Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The relationship between T-lymphocyte activation and residual beta-cell function was studied in 19 newly diagnosed Type I (insulin dependent) diabetic patients, aged 6-43 years, 7-10 days after beginning insulin therapy and once normoglycemia had been achieved. Residual beta-cell function was studied by measurement of plasma C-peptide concentration 6 minutes after intravenous glucagon administration. T-lymphocyte activation markers, HLA-DR/CD3 and interleukin-2 receptor (Tac) expression, were measured in peripheral blood mononuclear cells by dual- or single-colour flow cytometry. Six patients showed increased percentages of activated T lymphocytes (increased HLA-DR positivity in four patients, and an excess of Tac-positive cells in two). The mean percentage of activated T lymphocytes was higher in patients with stimulated C-peptide levels below 300 pmol/l (8.32 +/- 1.32%) than in those with plasma stimulated C-peptide above 300 pmol/l (3.93 +/- 0.49%), P less than 0.01, or controls (3.48 +/- 0.60%), P less than 0.01. Furthermore, the six patients with increased percentages of activated T lymphocytes were in the low stimulated C-peptide group. A negative correlation was found between the percentage of activated T lymphocytes and glucagon-stimulated C-peptide (r = -0.5877, P less than 0.01). We conclude that increased T-lymphocyte activation is associated with a higher impairment of beta-cell function at the onset of Type I diabetes mellitus.
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PMID:Activated T-lymphocytes in newly diagnosed type I diabetic patients: relationship to residual beta cell function. 214 47

A prospective, randomized, double-blind, placebo-controlled international multicenter trial including 188 newly diagnosed insulin-dependent diabetic (IDDM) patients was undertaken with the aim of investigating whether immunosuppression for one year with ciklosporin (Cs) could induce and maintain clinical remission and improvement of beta-cell function. The relative odds for non-insulin-requiring remission at one year were increased approximately five times in the Cs-treated group. After three months Cs-treated patients achieved more than a doubling of beta-cell function compared to baseline than did placebo-treated patients, and the Cs-treated group maintained this improvement in beta-cell function for 12 months, whereas the placebo-group lost beta-cell function during the same period. Short duration of disease (less than or equal to six weeks of symptoms, less than or equal to two weeks of insulin treatment) was associated positively with remission, as was an elevated proinsulin/C-peptide ratio, especially in patients with the tissue-type HLA-DR 3,4; 4,X and X,X. Cs-treatment inhibited the formation of antibodies against insulin and islet cell components, but islet cell antibody status at entry was not predictive of remission. Cs-treatment caused a reversible decrement of kidney function as measured with serum creatinine and the calculated creatinine clearance, but studies of renal physiology and kidney biopsies performed on a limited subset of patients indicated that Cs treatment in IDDM patients for one year induced a slight chronic nephropathy in some of these.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Immunosuppression with cyclosporin induces clinical remission and improved beta cell function in patients with newly diagnosed insulin-dependent diabetes. A national and international multicenter study]. 219 34

Analysis of the frequencies of class II HLA-DR and HLA-DQ alleles by serological and DNA typing in 49 Japanese patients with type 1 (insulin-dependent) diabetes and 31 Japanese controls indicates the following. (i) Susceptibility is more strongly associated with the HLA-DQ subregion than with the HLA-DR subregion. (ii) Of the class II alleles detected, the A3 allele of the DQA1 locus was the most strongly associated with disease. Ninety-six percent of the patients were positive for the A3 allele compared to 53% of the controls (P = 0.001; relative risk = 19.7; confidence limits = 3.72-188.64). (iii) The DQw8 allele of the DQB1 locus, which is associated with susceptibility to type 1 diabetes in Caucasians and Blacks, was not increased in frequency in Japanese patients (22%) versus controls (19%). (iv) Asp-57-encoding DQB1 alleles are associated with reduced susceptibility to type 1 diabetes in Caucasians. The major predisposing haplotypes in Japanese are DR4 and DR9. By DNA sequence analysis, both of these Japanese haplotypes have Asp-57-encoding DQB1 alleles. Oligonucleotide dot blot analysis showed that all, except 1, of the 49 Japanese patients and all of the 31 controls have at least one Asp-57-encoding DQB1 allele. In addition, 40% of the patients were homozygous for Asp-57-encoding DQB1 alleles versus 35% of the controls. The high frequencies of Asp-57-encoding DQB1 alleles in this ethnic group may account for the rarity of type 1 diabetes in Japan.
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PMID:The A3 allele of the HLA-DQA1 locus is associated with susceptibility to type 1 diabetes in Japanese. 230 May 72

In a large, representative sample of newly-diagnosed IDDM patients, using a highly sensitive assay to detect islet cell cytoplasmic antibodies (ICA), no marked differences were found between ICA+ and ICA- patients on various clinical, genetic, immunologic, and epidemiologic characteristics. In particular, there was no evidence for associations between ICA status at diagnosis and either sex, race, family history of IDDM, HLA-DR phenotype, antibody titers to Coxsackie B viruses, immunoglobulin levels, C-peptide and glycosylated hemoglobin concentrations, or insulin requirements. The most significant relationship was between the presence of ICA and a young age at diagnosis; however, the large overlap between the distributions of the ages at onset for ICA+ and ICA- groups on this variable suggests that this association is of limited importance. These data suggest that the presence or absence of ICA at diagnosis may not be useful in defining possible subtypes of IDDM.
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PMID:Analyses on possible heterogeneity of IDDM based on presence of islet cell cytoplasmic antibody at diagnosis. 249 97

INSULIN-dependent (type I) diabetes mellitus (IDDM) follows an autoimmune destruction of the insulin-producing beta-cells of the pancreas. Family and population studies indicate that predisposition is probably polygenic. At least one susceptibility gene lies within the major histocompatibility complex and is closely linked to the genes encoding the class II antigens, HLA-DR and HLA-DQ (refs 3, 4). Fine mapping of susceptibility genes by linkage analysis in families is not feasible because of infrequent recombination (linkage disequilibrium) between the DR and DQ genes. Recombination events in the past, however, have occurred and generated distinct DR-DQ haplotypes, whose frequencies vary between races. DNA sequencing and oligonucleotide dot-blot analysis of class II genes from two race-specific haplotypes indicate that susceptibility to IDDM is closely linked to the DQA1 locus and suggest that both the DQB1 (ref. 7) and DQA1 genes contribute to disease predisposition.
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PMID:Identification of susceptibility loci for insulin-dependent diabetes mellitus by trans-racial gene mapping. 249 58

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

We have investigated restriction fragment length polymorphism (RFLP) of HLA and non-HLA regions of the genome in the homogeneous Danish population. Insulin-dependent diabetes mellitus (IDDM) patients and healthy individuals were selected for being HLA-DR 3/4 heterozygous to evaluate the influence of genes other than DR on disease susceptibility. Five different probes were used: HLA alpha and beta DQ (chromosome 6), the Ins 310 genomic fragment which detects a polymorphic region 5' to the insulin gene (chromosome 11), and cDNA for the constant regions of the T cell receptor alpha and beta genes (chromosomes 14 and 7). Fifteen cells homozygous for the HLA-D region were used to obtain reference DNA patterns. This allowed us to describe four splits among the HLA-DQw3 haplotypes (DQw3.1 to DQw3.4). The two new haplotypes DQw3.3 and DQw3.4 do not code for the TA10 serological marker which is found on DQw3.1 positive cells. One-hundred per cent of IDDM patients were typed as DQw3.2 versus 68 per cent for controls (p = 0.003). However, our results do not indicate a role for the Ins 310 or for the alpha DX locus region in IDDM susceptibility, in contrast to previous reports by others. The restriction enzymes that we have used did not reveal significant differences between DNA patterns of patients and controls with probes for the constant region of the T cell receptor genes.
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PMID:Restriction fragment length polymorphism of HLA and non-HLA genes in DR3/4 heterozygous Danish insulin-dependent diabetic patients and healthy individuals: reassessment of the influence of alpha DX and insulin-linked polymorphic loci, and new splits of DQw3 haplotypes. 256 78

The relationship between glycemic control and complications of insulin-dependent diabetes mellitus (IDDM) remains controversial. With the use of glycosylated hemoglobin (HbA1) to assess glycemic control from diagnosis onward, the Pittsburgh Prospective Insulin-Dependent Diabetes Mellitus Cohort Study prospectively evaluated 80 new cases of IDDM diagnosed at Children's Hospital of Pittsburgh. This study presents findings in 62 patients at 5 yr postdiagnosis. Only 7 patients, all girls, had any retinopathy (microaneurysms). These subjects had an elevated 5-yr mean HbA1 compared to those with no retinopathy (13.0 vs. 11.7%; P less than .05). Six female subjects who had an elevated albumin excretion rate (AER; greater than or equal to 20 micrograms/min) had a higher 5-yr mean HbA1 (13.3%) than the 26 subjects with AER less than 20 micrograms/min (11.8%; P less than .05). Current HbA1 was correlated with AER (r = +.36, P less than .05) and systolic blood pressure (r = +.49, P less than .01) in females. However, these associations were not observed in males. Positive correlations were found between HbA1 (5-yr mean and current) and serum triglyceride and cholesterol, but only in females was HbA1 inversely related to high-density lipoprotein cholesterol. However, HbA1 was independent of sex, HLA-DR type, and urine C-peptide status. Age adjustment did not change the above results. These analyses suggest that glycemic control is related to AER, systolic blood pressure, presence of microaneurysms, and serum triglyceride and cholesterol concentrations during the first 5 yr of IDDM. However, these associations appear to be predominant in girls.
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PMID:Diabetes complications and glycemic control. The Pittsburgh Prospective Insulin-Dependent Diabetes Cohort Study Status Report after 5 yr of IDDM. 261 4

Thirty-six consecutive paediatric patients (0-16 years old) with recently contracted juvenile diabetes (IDDM) during 1982-84 were included in the study. Sera were assayed for recent or current Coxsackie B virus (CBV) infection using a specific and sensitive IgM RIA. Eighteen patients (50%) had IgM against CBV 1-5. The patients were also assayed for restriction fragment length polymorphism (RFLP) patterns with DNA probes coding for HLA-DR and DQ beta chains. The CBV-positive patients (n = 18) had either RFLP patterns associated with HLA-DR 3 or 4 or HLA-DQ patterns III or IV beta. Two of the CBV negative patients had neither HLA-DR 3 nor DR 4 and four of them had neither DQ patterns III nor IV. Eleven out of 18 CBV-positive patients had HLA-DQ III and DR 3 (61%) versus 5 out of 18 (28%) of the CBV-negative patients. All 11 patients with serology positive for CBV 2, 3, and 5 had HLA-DR 4 and DQ IV patterns. This was significantly (P less than 0.01) different from all five CBV 4-positive patients, who in contrast all had HLA-DR 3 or HLA-DQ III patterns. CBV 1-positive patients (n = 2) all had HLA-DR 3, 4, and HLA-DQ III, IV patterns. Thus CBV 4 seems to be significantly associated with a different host genetic constitution from at any rate CBV 2, 3, and 5, and possibly CBV 1.
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PMID:Matching of host genotype and serotypes of Coxsackie B virus in the development of juvenile diabetes. 288 88

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


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