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)

The presence of cytoplasmatic islet cell antibodies (ICA) and IgG insulin autoantibodies (IgG-IAA) has been observed in the prediabetic state of type 1 (insulin-dependent) diabetes (IDDM). We therefore analyzed the prevalence of these markers in sera from 1117 healthy HLA-typed first-degree relatives (1 degree Rel) of IDDM patients. ICA was determined by indirect immunofluorescence on cryostat sections of human pancreas. For IgG-IAA measurement a competitive solid-phase ELISA was used. ICA were present in 3.5% of 1 degree Rel vs 0.4% of controls (P less than 0.025). The highest frequencies of ICA were found in individuals of IDDM multiplex families (7.7%) and HLA-DR1,3 (5.4%), -DR1,4 (5.8%), and -DR3,4 (6.7%) positive subjects. We therefore conclude that the prevalence of ICA is increased in 1 degree Rel with high genetic risk for diabetes. IgG-IAA occurred in 9.9% of 1 degree Rel vs 1.4% of controls (P less than 0.01). Like ICA, IgG-IAA were significantly increased in a group of subjects being positive for either HLA-DR1,3 -DR1,4, or -DR3,4 (16.5%, P less than 0.01). In multiplex families, however, prevalence of IgG-IAA was not increased. In contrast to ICA there was an additional influence of age and sex: IgG-IAA were found more often in siblings (mean age, 16.6 years; prevalence, 15.0%) than in parents (mean age, 44.1 years; prevalence, 8.3%) of IDDM patients (P less than 0.01). In brothers the prevalence of IgG-IAA is higher than in other 1 degree Rel. Only a weak association between ICA and IgG-IAA was observed in subjects (n = 810) tested for both antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Prevalence of cytoplasmatic islet cell antibodies and insulin autoantibodies is increased in subjects with genetically defined high risk for insulin-dependent diabetes mellitus. 264 70

There is no doubt that the autoimmune process in human disease depends on genetic factors. Varying associations were noticed between HLA DR and autoimmune disorders. The frequency of HLA-A-B and DR antigens as well as the Bf and C4 allotypes have been investigated in insulinodependant diabetes mellitus (IDDM) and compared to that of healthy controls in Tunisian population. An increase of A30, DR3, DR4, BfF1, C4AQ0 and C4BQ0 and decrease of B40, DR2, DR5 and DR6 were found in diabetes when compared to the value observation controls. The strongest association was noticed with HLA, DR3 and DR4. The prospective role of DR2 and DR5 antigens were also confirmed. Examination of HLA, Bf and C4 alleles. Two supratypes associated with IDDM have been observed among the Tunisian patients.
 ...
PMID:[HLA, A, B, C, DR, C4, Bf in insulin-dependent diabetics in the Tunisian population]. 264

The present knowledge of the HLA system and its biological function is summarized as a basis for the subsequent discussion of the associations between this system and insulin-dependent diabetes (IDDM) and some mechanisms that may explain them. Although the serologically detectable DR determinants are still the most handy markers, there is now increasing evidence from studies of restriction enzyme fragment length polymorphism (RFLP) in IDDM that DQ determinants may play a primary role in causing susceptibility and/or resistance to this disease. Thus, it is now evident that about 90% of DR4-positive diabetics carry the DQw8 determinant present in only about 65% of DR4-positive controls. Most recently, it has been claimed that an aspartic acid in position 57 of the DQB1 (DQ-beta-1) chain confers resistance to IDDM. Although this may be true, it does not explain the disproportionate decrease of DR2 or the particularly high risk of DR3/4 heterozygotes, which is still good evidence that several HLA genes are involved. Because Class II antigens show the strongest associations, the most plausible hypothesis about the mechanism(s) involves specific presentation of as yet unknown antigenic peptides to T-helper lymphocytes, which may induced the formation of both anti-islet cell antibodies and T-cytotoxic lymphocytes capable of destroying beta cells. However, T-suppressor lymphocytes also may be involved. If this hypothesis is correct, the most urgent task is to define the antigenic peptides in question, whether they are environmental (e.g., viral) or autologous.
 ...
PMID:HLA and insulin-dependent diabetes: an overview. 265 26

In 79 diabetic patients, 37 patients with diabetes mellitus type I and 42 patients with diabetes mellitus type II, the HLA-A, B and DR antigens were examined. An association of diabetes mellitus type I with HLA-B8, DR3 and DR4 was found. For the first time a relation between diabetes mellitus type I and HLA-B21 antigen was established. The early onset of the disease and the exhaustion of the endogenic insulin secretion are linked with B8 and DR3 carrier state while the late manifestations of diabetes mellitus and the preservation of one's own insulin production correlate with antigen B21. In the patients with diabetes mellitus Type II the frequency of antigen B21 and DR1 is increased and the carriers of B21 develop in the course of the disease relative insulin insufficiency and a secondary resistance toward sulfanilurea drugs.
 ...
PMID:[The relationship of HLA antigens to certain clinical forms of diabetes mellitus]. 266 40

Experimental results and therapeutic strategies. Insulin-dependent diabetes mellitus (IDDM) results from an autoimmune aggression toward beta cells in genetically predisposed individuals. Examination of the frequency of the different antigens coded by the major histocompatibility complex reveals an increased proportion of DR3-DQ2 and DR4-DQ8 haplotypes in IDDM subjects. Sequencing DQ-beta chains in such patients indicates the absence of aspartate in position 57 when compared to control individuals. Islet cell cytoplasmic autoantibodies are early markers of ongoing autoimmunity in addition to insulin autoantibodies before administration of exogenous insulin. Experimental models of autoimmune diabetes like the NOD (NonObese Diabetes) mouse underline the predominant role of T lymphocytes in the constitution of both insulitis and beta cell destruction. In humans, an increased proportion of activated T lymphocytes can be observed but is not specific of the disease. This underlines the need for new cellular markers of the autoimmune process. Transgenic mice allow studies on the consequences of abnormal expression of new molecules on beta cell surface like cytokines or MHC class II molecules which represent a new field of investigation on the pathogenesis of IDDM. Prospective studies in first degree relatives of type I diabetic patients indicate the existence of an asymptomatic phase of beta cell destruction where specific autoimmune markers can be individualized. In some individuals abnormal insulin response to glucose--loss of first phase insulin release during intravenous glucose tolerance test--precedes insulin deficiency. The identification of an autoimmune process leading to beta cell destruction allows new therapeutic approaches with immunointervention at early stages of the disease.
 ...
PMID:[Autoimmunity and insulin-dependent diabetes mellitus. Experimental data and therapeutic prospects]. 267 68

We prospectively followed 29 children and adolescents over a 1- to 8-year period who were referred for evaluation of hyperglycemia (in the absence of diabetes) or glycosuria found on routine screening or during acute illness. On initial examination, four subjects had islet cell autoantibodies, 4 of 22 had an abnormal intravenous glucose tolerance test result, 6 of 22 had low first-phase insulin release on intravenous glucose tolerance testing, and 10 of 20 had impaired glucose tolerance on oral glucose tolerance testing. On follow-up, insulin-dependent diabetes had developed in two of the four subjects with islet cell autoantibodies. The other two subjects with islet cell antibodies have had persistently abnormal glucose tolerance on both oral and intravenous glucose tolerance testing and have low first-phase insulin responses. Diabetes has developed in none of 25 subjects without islet cell antibodies, although two have persistently abnormal glucose tolerance or insulinopenia. All five subjects with islet cell antibodies or human leukocyte antigen DR3/DR4 with initial impaired glucose tolerance have either acquired diabetes or have abnormal glucose tolerance. In contrast, only one of five subjects with initial impaired glucose tolerance but lacking these markers has persistent glucose intolerance. We conclude that in the absence of islet cell antibodies or human leukocyte antigen DR3/DR4 heterozygosity, incidental hyperglycemia or glycosuria is unlikely to be associated with progression or diabetes.
 ...
PMID:Natural history of incidental hyperglycemia and glycosuria of childhood. 268 35

The specific genes causing type 1 diabetes susceptibility in any species are unknown. Serological HLA studies have shown susceptibility to type 1 diabetes is linked to HLA DR3 and DR4 allels, whereas DR2 and DR5 alleles contain protective elements. DR4 chromosomes can be divided into diabetes prone or resistant by restriction fragment length polymorphism analyses with cDNA probes for DQ beta-gene. No type 1 diabetes-specific environmental factors have been revealed to be convincingly implicated in human type 1 diabetes. Congenital rubella, by its lasting influence on T cells creates susceptibility to many organ-specific autoimmune diseases. Certain dietary proteins shown in BB rats as well as hyperglycemia during the prenatal period increase the later incidence of type 1 diabetes. Human type 1 diabetes results from a progressive probably autoimmune loss of the pancreatic beta cells. The immunologic hallmarks of type 1 diabetes is the lymphocytic infiltration of pancreatic islets, the hyperexpression of class I MHC on all islet cells and the abarrent class II MHC expression on beta cells within inflamed islets, the increased frequency of activated T cells in islet and circulation. It is generally accepted that cellular immunity plays the major role in the pathogenesis of type 1 diabetes. The heightened autoimmune reactivity being detectable during the preclinical period, lasting months to years, has been proved by antibodies directed against cytoplasmic islet cell antigens (ICA), beta cell surface antigens (ICSA), insulin (IAA), and with a lower frequency against non-islet cell antigens. The presence of IgG insulin autoantibodies and complement fixing ICA confers increased risk for future type 1 diabetes development in genetically predisposed individuals than the presence of either marker alone. For ICSA a more specific and quantitative assay is needed. 90% of children developing type 1 diabetes were detected positive for ICA and/or IAA. By the time of clinical onset if type 1 diabetes some 90% of the insulin secretory beta cell mass has already been destroyed. For this reason, new approaches are needed to address the causes of diabetes and not just the consequences. The development of insulin-dependent diabetes may be reversible, or even preventable by early detection coupled with the judicious use of immunotherapy.
 ...
PMID:Immunological disorders of type 1 diabetes mellitus. 268 94

Studies of patients with insulin-dependent diabetes and their families have shown increased incidences of HLA markers B8, B15, DR3 and DR4. While these genetic predispositions are obviously important, additional factors such as environmental influences are presumed to trigger the events leading to the development of diabetes. Infectious triggers, in particular several viruses, have been suggested. The evidence from epidemiological and in vitro studies for a viral aetiology is summarized here. The significance of the recent finding of an increased proportion of non-secretors among patients with insulin-dependent diabetes is discussed in the context of other 'autoimmune' diseases for which infectious aetiologies have been proposed.
 ...
PMID:An infectious aetiology of insulin-dependent diabetes mellitus? Role of the secretor status. 269 33

Differences between Type 1 and Type 2 Diabetes Mellitus are briefly outlined with special emphasis on the immune mechanism in the development of juvenile diabetes. Autoimmune nature of Type 1 diabetes is based on: association with genetic markers of histocompatibility mainly with the DR3 and DR4 haplotypes of the HLA system; anomalies of the humoral and cellular immunity present in a significant percentage of Type 1 diabetic patients, its association with other autoimmune diseases; the histological features of the affected pancreas and the prevention of experimental diabetes by immunosuppression. Trials on immunotherapy with immunosuppressors (Cyclosporine A and Azathioprine) and immunomodulators (Thymic hormone) were able to achieve a 50-60% index of clinical and functional remission for more than one year. With Thymic hormone and Azathioprine in combined administration the glycemic control and residual beta-cell function one year after stopping immunotherapy exhibited positive comparative results. Other trials on immunotherapy are outlined. Side effects of immunosuppression and future prospectives for immune approaches in Type 1 diabetes are commented.
 ...
PMID:[Immunotherapeutic management of juvenile diabetes mellitus]. 270 66

The frequency of HLA A, B, and DR antigens as well as the Bf and C4 allotypes have been investigated in insulin-dependent diabetes mellitus (IDDM) and compared to that of healthy controls in the Tunisian population. An increase of A30, DR3, DR4, BfF1, C4Ao, and C4Bo and decrease of B40, DR2, DR5, and DR6 were found in diabetics when compared to the value observed in controls. The strongest association was noticed with HLA DR3 and DR4. Heterozygotes DR3 DR4 were very frequent in diabetics: 24.2 per cent versus 3.6 per cent in controls (relative risk 7.72). The protective role of DR2 and DR5 antigens were also confirmed. No supratypes of HLA, Bf, and C4 alleles associated with IDDM have been observed among these Tunisian patients.
 ...
PMID:HLA A, B, and DR antigens and complotype in Tunisian patients with diabetes mellitus. 271 46


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