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)

There is convincing evidence that certain combinations of alleles within the human leucocyte antigen (HLA) complex, particularly within HLA-DQ, are associated with either resistance or susceptibility to insulin-dependent diabetes mellitus (IDDM). A previous study conducted on a large, well-defined group of patients demonstrated that DQB1*0302 (DQw8) conferred 'dominant susceptibility' to IDDM while DQB1*0602 (DQw1.2) conferred 'dominant protection'. The availability of this population enabled us to further assess susceptibility associated with other class II alleles in an effort to map an outside HLA boundary of disease association. Using a group-specific polymerase chain reaction protocol and a series of oligonucleotide probes which define over twenty DP beta alleles, we studied 286 unrelated Caucasian patients with IDDM and 184 normal subjects. We found that while several alleles are increased (DPB1*0201, DPB1*0301, DPB1*0402) or decreased (DPB1*0101, DPB1*0202) in the diabetic population compared with the normal subjects, the HLA association with IDDM is considerably weaker at the DP locus. These data define the centromeric boundary for the HLA-associated susceptibility gene in IDDM, localizing susceptibility to the region telomeric to HLA-DP up to and including HLA-DQ.
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PMID:Analysis of HLA genotypes and susceptibility to insulin-dependent diabetes mellitus: association maps telomeric to HLA-DP. 150

Viral infection has been suggested to play a triggering role in the pancreatic beta cell destruction which occurs in insulin-dependent diabetes (IDDM). However, the underlying mechanism of this phenomenon is unknown. In this study a human insulinoma cell line has been infected with measles, mumps and rubella viruses since a temporal association is reported between the clinical onset of IDDM and diseases caused by these viruses. The infection with measles and mumps viruses induced the release of interleukin-1 (IL-1) and interleukin-6 (IL-6) by the cell line as assessed by a bioassay and up-regulated the expression of human leucocyte antigen (HLA) class I and class II antigens as evaluated by cytofluorimetric analysis. Stimulation with rubella virus induced the release of IL-6 only and had no effect on HLA antigen expression. These data show for the first time that IL-1 and IL-6 secretion by an insulinoma cell line may occur after viral infection and suggest that cytokine release and increased expression of HLA molecules by beta cells may act to induce the immune response towards beta cells in IDDM.
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PMID:Viral infection induces cytokine release by beta islet cells. 159 39

The syndrome of caudal dysplasia (CDS) and the wide spectrum of associated skeletal and other anomalies are reviewed, and a further case of this disorder is presented. The syndrome of CDS should be distinguished from the familial forms of sacral dysgenesis, three forms of which are tentatively identified. Two of these usually involve some degree of "hemi-sacrum." The third is usually manifested as partial sacral agenesis with absent distal segments. All these familial types are probably genetic dominants, and none is associated with maternal diabetes. Usually CDS is not familial, but it often is associated with a tendency toward diabetes in the mother. The suggestion is advanced here that CDS is the result of a combination of two principal factors represented by (a) a maternal diabetic tendency and (b) separate nondiabetogenic genes. Determination of the human leucocyte antigen (HLA) haplotypes involved in CDS is suggested to investigate the possibility of genetically distinctive factors in this condition.
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PMID:The syndrome of caudal dysplasia: a review, including etiologic considerations and evidence of heterogeneity. 639 99

Long QT syndrome (Romano-Ward syndrome) and insulin-dependent diabetes mellitus (IDDM) have been documented as being linked with gene(s) on chromosome 11p although concurrence of the two disorders has not been reported. Our case is a 13-year-old boy with Romano-Ward syndrome accompanied by IDDM. The long QT syndrome seemed to be transmitted in an autosomal-dominant mode because the Q-T intervals of his father and paternal grandfather were longer than normal. There was no family member with an abnormally high level of blood glucose except the patient. The human leucocyte antigen (HLA) haplotypes of the patient and the father were DR4/DR9 and DR2/DR9, respectively. This study suggests that in our patient IDDM, as well as Romano-Ward syndrome, is linked with chromosome 11p in the presence of HLA-DR4. The results support the previous study that chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility.
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PMID:Long QT syndrome with insulin-dependent diabetes mellitus: contiguous gene syndrome on chromosome 11p. 834 Jul 47

The aim of this study was to evaluate the role of HLA (human leucocyte antigen) class I (A, B, C) and class II (DR) alleles and familial insulin-dependent diabetes mellitus as possible risk markers for early retinopathy in a population of 103 Finnish adolescents with type I diabetes mellitus for 3.6-16.2 years. Fifty-one of the patients (49.5%) had signs of retinopathy in fundus photographs. HLA DR1 was found in 31% of the subjects with retinopathy, but in only 5% of those without retinopathy (p = 0.02). The corresponding figures for HLA DR1/4 were 17% and 2.6%, respectively (p = 0.22). The frequency of HLA DR3, DR4, or DR3/4 heterozygosity did not differ between the two groups of patients. Signs of early retinopathy showed thus an association with the presence of the HLA DR1 allele, and a mild protective effect of the HLA A9 and B40 alleles was indicated. Other HLA A, B, C, or DR alleles did not have any effect on the risk for early development of retinopathy, neither had a positive family history of type I diabetes.
J Diabetes Complications
PMID:Genetic markers in early diabetic retinopathy of adolescents with type I diabetes. 920 96

1. Autoimmune diseases are common conditions which appear to develop in genetically susceptible individuals, with expression of disease being modified by permissive and protective environments. Familial clustering and data from twin studies provided the impetus for the search for putative loci. Both the candidate gene approach in population-based case-control studies and entire genome screening in families have helped identify susceptibility genes in a number of autoimmune diseases. 2. After the first genome screen in type 1 (insulin-dependent) diabetes mellitus it seems likely that most autoimmune diseases are polygenic with no single gene being either necessary or sufficient for disease development. Of the organ-specific autoimmune diseases, genome screens have now been completed in insulin-dependent diabetes mellitus and multiple sclerosis. Furthermore, the clustering of autoimmune diseases within the same individuals suggests that the same genes may be involved in the different diseases. This is supported by data showing that both HLA (human leucocyte antigen) and CTLA-4 (cytotoxic T-lymphocyte-associated-4) appear to be involved in the development of insulin-dependent diabetes mellitus and Graves' disease. 3. Genome screens have also been completed in some of the non-organ-specific autoimmune diseases including rheumatoid arthritis, inflammatory bowel disease and psoriasis. Many candidate genes have also been investigated although these are predominantly in population-based case-control studies. 4. Substantial progress has been made in recent years towards the identification of susceptibility loci in autoimmune diseases. The inconsistencies seen between case-control studies may largely be due to genetic mismatching between cases and controls in small datasets. Family-based association studies are being increasingly used to confirm genetic linkages and help with fine mapping strategies. It will, however, require a combination of biology and genetics, as has been necessary with the major histocompatibility complex in insulin-dependent diabetes mellitus, to identify primary aetiological mutations.
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PMID:Genetic susceptibility to the development of autoimmune disease. 949 84

Several publications have shown that certain alleles at the HLA-DRB1, -DQA1, and -DQB1 loci are associated with insulin-dependent diabetes mellitus (IDDM). Many of these studies have claimed that HLA-DQalpha1Arg52 and DQbeta1Asp57 showed the strongest association with IDDM, but these results could not be confirmed in different populations. We have recently found that DRbeta1Lys71+ provided major susceptibility to IDDM and that DQbeta1Asp57- had an additive effect to DRbeta1Lys71+ [Zamani et al., 1994a: Eur J Hum Genet 2:177-184]. This was confirmed with haplotype analysis in multiplex IDDM families [Zamani et al., 1996a: J Med Genet 33:899-905]. Therefore, we have reanalyzed the data from the literature on the association of the human leucocyte antigen (HLA) DRB1, DQB1, and DQA1 with IDDM in different ethnic groups to determine whether different amino acids in the antigen binding cleft of HLA class II molecules play a preponderant role in the development of IDDM. The results showed that the DRbeta1Lys71+ allele provided the highest relative risk for IDDM in the Belgian, Danish, Greek Taiwanese, and Chinese population while this was not the case in Norwegians, Sardinians, and Algerians. Indeed, in the Sardinian and Algerian population the DRB1*0401 allele encoding Lys71+ is very rare. Nevertheless, the few positive cases were always in the patient group. We also measured the clinical relevance of the testing for DRbeta1Lys71, DQbeta1Asp57, and DQalpha1Arg52 by calculating a prevalence-corrected positive predictive value (PcPPV), a prevalence corrected negative predictive value (PcNPV), the sensitivity and specificity of these tests. The results indicated that the sensitivity of the test for DRbeta1Lys71+ was lower than for DQalpha1Ag52+ and DQbeta1Asp57-, while testing for DRbeta1Lys71+ was more specific than testing for DQbeta1Asp57- and DQalpha1Arg52+ and that the DRbeta1Lys71+ allele had a higher PcPPV than DQalpha1Arg52+ and DQbeta1Asp57- in all studied populations. These results also showed that testing for DRbeta1LyS71+/+ can be useful in IDDM risk assessment particularly in populations with a high prevalence (P) of IDDM such as the Danish (P[IDDM] = 0.65%). PcPPV for DRbeta1Lys71+/+ was 0.2313 in the Danish, indicating a 23.13% risk for an individual who is homozygous for the genotype DRbeta1Lys71+/+ to develop IDDM. Some mechanisms which might explain the role of these HLA class II alleles in susceptibility to IDDM are discussed.
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PMID:Reevaluation of the importance of polymorphic HLA class II alleles and amino acids in the susceptibility of individuals of different populations to type I diabetes. 951 82

Cyclosporin is a powerful immunosuppressive agent which has markedly improved the outcome of renal transplantation, a technique now well established as the treatment of choice for patients with end-stage renal disease (ESRD). Comparison of cyclosporin-based regimens with a regimen of azathioprine and a glucocorticoid (conventional immunosuppression) indicates an improved clinical course and increased long term graft survival rate with cyclosporin which is most apparent in the recipients of a kidney from a living related donor (human leucocyte antigen mismatched) or cadaver donor source. Cyclosporin has also improved the clinical outcome in patient subgroups previously associated with a higher risk of graft failure with conventional immunosuppression, namely older patients and those with diabetes mellitus. Cost-of-treatment studies conducted over the first post-transplant year in the US have found that higher pharmacy charges with cyclosporin-based regimens are associated with lower hospitalisation charges and total billed charges compared with conventional immunosuppression. Lower hospitalisation charges reflect an improved post-transplant clinical course with cyclosporin and this has been associated with an improved quality of life in the recipients of a cadaver donor kidney. Longer term, the direct cost to society of using cyclosporin-based dual therapy (in combination with a glucocorticoid) may be higher than that with conventional immunosuppression, although the difference is likely to be small compared with the ongoing cost of dialysis. Clinical research continues to focus on modified regimens which maximise the clinical benefits of cyclosporin while minimising the associated adverse events, in particular the potential for nephrotoxicity. Sequential drug therapy (induction with globulin, azathioprine and a glucocorticoid followed by delayed administration of cyclosporin) has been associated with an improved clinical course compared with dual therapy, as well as cost containment to a level comparable to that for conventional immunosuppression. Compared with sequential therapy, triple drug therapy (cyclosporin, azathioprine plus a glucocorticoid) has been associated with a similar clinical course and lower acquisition cost during the first post-transplant year, although its overall impact on the longer term cost of transplantation has yet to be assessed. Elimination of cyclosporin from the immunosuppressive protocol of carefully selected patients can be safely achieved during the first post-transplant year. However, it remains to be established whether savings in the long term acquisition cost of immunosuppression are more than offset by the cost of treating a potentially less favourable clinical course.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cyclosporin: a pharmacoeconomic evaluation of its use in renal transplantation. 1014 75

L-selectin (CD62L) is a cell adhesion molecule which plays a key role in the initiation of leucocyte migration from blood vessels to sites of local inflammation. The aim of this study was to investigate T-lymphocyte expression of CD62L antigen and serum levels of soluble L-selectin (sL-selectin) in subjects with clinical and preclinical type I diabetes to determine whether they could provide surrogate markers for disease activity. CD62L selectin expression on memory T lymphocytes was studied by cytometric analysis in 22 patients with newly diagnosed type I diabetes, 20 first-degree relatives of patients with type I diabetes, 14 patients with Graves' disease, and 22 healthy controls. sL-selectin levels were measured by enzyme-linked immunosorbent assay (ELISA) in enlarged groups of subjects in these categories, as well as in patients with long-standing type I diabetes, treated Graves' disease and type II (non-insulin dependent) diabetes. L-selectin levels were also related to islet autoantibodies, human leucocyte antigen (HLA) genotype and L-selectin T668C gene polymorphisms. L-selectin expression on memory T lymphocytes was reduced in newly diagnosed diabetes and islet autoantibody positive siblings compared with controls. sL-selectin levels were significantly raised in newly diagnosed type I diabetes compared with controls, with intermediate levels in family members, both with and without islet autoantibodies, and in long-standing type I diabetes. Levels were also raised in patients with untreated Graves' disease. Patients with type II diabetes had sL-selectin levels which did not differ from controls. sL-selectin levels correlated with the presence of diabetes-associated HLA alleles in both family members and controls; levels also fell with increasing age in family members. Multiple regression analysis showed that HLA genotype and age were independent determinants of sL-selectin levels. sL-selectin levels are raised at the time of diagnosis of type I diabetes and Graves' disease and appear to be modulated by disease activity, but levels are determined predominantly by HLA-associated genetic susceptibility and age. sL-selectin may provide a late marker of autoimmune destruction of islets and sequential measurement may be useful in monitoring disease activity and the effect of interventions preceding type I diabetes.
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PMID:Soluble L-selectin levels in type I diabetes mellitus: a surrogate marker for disease activity? 1069 53

Studies of two post-mortem pancreata of children at the onset of type I diabetes have suggested activation and expansion of islet infiltrating T cells by a superantigen. We present the first reported case of a superantigen mediated disease, toxic shock syndrome (TSS), occurring at the diagnosis of type I diabetes. A 12-year-old girl presented with TSS and newly diagnosed diabetes with ketoacidosis. At presentation she was unconscious, febrile and hypotensive, with a desquamating erythematous rash and Kussmaul breathing. During resuscitation, her renal impairment, diarrhoea, thrombocytopaenia and ketoacidosis resolved. Vaginal discharge and blood cultures grew Staphylococcus aureus. T cell studies at 2 weeks after diagnosis detected a high level of spontaneous and islet antigen-specific proliferation with associated interleukin-10 production compared to human leucocyte antigen DR matched controls.
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PMID:Toxic shock syndrome associated with newly diagnosed type I diabetes. 1084 34


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