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)

Family history of type 1 diabetes and autoantibodies to the islet antigens insulin (IAA), glutamate decarboxylase (GADA), and the protein tyrosine phosphatase-like protein IA-2 (IA-2A) are strong predictors of type 1 diabetes, but the rate of progression to diabetes in multiple islet autoantibody-positive relatives varies widely. We asked whether detailed characterization of islet autoantibodies that included determination of titer, epitope specificity, and IgG subclass would improve diabetes prediction in a large cohort of autoantibody-positive relatives. The study shows a strong association between risk and high titer, broad antibody responses to IA-2 and insulin. The highest risks were associated with high-titer IA-2A and IAA, IgG2, IgG3, and/or IgG4 subclass of IA-2A and IAA, and antibodies to the IA-2-related molecule IA-2beta. Using models based on these antibody characteristics, autoantibody-positive relatives can be classified into groups with risks of diabetes ranging from 7 to 89% within 5 years.
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PMID:Stratification of type 1 diabetes risk on the basis of islet autoantibody characteristics. 1474 89

Insulinoma-associated protein (IA)-2beta, also known as phogrin, is an enzymatically inactive member of the transmembrane protein tyrosine phosphatase family and is located in dense-core secretory vesicles. In patients with type 1 diabetes, autoantibodies to IA-2beta appear years before the development of clinical disease. The genomic structure and function of IA-2beta, however, is not known. In the present study, we determined the genomic structure of IA-2beta and found that both human and mouse IA-2beta consist of 23 exons and span approximately 1,000 and 800 kb, respectively. With this information, we prepared a targeting construct and inactivated the mouse IA-2beta gene as demonstrated by lack of IA-2beta mRNA and protein expression. The IA-2beta(-/-) mice, in contrast to wild-type controls, showed mild glucose intolerance and impaired glucose-stimulated insulin secretion. Knockout of the IA-2beta gene in NOD mice, the most widely studied animal model for human type 1 diabetes, failed to prevent the development of cyclophosphamide-induced diabetes. We conclude that IA-2beta is involved in insulin secretion, but despite its importance as a major autoantigen in human type 1 diabetes, it is not required for the development of diabetes in NOD mice.
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PMID:Targeted disruption of the IA-2beta gene causes glucose intolerance and impairs insulin secretion but does not prevent the development of diabetes in NOD mice. 1522 Jan 91

Female infertility is a worldwide problem affecting 10-15% of the population. The cause of the infertility in many cases is not known. In the present report, we demonstrate that alterations in two transmembrane structural proteins, IA-2 and IA-2beta, located in dense core secretory vesicles (DCV) of many endocrine and neuroendocrine cells, can result in female infertility. IA-2 and IA-2beta are best known as major autoantigens in type 1 diabetes, but their normal function has remained an enigma. Recently we showed in mice that deletion of IA-2 and/or IA-2beta results in impaired insulin secretion and glucose intolerance. We now report that double knockout (DKO), but not single knockout, female mice are essentially infertile. Vaginal smears showed a totally abnormal estrous cycle, and examination of the ovaries revealed normal-appearing oocytes but the absence of corpora lutea. The LH surge that is required for ovulation occurred in wild-type mice but not in DKO mice. Additional studies showed that the LH level in the pituitary of DKO female mice was decreased compared with wild-type mice. Treatment of DKO females with gonadotropins restored corpora lutea formation. In contrast to DKO female mice, DKO male mice were fertile and LH levels in the serum and pituitary were within the normal range. From these studies we conclude that the DCV proteins, IA-2 and IA-2beta, play an important role in LH secretion and that alterations in structural proteins of DCV can result in female infertility.
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PMID:Disruption of the transmembrane dense core vesicle proteins IA-2 and IA-2beta causes female infertility. 1626 63

Ghrelin is a newly discovered peptide and an endogenous ligand for growth hormone (GH) secretagogue (GHS) receptor. It has been shown to possess various central and peripheral effects, including GH secretion, food intake, and gastric and cardiac effects. Ghrelin and the GHS receptor are expressed also in pancreatic islets. We have identified several ghrelin-induced genes by PCR-select subtraction methods, among which is a beta-cell autoantigen for type 1 diabetes, IA-2beta. Administration of ghrelin increased IA-2beta mRNA in mouse brain, pancreas, and insulinoma cell lines (MIN6 and betaTC3). However, the expression of IA-2, another structurally related beta-cell autoantigen, was not induced by ghrelin. Administration of ghrelin or overexpression of IA-2beta, but not overexpression of IA-2, inhibited glucose-stimulated insulin secretion in MIN6 insulinoma cells and, moreover, inhibition of IA-2beta expression by the RNA interference technique ameliorated ghrelin's inhibitory effects on glucose-stimulated insulin secretion. These findings strongly suggest that inhibitory effects of ghrelin on glucose-stimulated insulin secretion are at least partly due to increased expression of IA-2beta induced by ghrelin. Our data demonstrate the link among ghrelin, IA-2beta, and glucose-stimulated insulin secretion.
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PMID:IA-2beta, but not IA-2, is induced by ghrelin and inhibits glucose-stimulated insulin secretion. 1641 80

IA-2 and IA-2beta are highly related proteins that are autoantigens in type 1 diabetes, and provide a model for developing reagents and assays that distinguish similar proteins with unique autoantibody epitopes. Monoclonal antibodies (mAb) to IA-2 and IA-2beta were prepared and tested for their ability to bind to the related proteins and their ability to compete for specific autoantibody epitope binding by sera from patients with type 1 diabetes. Monoclonal antibodies that specifically bound IA-2 (76F) or bound both IA-2 and IA-2beta (A9) were isolated and characterized. 76F mAb recognized IA-2 of human, rat and mouse origin in native and denatured forms and had an epitope specificity for residues 626-630 (FEYQD) which are found in the juxtamembrane (JM) region of human and mouse IA-2, but not IA-2beta. This region overlaps with the autoantibody epitope JM2. Binding to the 76F monoclonal antibody was specifically inhibited by sera with antibodies to the JM2 epitope but not with antibodies to the adjacent JM1 epitope, indicating that unique epitopes can be distinguished by this approach. 76F mAb has the unique property to distinguish between the two closely related autoantigens IA-2 and IA-2beta by targeting an IA-2 specific epitope of the juxtamembrane region. The findings define an approach to develop assays for specific antibody epitope measurements which may be relevant for disease prognosis and monitoring intervention therapies.
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PMID:Monoclonal antibody 76F distinguishes IA-2 from IA-2beta and overlaps an autoantibody epitope. 1650 16

The natural history of preclinical diabetes is partly characterized, but there is still limited information on the dynamics of the immune response to beta-cell autoantigens during the course of preclinical disease. The aim of this work was to assess the maturation of the humoral immune response to the protein tyrosine phosphatase(PTP)-related proteins (IA-2 and IA-2beta) in preclinical type I diabetes (TID). Forty-five children participating in the Finnish Type I Diabetes Prediction and Prevention (DIPP) Study who had seroconverted to IA-2 antibody positivity were analysed. Specific radiobinding assays were used to determine IA-2/IA-2beta epitope-specific antibodies (the juxtamembrane (JM) region of IA-2, PTP-like domain and betaPTP-like domain) and isotype-specific IA-2 antibodies. Individual areas under the curve (AUC) over the observation period were calculated for total IA-2 antibodies, each isotype and specific epitope responses. The children who progressed to TID tended to have an initial IA-2 JM epitope response more frequently (P = 0.06), and this response was more often dominant during the observation period (P < 0.05). The children who did not progress to TID had IgE-IA-2 more frequently (70%; versus progressors 27%; P < 0.05), and had higher integrated titres of IgE-IA-2 antibodies (P < 0.05). The occurrence of IgE-IA-2 antibodies was protective even when combined with positivity for IA-2 JM antibodies (P = 0.002). IgE-IA-2 antibody reactivity may be a marker of a regulatory immune response providing protection against or delaying progression to TID among IA-2 antibody-positive young children with HLA-conferred disease susceptibility.
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PMID:IA-2 antibody isotypes and epitope specificity during the prediabetic process in children with HLA-conferred susceptibility to type I diabetes. 1654 66

Haemolytic-uraemic syndrome (HUS) is a rare cause of insulin-dependent diabetes mellitus during the acute stage. We previously reported the case of a 3-year-old girl having presented with typical HUS with diarrhea, microangiopathic anaemia, thrombocytopenia and acute renal failure (17 days of anuria). Transient hyperglycaemia (highest level: 513 mg/dl) was observed, requiring continuous intravenous insulin infusion for 9 days. Subcutaneous insulin injections were stopped after 24 days. Oral glucose tolerance test performed 4 months after normalization of blood glucose was normal. HLA DQ genotype (DQA1-DQB1.AZH/DQA3-DQB3.1) was not at risk for type 1 diabetes and there were no auto-antibodies (ICA and IAA). The 3-years follow-up was marked by persistent arterial hypertension, proteinuria and slight renal insufficiency despite angiotensin-converting enzyme inhibitor treatment. Ten years after HUS occurred (the patient had been lost to follow-up for 7 years), she came back with complaints of headache but neither polyurodipsia nor weight loss. She was found to have arterial hypertension. Chronic renal impairment had moderately progressed with decreased glomerular filtration rate (63 ml/min/1.73 m2) and proteinuria (2 g/24 hours). Fasting blood glucose was 189 mg/dl and reached 315 mg/dl during an oral glucose tolerance test. HbA1c level was 8.2% (N<6.2%) and diabetes mellitus was diagnosed without any signs of autoimmunity (IAA, ICA, GADA and IA2B were negative). Good glycaemic control was obtained with 0.5 U/kg/day of insulin. In conclusion, transient beta-cell dysfunction complicating HUS acute stage may evolve to overt non-autoimmune diabetes mellitus (microangiopathic process?), even after a long free interval. This case emphasizes the need for a long-term follow-up of patients with HUS.
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PMID:Insulin-dependent diabetes mellitus as long term complication of haemolytic-uraemic syndrome. 1679 6

Type 1 diabetes results from the autoimmune destruction of insulin-producing pancreatic beta-cells by cytotoxic T-lymphocytes (CTLs). In humans, few beta-cell epitopes have been reported, thereby limiting the study of beta-cell-specific CTLs in type 1 diabetes. To identify additional epitopes, HLA class I peptide affinity algorithms were used to identify a panel of peptides derived from the beta-cell proteins islet amyloid polypeptide (IAPP), islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), insulin, insulinoma-associated antigen 2 (IA-2), and phogrin that were predicted to bind HLA-A*0201. Peripheral blood mononuclear cells from 24 HLA-A*0201 recent-onset type 1 diabetic patients and 11 nondiabetic control subjects were evaluated for gamma-interferon secretion in response to peptide stimulation in enzyme-linked immunospot assays. We identified peptides IAPP9-17, IGRP215-223, IGRP152-160, islet IA-2(172-180), and IA-2(482-490) as novel HLA-A*0201-restricted T-cell epitopes in type 1 diabetic patients. Interestingly, we observed a strong inverse correlation between the binding affinity of beta-cell peptides to HLA-A*0201 and CTL responses against those peptides in recent-onset type 1 diabetic patients. In addition, we found that self-reactive CTLs with specificity for an insulin peptide are frequently present in healthy individuals. These data suggest that many beta-cell epitopes are recognized by CTLs in recent-onset type 1 diabetic patients. These epitopes may be important in the pathogenesis of type 1 diabetes.
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PMID:Recognition of HLA class I-restricted beta-cell epitopes in type 1 diabetes. 1706 44

Islet antigen-2 (IA-2 or ICA 512) and IA-2beta (or phogrin) are major autoantigens in type 1 diabetes. They are located in dense core secretory vesicles including insulin granules, but their role in beta-cell function is unclear. Targeted disruption of either IA-2 or IA-2beta, or both, impaired glucose tolerance, an effect attributed to diminution of insulin secretion. In this study, we therefore characterized the dynamic changes in cytosolic Ca2+([Ca2+](c)) and insulin secretion in islets from IA-2/IA-2beta double knockout (KO) mice. High glucose (15 mM) induced biphasic insulin secretion in IA-2/IA-2beta KO islets, with a similar first phase and smaller second phase compared with controls. Since the insulin content of IA-2/IA-2beta KO islets was approximately 45% less than that of controls, fractional insulin secretion (relative to content) was thus increased during first phase and unaffected during second phase. This peculiar response occurred in spite of a slightly smaller rise in [Ca2+](c), could not be attributed to an alteration of glucose metabolism (NADPH fluorescence) and also was observed with tolbutamide. The dual control of insulin secretion via the K(ATP) channel-dependent triggering pathway and K(ATP) channel-independent amplifying pathway was unaltered in IA-2/IA-2beta KO islets, and so were the potentiations by acetylcholine or cAMP (forskolin). Intriguingly, amino acids, in particular the cationic arginine and lysine, induced larger fractional insulin secretion in IA-2/IA-2beta KO than control islets. In conclusion, IA-2 and IA-2beta are dispensable for exocytosis of insulin granules, but are probably more important for cargo loading and/or stability of dense core vesicles.
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PMID:Insulin secretion in islets from mice with a double knockout for the dense core vesicle proteins islet antigen-2 (IA-2) and IA-2beta. 1831 Apr 53

IA-2 and IA-2beta, major autoantigens in type 1 diabetes, are transmembrane proteins in dense-core vesicles, and their expression influences the secretion of hormones and neurotransmitters. The present experiments were performed to examine whether IA-2 and IA-2beta modulate the release of renin from dense-core vesicles of juxtaglomerular granular cells in the kidney. Plasma renin concentration (PRC; ng angiotensin I.ml(-1).h(-1)) was significantly reduced in mice with null mutations in IA-2, IA-2beta, or both IA-2 and IA-2beta compared with wild-type mice (876 +/- 113, 962 +/- 130, and 596 +/- 82 vs. 1,367 +/- 93; P < 0.01, P < 0.02, and P < 0.001). Renin mRNA levels were reduced to 26.4 +/- 5.1, 39 +/- 5.4, and 35.3 +/- 5.5% of wild-type in IA-2-/-, IA-2beta-/-, and IA-2/IA-2beta-/- mice. Plasma aldosterone levels were not significantly different among genotypes. The regulation of PRC by furosemide and salt intake, and of aldosterone by salt intake, was maintained in all genotypes. IA-2 and IA-2beta expression did not colocalize with renin but showed overlapping immunoreactivity with tyrosine hydroxylase. While propranolol reduced PRC in wild-type mice, it had no effect on PRC in IA-2/ IA-2beta-/- mice. Renal tyrosine hydroxylase mRNA and immunoreactivity were reduced in IA-2/IA-2beta-/- mice as was the urinary excretion of catecholamines. We conclude that IA-2 and IA-2beta are required to maintain normal levels of renin expression and renin release, most likely by permitting normal rates of catecholamine release from sympathetic nerve terminals.
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PMID:Dense-core vesicle proteins IA-2 and IA-2{beta} affect renin synthesis and secretion through the {beta}-adrenergic pathway. 1901 14


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