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

Diabetes may be associated with many genetic disorders. The scientific importance of these often rare disorders resides in the insight they may provide into the possible mechanisms of common diabetes. The type of diabetes varies in these syndromes. Non-insulin-dependent diabetes (NIDDM), clinically similar to common NIDDM, may be found in some syndromes (e.g. Werner's syndrome). In others there may be considerable insulin resistance, such as that present in ataxia telangiectasia. Extreme insulin resistance due to abnormal insulin receptor function is found in the Mendenhall syndrome. The mechanism of diabetes is more obscure in acute intermittent porphyria (AIP), although haem deficiency affecting the cytochrome chain raises interesting possibilities. In glycogen storage disease type I, the diabetes is associated with insulinopenia, following an earlier period in the disease when hypoglycaemia is the rule. IDDM, clinically similar to the common form, is present in the autoimmune polyglandular syndromes. Although a change in the lean:fat ratio is common in many neuromuscular disorders, mechanisms other than insulin resistance would seem to operate. The increased incidence of diabetes in heterozygotes for some of these genetic disorders raises the possibility that many common diabetics are, in fact, heterozygotes for some other disorder. The increased frequency of diabetes in Klinefelter's syndrome, Turner's syndrome and possibly Down's syndrome leads to the hypothesis that non-disjunction may, in some way be associated with the predisposition to diabetes. In several syndromes there is an increased incidence of diabetes in otherwise unaffected relatives of individuals with these syndromes. It is impossible to assess what proportion of common NIDDM or IDDM is made up of heterozygotes for these genetic syndromes.
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PMID:Diabetes secondary to genetic disorders. 144 74

Family studies suggest a strong genetic component in the aetiology of non-insulin dependent diabetes (NIDDM), with evidence for a major gene of co-dominant or dominant effect. A gene-dosage effect, whereby diabetes develops earlier in people with two susceptibility genes than in those with one susceptibility gene is likely. The search for the diabetes gene has led to the cloning and characterization of many genes involved in controlling glucose homeostasis. These include the insulin, insulin receptor, glucose transporter, amylin and glucokinase genes. Molecular techniques have permitted rapid screening of these genes in NIDDM patients and controls. There is now a rather contradictory genetic literature for NIDDM, with weak disease associations reported and refuted for most candidate genes. However, pedigree analyses and DNA sequencing of available candidate genes and their regulatory regions have failed to implicate any of these in the common form of diabetes, NIDDM. Methodical application of random clones in well-defined NIDDM families may be the strategy of choice in finding the NIDDM genes, given the wide range of genes potentially involved in the glucose and lipoprotein metabolic disturbances seen in NIDDM.
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PMID:Genetics of non-insulin dependent diabetes mellitus in 1990. 189 73

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

Studies on erythrocyte insulin receptors were performed in a family with hereditary motor sensory neuropathy (Charcot-Marie-Tooth) with superimposed type I diabetes mellitus. The maximum specific insulin binding of the erythrocytes was high and the increase was shown to be due to increased affinity of the insulin receptor to erythrocytes.
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PMID:Erythrocyte insulin binding in a family with hereditary motor sensory neuropathy (Charcot-Marie-Tooth) with superimposed insulin-dependent type I diabetes mellitus. 266 41

Glucocorticoid receptor binding characteristics were investigated in 8 males with poorly controlled Type 1 diabetes mellitus and 14 healthy males. The cell type studied was monocytes, and a method for correction for heterogeneity in glucocorticoid binding in a mononuclear leucocyte population was introduced. The number of receptors and the dissociation constant KD were, respectively, 13,699 and 2.93 X 10(-8) mol/l for the control group and 15,788 and 2.75 X 10(-8) mol/l for diabetics (p greater than 0.05). In diabetics, KD correlated negatively with blood glucose (r = 0.762, p less than 0.05) indicating an increased sensitivity to cortisol at high blood glucose levels. In 6 of the diabetics and 7 of the control group, a simultaneous insulin receptor study was carried out. However, glucocorticoid receptor binding characteristics did not correlate with insulin receptor binding characteristics or with HbA1c. In conclusion, no major abnormalities in glucocorticoid receptor binding characteristics could be demonstrated in Type 1 diabetes mellitus.
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PMID:Glucocorticoid receptors in monocytes in type 1 diabetes mellitus. 269 Nov 20

Diabetes mellitus is a clinically heterogeneous disorder which is characterized by hyperglycaemia due to an absolute or relative deficiency of insulin. Both genetic and non-genetic factors contribute to its development and, as such, it represents a multifactorial disorder. In addition, it may also be, in some instances, a polygenic disorder resulting from the cumulative effects of several genes with or without environmental factors. Serological and/or DNA markers for genes that confer susceptibility to the insulin-dependent form of the disorder (IDDM; type 1) have been identified in the HLA-D region of chromosome 6 and near the insulin gene on chromosome 11. Patients with non-insulin-dependent diabetes mellitus (NIDDM; type 2) make up a more heterogeneous group than those with IDDM and it is likely that in these patients similar clinical phenotypes may be produced by different genetic defects. The synthesis of either an abnormal insulin/proinsulin molecule or an abnormal insulin receptor can confer susceptibility to NIDDM. The genes encoding insulin and the insulin receptor are on chromosomes 11 and 19, respectively. In addition, studies of restriction fragment length polymorphism and disease associations suggest that two other genes may contribute to the development of NIDDM on chromosome 11, one near the insulin gene on the short arm of this chromosome and the other near the apolipoprotein A-I gene on the long arm. None of the susceptibility genes that have been identified to date causes diabetes in the absence of other genetic or non-genetic contributing factors, which is consistent with a multifactorial or polygenic origin for this disorder.
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PMID:The molecular genetics of diabetes mellitus. 289 28

DNA variation related to the insulin receptor gene was studied with the restriction endonucleases Sst 1 and Bgl II. These identified 4 alleles, termed S1 (5.3 kilobases), S2 (5.8 kilobases), B1 (23.4 kilobases) and B2 (20.0 kilobases). Random association between these two insulin receptor polymorphisms was found in all of the study groups. The frequencies of genotypes possessing the S2 allele in Caucasian controls (n = 54), race matched non-insulin dependent diabetics (n = 56) and insulin dependent diabetics (n = 34) were 0.06, 0.18 and 0.04 respectively (p less than 0.01 for NIDDM versus IDDM or controls by chi-squared test). There were no significant differences in frequencies of genotypes with the B1 or B2 alleles amongst these three groups. The S2 allele or adjacent loci may provide a useful genetic marker for NIDDM.
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PMID:Genetic variants of the insulin receptor in type II (non-insulin dependent) diabetes mellitus. 290 93

Sera from 80 subjects with IDDM and NIDDM, together with sera from 20 patients with miscellaneous autoimmune conditions and 20 healthy adult subjects were tested for insulin receptor antibodies by (1) inhibition of 125I-insulin binding to EBV-transformed lymphoid cells, and by (2) immunoprecipitation of solubilized insulin receptors in the presence of an excess of mono-specific anti-human IgG or IgM; this test allowed the assessment of the class of antibody activity. Anti-insulin antibodies in the sera were also measured using a double antibody technique. Anti-insulin receptor antibodies were found in 13 of 33 subjects with IDDM and six of 47 with NIDDM. These were principally in the IgM class, and in both groups of diabetics there was a good correlation between % inhibition of insulin binding to intact cells, and % of antibody precipitated by IgM (P less than 0.001), but not by IgG (P greater than 0.1). There was also a good correlation between the % inhibition of insulin binding to intact cells and the daily dose of insulin used in treatment (P less than 0.001). Insulin antibodies were found in seven of 33 subjects with IDDM and six of 12 with NIDDM, all of whom were on insulin treatment. These six subjects were the only ones with NIDDM who also had anti-insulin receptor antibody activity, suggesting that such antibodies may represent auto-anti-idiotype activity. This study shows that autoimmunity in insulin dependent (Type I) diabetes is not limited to islet cells and that such patients also develop antibodies to the insulin receptor. While three out of five patients with relative insulin resistance (requirement greater than 90 u/day) also showed evidence of insulin receptor antibody activity, the clinical significance of these antibodies has yet to be determined.
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PMID:Insulin receptor antibodies in diabetes mellitus. 328 Jan 81

Susceptibility to IDDM is linked to the HLA-D locus on the short arm of chromosome 6, a region believed to be involved in the process of communication between cells which determines immune responses. Presumably an HLA molecule encoded by this region, unable to present a particular antigenic pathogen to the immune system, is inherited. The HLA-DR locus is quite complex, however. The gene which codes for this defective molecule may be identified by a combination of use of monoclonal antibodies and cloned gene probes which specifically hybridize to various portions of this region. Investigators are searching for HLA-DR4 containing chromosomes in IDDM which show similar patterns of restriction enzyme polymorphism. Hopefully, complete structural analysis of these related sequences will provide information about the mechanisms which confer susceptibility to develop IDDM. A strong genetic component is involved in NIDDM evidenced by a high concordance in monozygotic twins. Nevertheless, there is much evidence of genetic heterogeneity. At the present time no clear cut genetic marker has been defined. The human insulin gene has been cloned and by Southern blot hybridization analysis of peripheral leukocyte DNA, the insulin gene locus is being evaluated as a possible contributor to the genetic defect. Population studies at the present time have not identified any particular polymorphic insulin allele associated with NIDDM. Population studies are complicated by heterogeneity of NIDDM, racial and ethnic differences, and heterogeneity of insulin alleles. Linkage analysis in family studies will provide an alternative approach to population studies to determine what role if any the insulin gene plays in the genetic component of this disease. Because NIDDM is heterogeneous and perhaps polygenic in nature, these linkage analyses in families with NIDDM can be extended to other genes when they are cloned such as that coding for the insulin receptor. The familial aggregation of diabetes has long been noted (see ref. 1 for review). In relatives of diabetics, the prevalence ranges from 10-30%, while it is variously estimated to be between 0.1-3% in the general population. But familial aggregation of a trait may be caused either by genetic or environmental factors. One approach to dissecting the contribution of these factors is the study of concordance in twins. Pyke and associates observed that overall identical twins always show a higher concordance rate than dizygotic twins, irrespective of their age of diagnosis. Furthermore, they noted that identical twins of younger onset are often discordant for diabetes while identical twins of older onset are usually concordant.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The genetics of type I and type II diabetes: analysis by recombinant DNA methodology. 389 68

Studies on erythrocyte insulin receptors were performed in a boy with type I diabetes mellitus and superimposed adrenocortical insufficiency before and during treatment with hydrocortisone and 9-alpha-fluorohydrocortisone. The development of the adrenal insufficiency was associated with a progressively increased sensitivity to insulin which reverted after therapy. The maximum specific insulin binding of the erythrocytes was low during threatening addisonian crisis (6.9%) but normalized during hydrocortisone treatment (12.0%). These findings suggest that the increased insulin sensitivity characteristic for adrenocortical insufficiency is not an effect of an increased insulin receptor concentration and that hypocortisolaemia is associated with a down-regulation of the insulin receptors.
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PMID:Erythrocyte insulin receptors and insulin sensitivity in adrenocortical insufficiency. Report of a case of diabetes mellitus type I with superimposed Addison's disease. 633 70


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