (c) inhibition of active calcium transport and calmodulin-activated protein kinase activity. (ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The role of viruses and environmental factors in the induction of diabetes. 207 86

Self-tolerance is generally induced by intrathymic clonal deletion of T cells with reactivity directed to antigens synthesized within the thymus (Kappler et al. 1987, Kisielow et al. 1988). It may also be induced in peripheral T cells when these encounter antigens unique to extra-thymic tissues. Two transgenic models have been particularly useful in the study of peripheral self tolerance: in one model, a known antigen is expressed in a particular extra-thymic site; in the other, the T-cell repertoire is predominantly reactive to this antigen. We, and others, have shown that expression of class I or II MHC molecules in defined extra-thymic sites leads to a state of T-cell tolerance. To account for this, we have proposed two hypotheses which have different implications for autoimmune disease. According to one, tolerance is imposed by deletion or functional silencing of specific high-affinity cytolytic T cells; alternatively, the target cell for tolerance induction may be a regulatory IL-2-producing T-cell, rather than the effector cell itself. To distinguish between these hypotheses it is essential to examine the fate of T cells which have the potential to react to the transgene product. Since the frequency of such T cells is low and there is no dominant clonotype for H-2Kb, which is the class I molecule we used, it was necessary to create double transgenic mice by mating class I transgenic mice with transgenic mice whose T-cell pool was compared of cells reactive to H-2Kb and could be detected by an antibody directed to the TCR. Initial studies showed that such T cells did persist despite the presence of antigen to which they may be reactive. If these double transgenic mice can be shown to be tolerant, they will offer a rich source of tolerant T cells for detailed investigation of their phenotype and fate, and they will be most useful in enabling us to probe the mechanisms responsible for the induction of peripheral self tolerance. Transgenic mouse technology has also been used successfully to unravel the genetic influences which may lead to or prevent autoimmunity. In particular, we have prevented autoimmune diabetes in the nonobese diabetic mouse by introducing a non-NOD MHC class II gene and further work is implicating the failure of intrathymic positive selection of a protective cell as one step in the pathogenesis of diabetes in NOD mice.
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PMID:Transgenic models of T-cell self tolerance and autoimmunity. 207 27


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