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)

Islet cell autoantigen (ICA) 512 of type I diabetes is a receptor tyrosine phosphatase-like protein associated with the secretory granules of neurons and endocrine cells including insulin-secreting beta-cells of the pancreas. Here we show that in a yeast two-hybrid assay its cytoplasmic domain binds beta2-syntrophin, a modular adapter which in muscle cells interacts with members of the dystrophin family including utrophin, as well as the signaling molecule neuronal nitric oxide synthase (nNOS). The cDNA isolated by two-hybrid screening corresponded to a novel beta2-syntrophin isoform with a predicted molecular mass of 28 kDa. This isoform included the PDZ domain, but not the C-terminal region, which in full-length beta2-syntrophin is responsible for binding dystrophin-related proteins. In vitro binding of the beta2-syntrophin PDZ domain to ICA512 required both ICA512's C-terminal region and an internal polypeptide preceding its tyrosine phosphatase-like domain. Immunomicroscopy and co-immunoprecipitations from insulinoma INS-1 cells confirmed the occurrence of ICA512-beta2-syntrophin complexes in vivo. ICA512 also interacted in vitro with the PDZ domain of nNOS and ICA512-nNOS complexes were co-immunoprecipitated from INS-1 cells. Finally, we show that INS-1 cells, like muscle cells, contain beta2-syntrophin-utrophin oligomers. Thus, we propose that ICA512, through beta2-syntrophin and nNOS, links secretory granules with the actin cytoskeleton and signaling pathways involving nitric oxide.
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PMID:The receptor tyrosine phosphatase-like protein ICA512 binds the PDZ domains of beta2-syntrophin and nNOS in pancreatic beta-cells. 1104 3

We report a case of long-term (>4 yr) successful intrahepatic islet transplantation into a type 1 diabetic patient chronically immunosuppressed for a prior kidney graft. The exogenous insulin requirement decreased progressively after transplantation, and insulin treatment was withdrawn at 6 months. Glycosylated hemoglobin levels were in the normal range at 1 and 2 yr (5.3%) and increased slightly above the upper normal limit at 3 and 4 yr (6.3% and 6.4%). Fasting C peptide levels remained stable during the entire follow-up, but the proinsulin to insulin ratios increased dramatically at yr 3. Glycemic levels after an oral glucose tolerance test showed a diabetic profile at 1 yr, a normal profile at 2 yr, and an impaired glucose tolerance profile at 3 yr. Intravenous glucose tolerance test-induced first phase insulin release, present at 1 and 2 yr, disappeared at 3 yr. Diabetes-related autoantibodies (islet cell antibodies, glutamic acid decarboxylase antibodies, and tyrosine phosphatase-like protein antibodies) were undetectable before transplantation and remained so during the entire follow-up. The patient died of myocardial infarction 50 months after transplantation while she was still in good metabolic control (glycosylated hemoglobin, <6.8%) in the absence of exogenous insulin administration. The autoptic liver showed well granulated islets, richly vascularized and without evidence of lympho-mononuclear cell infiltration. The morphometrically extrapolated intrahepatic beta-cell mass was 99.9 mg. In conclusion, this successful islet graft showed a bell-shaped clinical effect, maximal at 2 yr after transplantation, followed by a slow progressive decline. The absence of allo- and autoreactivities against the transplanted islets points to a nonimmune-mediated beta-cell loss as the cause of graft functional deterioration.
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PMID:Insights from a successful case of intrahepatic islet transplantation into a type 1 diabetic patient. 1106 48

IA-2, a member of the tyrosine phosphatase family, has been identified as a dominant autoantigen in type 1 diabetes. To define humoral IA-2 epitopes, we generated a panel of IA-2 deletion mutants and chimeric proteins using the highly homologous tyrosine phosphatase-like protein IA-2beta. Analysis of autoantibody reactivity in 111 IA-2 antibody positive sera from patients with type 1 diabetes revealed that humoral epitopes cluster to several domains of the intracytoplasmic part of IA-2 [IA-2ic, amino acid (aa) 604-979]. Immunodominant epitopes were found in the first N-terminal 73 amino acids (56% positive), in the middle domain residing between residues 699-874 (45% positive) and the C-terminus depending on the presence of aa 931-979 (at least 37% positive). Competition experiments with overlapping peptides revealed that autoantibody binding towards the N-terminus was dependent on residues 621-628. In the C-terminal domain, two novel conformation-dependent epitopes were identified. The first epitope requires the presence of the C-terminal part of IA-2 (aa 933-979) and an IA-2-specific region between residues 771-932. Reactivity against the second epitope was dependent on intact C-terminal domains as well as residues in the middle (aa 887-932) and N-terminal regions (aa 604-771) which are conserved in IA-2 and IA-2beta. We here defined novel autoantigenic determinants in the N-terminus of IA-2 and characterized conformational epitopes residing in the C-terminal region or spanning from C-terminal residues to the N-terminal domain of IA-2ic. The identification of dominant target regions of diabetes-specific autoantibodies may help to elucidate the molecular mechanisms involved in the autoimmunity towards IA-2.
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PMID:Mapping of novel autoreactive epitopes of the diabetes-associated autoantigen IA-2. 1109 Dec 69

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by lack of functional products of the autoimmune regulator gene located on chromosome 21q22.3. The patients are at high risk of developing insulin-dependent (type 1) diabetes, but the positive predictive value of GAD65 or islet cell antibodies for type 1 diabetes is only 27%. Autoantibodies against the IA-2 tyrosine phosphatase-like protein (IA-2 ab) or insulin (IAA) have been suggested to be better markers for active ss-cell destruction. We studied these antibodies in sera from 60 Finnish patients with APECED, 12 of whom subsequently developed type 1 diabetes. Four (36%) of the 11 patients for whom we had prediabetic samples had IA-2 ab, and 4 (36%) had IAA. None of the 48 nondiabetics had IAA, and only 2 (4%) had IA-2 ab. Both had the antibodies for years without diabetes. Thus, IA-2 ab or IAA have a low sensitivity (36%), but high specificity (96% or 100%), with a positive predictive value of 67% for type 1 diabetes in patients with APECED. Data for human leukocyte antigen haplotypes were available for 59 of the patients, including 11 diabetics, and for 8 additional nondiabetic Finnish patients. No association between type 1 diabetes and high risk genotypes was seen. None of the 11 patients with type 1 diabetes, but 15 of the 56 (27%; P: < 0.05) nondiabetic patients and 24 of 93 (26%; P: < 0.05) of the control subjects had the DQB1*0602 allele, which is considered protective for type 1 diabetes. This is remarkable, as previously no positive or negative associations have been reported for any disease components of APECED with human leukocyte II antigens.
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PMID:ss-cell autoantibodies, human leukocyte antigen II alleles, and type 1 diabetes in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. 1113 89

This study presents a 2-yr follow-up of 281 patients, aged 15-34 yr, diagnosed with diabetes between 1992 and 1993. At diagnosis, 224 (80%) patients were positive for at least one of the following autoantibodies: islet cell antibodies (ICAs), glutamic acid decarboxylase antibodies (GADAs), or tyrosine phosphatase antibodies (IA-2As); the remaining 57 (20%) patients were negative for all three autoantibodies. At diagnosis, C-peptide levels were lower (0. 27; 0.16-0.40 nmol/L) in autoantibody-positive patients compared with autoantibody-negative patients (0.51; 0.28-0.78 nmol/L; P: < 0. 001). After 2 yr, C-peptide levels had decreased significantly in patients with autoimmune diabetes (0.20; 0.10-0.37 nmol/L; P: = 0. 0018), but not in autoantibody-negative patients. In patients with autoimmune diabetes, a low initial level of C-peptide (odds ratio, 2. 6; 95% confidence interval, 1.7-4.0) and a high level of GADAs (odds ratio, 2.5; 95% confidence interval, 1.1-5.7) were risk factors for a C-peptide level below the reference level of 0.25 nmol/L 2 yr after diagnosis. Body mass index had a significant effect in the multivariate analysis only when initial C-peptide was not considered. Factors such as age, gender, levels of ICA or IA-2A or insulin autoantibodies (analyzed in a subset of 180 patients) had no effect on the decrease in beta-cell function. It is concluded that the absence of pancreatic islet autoantibodies at diagnosis were highly predictive for a maintained beta-cell function during the 2 yr after diagnosis, whereas high levels of GADA indicated a course of decreased beta-cell function with low levels of C-peptide. In autoimmune diabetes, an initial low level of C-peptide was a strong risk factor for a decrease in beta-cell function and conversely high C-peptide levels were protective. Other factors such as age, gender, body mass index, levels of ICA, IA-2A or IAA had no prognostic importance.
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PMID:Prognostic factors for the course of beta cell function in autoimmune diabetes. 1113 17

Insulin receptor substrate (IRS)-1 protein expression is markedly reduced in many insulin-resistant states, although the mechanism for this downregulation is unclear. In this study, we have investigated the early events in the insulin pathway that trigger the degradation of IRS-1. Incubation of the adipocytes with insulin induced a fast electrophoretic mobility shift of IRS-1 and a subsequent degradation of the protein. Wortmannin and rapamycin blocked this mobility shift of IRS-1, maintained the insulin-induced tyrosine phosphorylation of IRS-1, and blocked its degradation. In contrast, a glycogen synthase kinase 3 inhibitor, a mitogen-activated protein kinase/extracellular-regulated kinase inhibitor, and various protein kinase C inhibitors had no effect. Incubation with okadaic acid increased the serine/threonine phosphorylation of IRS-1 and its degradation, mimicking insulin, and its effect was prevented by the proteasome inhibitor lactacystin, as well as by rapamycin. Treatment of the cells with the tyrosine phosphatase inhibitor orthovanadate in the presence of insulin or okadaic acid partially inhibited the degradation of IRS-1. We propose that a rapamycin-dependent pathway participates as a negative regulator of IRS-1, increasing its serine/threonine phosphorylation, which triggers degradation. Thus, regulation of serine/threonine versus tyrosine phosphorylation may modulate IRS-1 degradation, affecting insulin sensitivity.
Diabetes 2001 Jan
PMID:Serine/threonine phosphorylation of IRS-1 triggers its degradation: possible regulation by tyrosine phosphorylation. 1114 90

An increased prevalence of hepatitis C virus (HCV) infection in patients with diabetes and a higher prevalence of diabetes in HCV-infected patients have been reported. However, the relationship between these two conditions remains controversial. In addition, although the effect of interferon treatment on thyroid autoimmunity has been extensively reported, its influence on beta-cell autoantibodies has not been investigated. The aims of the study were (1) to evaluate whether autoimmune beta-cell damage could be involved in the development of diabetes mellitus in HCV-infected patients and (2) to determine whether interferon treatment influences the appearance of beta-cell and thyroid autoantibodies. The prevalence of islet cell autoantibodies (glutamic acid decarboxylase antibodies [GADAs], tyrosine phosphatase antibodies [IA-2s], islet cell antibodies [ICAs]) was assessed in 303 non-selected HCV-infected patients (277 non-diabetic and 26 type 2 diabetic patients) and in 273 sex- and age-matched control subjects. ICAs and thyroid autoantibodies were also determined before and 6 and 12 months after treatment with interferon for 24 weeks in a subgroup of 46 HCV-infected patients. GADAs were detected in 4 of 277 (1.4%) HCV-infected non-diabetic patients, 1 of 273 (0.3%) control subjects, and 0 of 26 (0%) HCV-infected patients with diabetes. Anti-IA2s and ICAs were negative in all subjects. Both GADAs and anti-IA2s were negative in all HCV-infected patients treated with interferon. After therapy, only thyroid antibodies became positive in 5 of 46 (10.9%) treated patients, disappearing in all but 1 of these at the 12-month follow-up. Our results suggest that beta-cell autoimmunity is not associated with HCV infection, thus making it unlikely that the increased diabetes mellitus prevalence among HCV-infected patients could be mediated by autoimmune mechanisms. In addition, interferon treatment induces a transient increase in thyroid autoantibodies but does not influence the appearance of beta-cell autoantibodies.
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PMID:Islet cell and thyroid antibody prevalence in patients with hepatitis C virus infection: effect of treatment with interferon. 1115 22

Type 1 diabetes mellitus is an autoimmune disease in which the presence of different autoantigens can often be found. The aim of our study was to evaluate the prevalence of antibodies against insulin (IA) and autoantibodies against glutamic acid decarboxylase (anti-GAD), tyrosine phosphatase IA-2 (anti-IA-2), thyroid microsomal peroxidase (anti-TPO) and thyroglobulin (anti-TG) in 55 randomly selected Type 1 diabetic patients (34 males, 21 females). Mean age of these patients was 39 +/- 12 yrs, mean duration of diabetes 18 +/- 13 yrs. Positivity of anti-GAD was found in 29 (58%) patients, anti-IA-2 in 13 (25%) patients, IA in 46 (85%) patients, anti-TPO in 10 (21%) and anti-TG in 11 (23%) patients. Simultaneous positivity of thyroid and islet autoantibodies was found in 6 (11%) patients whereas the positivity at least one of them was in 38 (69%) patients. No relationship between glycated hemoglobin and autoantibody concentration was found in the whole group of patients. The autoimmune thyroid disease was newly detected in 4 patients from high concentration of thyroid autoantibodies together with impaired TSH and T4 values and ultrasonography finding. No clinical evidence of thyroid disease was previously found in these patients. Positivity of anti-GAD or anti-IA-2 was found in almost 65% and of any thyroid autoantibody in almost 30% of our patients. Four patients with autoimmune thyroid disease were newly identified. We conclude that the evaluation of thyroid autoantibodies in Type 1 diabetic patients may improve the diagnosis of thyroid disease in very early stage and thus prevent consequent complications.
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PMID:The evaluation of thyroid and islet autoantibodies in type 1 diabetes mellitus. 1122 67

To explore the natural course of beta cell function in recent onset diabetes, a subgroup (n=157) of all incident cases (n=879) 15-34 years old, 1992-1993 in Sweden, and with positivity for at least one autoantibody of islet cell antibodies (ICA), glutamic acid decarboxylase antibodies (GADA) or tyrosine phosphatase antibodies (IA-2A) were followed prospectively for the first four years with annual analysis of C-peptide. The aim was to relate the course of beta cell function, measured as C-peptide, in early diabetes with the presence of different islet autoantibodies at diagnosis. We found that patients positive for ICA alone (n=11) had significantly higher C-peptide levels both at diagnosis and during the first three years compared with the other patients (n=146; p=0.022, p<0.001, p=0.004 and p=0.0022). Patients positive for GADA alone or in combination with other antibodies (n=125) had significantly lower C-peptide during the first three years after diagnosis compared with the other patients (n=32, p<0.001, p=0.0011 and p=0.0136). Patients with two or three autoantibodies had C-peptide levels similar to levels found in patients positive only for GADA. However, after four years, there were no significant differences between any of the groups of different autoantibody combinations. At diagnosis, 55% (86/157) of the patients had C-peptide levels above the lower normal range of 0.25 nmol/l, but the frequency of patients with beta cell function above this level decreased after two years to 41% (65/157; p=0.035) and after four years to 22% (35/157; p=0.0041). It is concluded that young adult diabetic patients positive only for ICA at diagnosis have a better preserved beta cell function with higher levels of C-peptide during the first three years compared with patients positive for GADA alone or in combinations with other autoantibodies.
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PMID:Combinations of beta cell specific autoantibodies at diagnosis of diabetes in young adults reflects different courses of beta cell damage. 1126 90

Type 1 diabetes results from the autoimmune destruction of pancreatic beta-cells in genetically susceptible individuals. Growing evidence suggests that genetically determined variation in the expression of self-antigens in thymus may affect the shaping of the T-cell repertoire and susceptibility to autoimmunity. For example, both allelic variation and parent-of-origin effects influence the thymic expression of insulin (a known type 1 diabetes autoantigen), and insulin gene transcription levels in thymus inversely correlate with susceptibility in both humans and transgenic models. It is unclear why patients lose tolerance to IA-2 (insulinoma-associated tyrosine phosphatase-like protein, or islet cell antigen 512 [ICA512]), especially because IA-2 polymorphisms are not associated with type 1 diabetes. We report that alternative splicing determines differential IA-2 expression in islets compared with thymus and spleen. Islets express full-length mRNA and two alternatively spliced transcripts, whereas thymus and spleen exclusively express an alternatively spliced transcript lacking exon 13. This encodes for the transmembrane (TM) and juxta-membrane (JM) domains that comprise several type 1 diabetes target epitopes, supporting the concept that tolerance to IA-2 epitopes not expressed in lymphoid organs may not be achieved. We propose differential splicing as a regulatory mechanism of gene expression playing a permissive role in the development of autoimmune responses to IA-2. Our findings also show that candidate gene expression studies can help in dissecting the complex genetic determinants of a multifactorial disease such as type 1 diabetes.
Diabetes 2001 Apr
PMID:Differential splicing of the IA-2 mRNA in pancreas and lymphoid organs as a permissive genetic mechanism for autoimmunity against the IA-2 type 1 diabetes autoantigen. 1128 59


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