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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is now widely accepted, that the development of type 1 diabetes is based on an autoimmune destruction of the insulin-producing betacells of the pancreas; however, a genetic predisposition is required. 90 to 95% of patients with type 1 diabetes are HLA-DR3 positive and/or HLA-DR4 positive. In addition, recent results from molecular-genetic research suggest an aspartate on position 57 of the HLA-DQ-beta protein, which seems to protect against the autoimmune destruction of the betacell, since it is not found in patients with type 1 diabetes in contrast to control persons. Trigger substances inducing the initial betacell destruction are not known, but might not be necessary according to an actual hypothesis. Finally, all insulin-producing cells are destroyed, and lifelong insulin replacement therapy cannot be circumvented. Prevention of the autoimmune destruction is not possible today; especially, not using immunosuppressive drugs because of side effects.
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PMID:[The pathogenesis of type 1 diabetes mellitus]. 240 78

To examine the effect of the major histocompatibility locus (HLA) and the duration of insulin-dependent diabetes (IDDM) on immune responses to insulin we assayed insulin induced proliferation of blood mononuclear cells and measured insulin antibodies in 66 patients with newly diagnosed and in 56 patients with longstanding IDDM matched for the age at onset (less than or equal to 15 years). In up to two thirds of the patients blood mononuclear cells responded to insulins by proliferation, and insulin antibodies were found in two thirds of patients with IDDM of long duration. Insulin proliferation or antibodies were not associated to any particular HLA antigen. The frequency of HLA-DR3 in patients with newly diagnosed IDDM was not increased unlike in patients with IDDM of long duration. In addition, HLA-B8 was associated to HLA-DR3 nearly twice as often in patients with newly diagnosed IDDM as in patients with longstanding IDDM. Thus, patients with IDDM of recent onset and diagnosed within the last three years more frequently responded to insulin by proliferation and less often had HLA-DR3 than patients with IDDM of long duration and diagnosed about 20-25 years earlier.
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PMID:Immune responses to insulin in patients with insulin-dependent diabetes mellitus. 249 43

It is now well known that insulin-dependent diabetes is a chronic progressive autoimmune disease. The prolonged prediabetic phase of progressive beta-cell dysfunction is associated with immunological abnormalities. A prediabetic period is suggested by the appearance of islet cell antibodies, anti-insulin antibodies, and anti-insulin receptor antibodies. The existence of activated T lymphocytes and abnormal T cell subsets are also other markers. There is still no concensus about the use of the immunosuppression superimposed upon conventional insulin therapy in early diagnosed IDDM and the follow-up of the relatives of IDDM patients who share the genetic predisposition and serological markers for the risk of future onset of IDDM. Treatment in the prodromal period cannot be justified because a link between the disease and early markers such as ICA has not been established with certainty (Diabetes Research Program NIH, 1983). Many immunopharmacological manipulations were reported to be effective in animal models. However, most of them are not readily applied to human subjects. Moreover, IDDM patients are now believed to be heterogeneous, with a complex genetic background. HLA-DR, and more recently DQ, are closely related to the genetic predisposition to IDDM but those genes are not themselves diabetogenic. The contribution of autoimmunity does not appear to be uniform, and in some cases, the contribution of virus is considered more important. There is a lack of a marker for the future onset of IDDM. ICA and ICSA were found after mumps infection, but the existence of those autoantibodies and even the co-existence of HLA-DR3 do not always indicate the future trend to insulin dependency. More precise markers will be disclosed through the biochemical analysis of the target antigens on pancreatic beta-cell for islet antibodies and effector T cells. Much safer and more effective immunopharmacological treatment will be developed through animal experimentation using rat and mouse models. The recent development and interest in this field will further facilitate the attainment of the goal for the complete prevention of IDDM.
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PMID:Immunological aspects of diabetes mellitus: prospects for pharmacological modification. 251 48

The majority of the genetic component in insulin dependent (Type 1) diabetes mellitus can be explained by associations with genes on short arm of chromosome 6 located in the major histocompatibility complex. With the advent of cloning of the HLA Class II region genes it has been possible to refine the previous known association of HLA-DR3 and DR4 with this disease. Strong associations of IDDM have now been shown to exist with the DQB1 gene and/or linked genes, although this does not completely explain the HLA susceptibility to this disease.
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PMID:The major histocompatibility complex and insulin dependent (type 1) diabetes. 257 93

Insulin autoantibodies (IAAs) are associated with type I diabetes mellitus (DM) and have been suggested as predictive markers of the disease. Using an ELISA assay, we have studied the prevalence of binding to human insulin in sera from an Arab type I DM population and compared it with the prevalence in the family members (FMs) of the probands, in type II DM patients from the same population, and in Arab control subjects. Significant levels of binding occurred in 11/16 (69%) of type I DM patients and in 21/34 (62%) of their FMs, but in only 5/31 (16%) of type II DM patients and in 1/25 (4%) of control subjects. Within families, there was homogeneity with regard to the level of insulin binding and the mean family levels correlated with those of the proband (r = 0.68, df = 7, p = 0.05). HLA-DR3 or -DR4 antigens occurred in 55/63 (87%) of type I DM patients and in 95/118 (81%) of their FMs. This was significantly higher (p less than 0.001) than in either type II DM patients (39/75, 52%) or in control subjects (34/93, 37%). ICAs were present in significantly more (25/43, 58%) of type I DM patients than their FMs (3/82, 3%) (p less than 0.001). They did not occur in either type II DM patients or in the control group. In conclusion, insulin binding occurred in sera from both type I diabetic patients and their kindred, and hence did not appear to be specifically associated with the development of clinical diabetes.
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PMID:Insulin binding substances, autoimmunity and type I diabetes in Kuwaiti patients and their kindred. 278 62

Human genomic DNA samples from Caucasoids, Chinese, and Koreans of known serological DR antigen specificity were studied for IDDM-associated variation in HLA-DR and -DQ RFLPs (restriction fragment length polymorphisms). Genotyping allowed for accurate assignment of HLA-DR types and in Caucasoids DRw6 as well as DR2 was unequivocally decreased in IDDM. Further, the universality of certain DR2-associated DQ beta subtypes in protection against IDDM was established. HLA-DR3 was found to be increased in IDDM irrespective of whether carried on the B8. DR3 or B18. DR3 haplotype in Caucasoids or on the Bw58. DR3 haplotype in Chinese. These haplotypes have different DR alpha and DX alpha arrangements, so the region of susceptibility is confined to DQ alpha, DQ beta. For HLA-DR4, a 12kb/DQ beta/Bam HI fragment was increased in Caucasoid IDDM, but since this fragment is haplotype specific in Caucasoids and occurs in most healthy DR4- and w9-positive Asians, the 12 kb fragment may be a marker for a DR beta subtype of DR4 associated with IDDM in Caucasoids only. This study has shown the value of ethnic comparisons of HLA-associated diseases, where different linkage disequilibrium relationships have permitted identification of common susceptibility determinants and have provided evidence for some heterogeneity between Caucasoid and Asian populations, in the genetics of IDDM.
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PMID:Insulin-dependent diabetes mellitus: HLA-DR and -DQ genotyping in three ethnic groups. 290 33

Associations of insulin dependent diabetes mellitus exist with the HLA-DR antigens DR3 and DR4 in both British Caucasoid and Dravidian subjects. However, it is only in British Caucasoids that an increased relative risk is found in those subjects who co-inherit both of these antigens. The nature of these HLA associations has been explored using Southern blot techniques and radioactive HLA-D region probes. In both populations the same DR4 related polymorphism was found in IDDM subjects whereas different HLA-DR3 preferential allelic associations were observed between British Caucasoid and Dravidian subjects. The best differentiation between diabetics and controls was found by a combination of HLA-DQ region alpha and beta polymorphisms which were totally different for the two populations. These data indicate that at least one gene involved in the susceptibility to IDDM is located within the HLA-DQ region and this may be related to HLA-DR4. The location of a DR3 related gene remains elusive and may be the DR beta gene encoding DR3 itself. In both populations it is a combination of two HLA-D region haplotypes which is strongly associated with IDDM leading to the possibility of trans complementation leading to the formation of mixed isotypic dimers.
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PMID:The genetic susceptibility to IDDM in British and south Indian subjects. 314 91

The Wolfram, or DIDMOAD, syndrome is a rare congenital disease that is associated with diabetes insipidus, insulin dependent diabetes mellitus of an early onset, bilateral optic atrophy and deafness. Urological disorders are usually present as well. We have studied nine patients belonging to five different families. All of the family members were HLA typed (including DR), and islet cell as well as antinuclear antibody determinations were carried out. Although individuals with insulin dependent diabetes mellitus are very prone to have either HLA-DR3 or -DR4 antigens, none of our patients had DR3 antigens and only one was DR4 positive. On the other hand, three of our patients were typed as HLA-DR2 positive. This antigen is uncommon in classical insulin dependent diabetes. In one of the families, the affected siblings did not share the same HLA haplotype. Islet cell and antinuclear antibodies were not found in any of the cases and six of the patients had a small, but significant, insulin secretory reserve. On the basis of some of the clinical features it was also possible to further distinguish between the DIDMOAD syndrome and the classical insulin dependent diabetes mellitus. The differences encountered between classical and DIDMOAD insulin dependent diabetes mellitus--the presence/absence of HLA linkage, HLA-DR2, -DR3 and -DR4 associations, islet cell or antinuclear antibodies, the tendency to ketosis and diabetic retinopathy--indicate that their etiopathogenies are triggered by distinct mechanisms.
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PMID:Contrasting features of insulin dependent diabetes mellitus associated with neuroectodermal defects and classical insulin dependent diabetes mellitus. 329 50

Graves' disease and type 1 (insulin-dependent) diabetes are common autoimmune endocrine disorders which may co-exist. Since the class II HLA-DR3 antigen is associated with both these diseases, and since an association between DR3 and the thyrotrophin receptor antibody (TRAb) has been suggested, we wished to determine whether TRAb levels were increased and were HLA-D related in diabetes mellitus. In 115 clinically euthyroid subjects (33 type 1 diabetics, 82 healthy controls) there was a correlation between age and TRAb levels (r = -0.39, p less than 0.001). TRAb levels were elevated in DR3 subjects (n = 32) compared to an age matched group of non-DR3 (n = 61) subjects [median (range): 18.1 (-1.7 to 47.4) versus 6.7 (-9.8 to 19.1), p less than 0.001]. Diabetic DR3 and control DR3 subjects had similar TRAb levels which were elevated when compared to their respective non-DR3 control group (both p less than 0.001). All but two subjects (both diabetic) had TRAb levels in our normal range. Thus TRAb levels are elevated in the subjects who possess the HLA-DR3 antigen. Since DR3 is found so commonly in type 1 diabetes this phenomenon may partly explain the association with Graves' disease in this patient population.
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PMID:Thyrotrophin receptor antibodies in type 1 (insulin-dependent) diabetes mellitus. 341 55

One hundred and thirty-six Finnish patients with insulin-dependent (type I) diabetes mellitus were investigated for the HLA-A, B, D and DR antigens as well as the Bf and C4 allotypes. The statistically significant increase in the frequencies of HLA-A9, B8, B15, Dw3, Dw4, DR3, DR4, C4A0 and C4B3 was observed when compared with the healthy controls. About 79% of the patients had HLA-DR4, and 53% had HLA-DR3 antigens. A rare C4 allele C4B3 was found in 21% of the patients, whereas only in 2% among the controls (relative risk 16.35). The etiological fraction (EF) values indicated that HLA D/DR alleles were the best markers for IDDM, the observed EF for HLA-DR4 in diabetes was as high as 0.70. Examination of HLA, Bf and C4 phenotypes suggested that at least two supratypes "B15 BfS C4A3B3 D(R)4" and "B8 BfS C4A0B1 D(R)3" were markers for the susceptibility to type I diabetes, one third of our patients had either of these supratypes. The protective role of DR2 and Dw2 antigens was also confirmed: no HLA-Dw2 positive patients and only one with HLA-DR2 was found.
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PMID:HLA antigens and complotypes in insulin-dependent diabetes mellitus. 346 Feb 20


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