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)

Vitamin D has important immunomodulatory properties and prevents development of diabetes mellitus in an animal model of insulin-dependent diabetes (IDDM). We have studied the vitamin D receptor locus as a candidate for genetic susceptibility to IDDM in Southern Indian families. We found evidence for an association of one particular vitamin D receptor allele with IDDM susceptibility in this community. Ninety-three South Indian families consisting of available parents and an affected offspring were genotyped for three vitamin D receptor polymorphisms using the restriction enzymes TaqI, ApaI and BsmI as well as an adjacent microsatellite located to 12q14 (D12S85). Transmission disequilibrium testing analysis was used to assess preferential transmission of polymorphic markers and haplotypes with IDDM. There was significant excess transmission of vitamin D receptor alleles containing the BsmI restriction site to affected offspring in these families (p = 0.016). No association was found between D12S85 and IDDM. This study suggests that a polymorphism within or close to the vitamin D receptor gene may modify susceptibility to IDDM in this ethnic group.
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PMID:Allelic variation in the vitamin D receptor influences susceptibility to IDDM in Indian Asians. 926 94

Vitamin D has been shown to exert manifold immunomodulatory effects. Because type 1 diabetes is regarded to be immune-mediated and vitamin D prevents the development of diabetes in the NOD mouse, we investigated the role of the vitamin D receptor (VDR) gene as a candidate for type 1 diabetes susceptibility. A total of 152 Caucasian families with at least one affected offspring were genotyped for four VDR restriction-site polymorphisms (FokI, BsmI, ApaI, and TaqI). Whereas the BsmI, ApaI, and TaqI polymorphisms are in strong linkage disequilibrium with each other, no significant linkage disequilibrium with the FokI site was observed. Extended transmission disequilibrium testing (ETDT) was used to detect preferential transmission of allelic combinations to affected offspring. We found significant haplotype-wise ETDT results for the BsmI/ApaI/TaqI (chi2 = 18.886, df = 7, P = 0.0086), the BsmI/TaqI (chi2 = 8.373, df = 3, P = 0.0389), and theApaI/TaqI (chi2 = 17.182, df = 3, P = 0.0006) haplotypes. The "At" and "Bt" alleles confer an increased risk, whereas "AT" and "at" are protective. The combination with the strongest susceptibility was the "BAt" haplotype (64% transmitted, P = 0.0106). Analysis of the FokI site does not provide more information on susceptibility (FokI/BsmI/ApaI/TaqI [chi2 = 24.702, df = 15, P = 0.0541]). These findings suggest a linkage of VDR itself or a nearby gene with type 1 diabetes susceptibility in Germans, confirming respective observations previously made in Indian Asians.
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PMID:Vitamin D receptor allele combinations influence genetic susceptibility to type 1 diabetes in Germans. 1086 75

Associations have been reported between vitamin D receptor (VDR) gene polymorphisms, type 1 diabetes, insulin secretion, and the insulin resistance syndrome. As VDR polymorphisms have no known functional significance, these findings may implicate a variant of the VDR gene or a locus in linkage disequilibrium with the VDR. We have examined VDR mRNA and VDR protein levels in relation to VDR polymorphisms (41 Bangladeshi subjects) and analyzed insulin secretory capacity (143 Bangladeshi subjects), allowing for other known determinants. Peripheral blood mononuclear cells (PBMCs) from subjects who had been genotyped for BsmI, ApaI, TaqI, and FokI VDR restriction fragment length polymorphisms were used for both total VDR mRNA quantitation (using TaqMan) and measurement of VDR protein levels (using a specific micro-immunoassay). Stepwise multiple regression analyses were used (to P < 0.05) to analyze the data. For the insulin secretion index, the best-fit model (n = 143, P < 0.0001) gave age (P = 0.002), TaqI (P < 0.0001), and BMI (P = 0.001) as independent determinants; with the inclusion of VDR mRNA and VDR protein levels, VDR mRNA was the sole independent determinant (n = 41, P = 0.024). However, the best-fit model for VDR mRNA (P = 0.004) gave FokI (P = 0.044) and TaqI (P = 0.04) genotypes and insulin secretory capacity (P = 0.042) as independent determinants. For VDR protein levels, the best-fit model (P = 0.006) gave TaqI genotype (P = 0.005) and circulating 1,25-dihydroxyvitamin-D levels (P = 0.03) as independent determinants. In conclusion, these studies confirm an association between VDR polymorphisms and insulin secretory capacity and demonstrate the VDR genotype to be a significant determinant of VDR mRNA and VDR protein levels in PBMCs, providing functional support to previously described genetic associations with the VDR gene. Furthermore, VDR expression has been shown to be a determinant of insulin secretory capacity.
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PMID:Vitamin D receptor (VDR) mRNA and VDR protein levels in relation to vitamin D status, insulin secretory capacity, and VDR genotype in Bangladeshi Asians. 1208 63

Type 1 diabetic individuals are known to develop disorders of bone metabolism resulting in osteopenia. Previous studies have suggested an influence of vitamin D receptor alleles on bone metabolism and susceptibility for type 1 diabetes mellitus. The present study was initiated to investigate the distribution of vitamin D receptor alleles in Caucasian type 1 diabetic patients and their relation to bone turnover parameters. 75 patients were included and compared to 57 healthy controls. Three vitamin D receptor alleles were examined (BsmI, TaqI and FokI); serum levels of intact osteocalcin, parathyroid hormone, bone specific alkaline phosphatase, the carboxy terminal extension peptide of type I procollagen, 25-OH-vitamin D levels, HbA1c and urinary deoxypyridinoline excretion were measured. We observed a higher frequency of the TT genotype in diabetic patients, but no difference in markers of bone turnover between diabetics and non-diabetics in either sex. Bone turnover was different in men and in women without any association with vitamin D receptor genotype. No association was found between diabetes duration, age of onset or metabolic control and bone turnover parameters. In summary, our results show an association between the TT genotype and diabetes in Germans, but no difference in bone turnover markers between diabetics and non-diabetics.
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PMID:VDR gene polymorphisms are overrepresented in german patients with type 1 diabetes compared to healthy controls without effect on biochemical parameters of bone metabolism. 1217 74

Several studies have found a relationship between polymorphisms of the vitamin D receptor gene (VDR) and development of type 1 diabetes (T1DM). The meaning of this observation remains unclear and its relevance must be checked in different population samples. To examine the association of VDR polymorphisms and susceptibility to T1DM in the Dalmatian population of South Croatia we studied 134 individuals with type 1 diabetes and 132 control subjects. VDR genotyping was performed using PCR and BsmI, ApaI and TaqI restriction enzymes. Data were analysed using the chi(2)-test. The genotype combination which conferred strongest susceptibility to T1DM was BBAAtt (P=0.002). Interestingly, the BAt haplotype was found to be a risk factor in a German population, the only European population tested thus far. Our results indicate that VDR polymorphisms are associated with increased risk of T1DM in the Dalmatian population of South Croatia and warrant further studies.
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PMID:Vitamin D receptor polymorphism and susceptibility to type 1 diabetes in the Dalmatian population. 1248 39

Recent findings have indicated that calbindin-D(28k), the first known target of vitamin D action, is present in osteoblasts and protects against TNF and glucocorticoid induced apoptosis of osteoblastic cells. Cytokine mediated destruction of pancreatic beta cells, a cause of insulin dependent diabetes, is also inhibited by calbindin-D(28k). In calbindin-D(28k) transfected pancreatic beta cells free radical formation by cytokines is inhibited by calbindin. Thus, besides its role as a facilitator of calcium diffusion, calbindin has a major role in protecting against cellular degeneration in different cell types. Besides calbindin, the other known pronounced effect of 1,25(OH)(2)D(3) in intestine and kidney is increased synthesis of 25(OH)D(3) 24-hydroxylase (24(OH)ase) which is involved in the catabolism of 1,25(OH)(2)D(3). We have noted that CCAAT enhancer binding protein beta (C/EBPbeta) is induced by 1,25(OH)(2)D(3) in kidney and osteoblastic cells and can enhance the transcriptional response of 24(OH)ase to 1,25(OH)(2)D(3). These studies establish C/EBPbeta as a novel 1,25(OH)(2)D(3) target gene and indicate a role for C/EBPbeta in 24(OH)ase transcription. These studies extend our previous studies related to factors that affect vitamin D receptor (VDR) mediated 24(OH)ase transcription (YY1, TFIIB, CBP) and the effect of signaling pathways on 24(OH)ase transcription and cofactor recruitment.
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PMID:Vitamin D target proteins: function and regulation. 1252 May 21

Dendritic cells (DCs) not only induce but also modulate T cell activation. 1,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] induces DCs with a tolerogenic phenotype, characterized by decreased expression of CD40, CD80, and CD86 co-stimulatory molecules, low IL-12, and enhanced IL-10 secretion. We have found that a short treatment with 1,25-(OH)(2)D(3) induces tolerance to fully mismatched mouse islet allografts, and that this tolerance is stable to challenge with donor-type spleen cells and allows acceptance of donor-type vascularized heart grafts. This effect is enhanced by co-administration of mycophenolate mofetil (MMF), a selective inhibitor of T and B cell proliferation, that also has effects similar to 1,25-(OH)(2)D(3) on DCs. Graft acceptance is associated with impaired development of type 1 CD4(+) and CD8(+) cells and an increased percentage of CD4(+)CD25(+) regulatory cells expressing CD152 in the spleen and in the draining lymph node. Transfer of CD4(+)CD25(+) cells from tolerant mice protects 100% of the syngeneic recipients from islet allograft rejection. CD4(+)CD25(+) cells that are able to inhibit the T cell response to a pancreatic autoantigen and to significantly delay disease transfer by pathogenic CD4(+)CD25(-) cells are also induced by treatment of adult nonobese diabetic (NOD) mice with a selected vitamin D receptor (VDR) ligand. This treatment arrests progression of insulitis and Th1 cell infiltration, and inhibits diabetes development at non-hypercalcemic doses. The enhancement of CD4(+)CD25(+) regulatory T cells able to mediate transplantation tolerance and to arrest type 1 diabetes development by a short oral treatment with small organic compounds that induce tolerogenic DCs, like VDR ligands, suggests possible clinical applications of this approach.
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PMID:Tolerogenic dendritic cells induced by vitamin D receptor ligands enhance regulatory T cells inhibiting autoimmune diabetes. 1272 48

Type 1 diabetes mellitus is recognized as a T-cell-mediated autoimmune disease. Vitamin D compounds are known to suppress T-cell activation by binding to the vitamin D receptor (VDR); and thus, VDR gene polymorphisms may be related to T-cell-mediated autoimmune diseases. We, therefore, investigated a VDR gene polymorphism in type 1 diabetes. We examined the VDR gene Bsm I polymorphism in 203 type 1 diabetic patients and 222 controls, and the association between the VDR gene polymorphism and type 1 diabetes and their onset pattern. We found a significantly higher frequency of B allele in type 1 diabetics overall, compared with controls (P = 0.0010). Moreover, there was a significant difference in B-allele frequency between acute-onset type 1 diabetics and controls (P = 0.0002), whereas this difference was not observed between slow-onset type 1 diabetics and controls. Regardless of the existence of islet-associated autoantibody, we found a significant difference in B-allele frequency between acute-onset type 1 diabetics and controls. In conclusion, we found an association between a VDR gene polymorphism and acute-onset type 1 diabetes. Assessment of this VDR gene polymorphism may contribute to prediction of the onset pattern in individuals with a high risk of type 1 diabetes.
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PMID:Vitamin D receptor gene polymorphism affects onset pattern of type 1 diabetes. 1284 55

Genetic association with type 1 diabetes (T1D) has been established for two chromosomal regions: HLA DQ/DR (IDDM1) and INS VNTR (IDDM2). To identify additional genetic markers, we tested polymorphisms in regulatory regions of several cytokine and important metabolic genes. These polymorphisms exhibit functional consequences for expression and function. Functional genetic polymorphisms of proinflammatory (T-helper-1: IL-2, IL-12 and IFN-gamma), anti-inflammatory (T-helper-2: IL-4, IL-6 and IL-10) and metabolic (IGF-I, VDR and INS) genes were determined in 206 Dutch simplex families with juvenile onset T1D and the results were analysed using the transmission disequilibrium test. Significantly increased transmission to T1D probands was observed for the loci IDDM1, IDDM2 and the vitamin D receptor. Although none of the other individual polymorphisms was associated with disease individually, the combination of T-helper-2 and metabolic/growth alleles IL-10(*)R2, IL-4(*)C, VDR(*)C and IGF-I(*)wt was found to be transmitted more frequently than expected (67%, P(c)=0.015). We conclude that additional genetic predisposition to T1D is defined by combinations of markers (eg Th2 and metabolic) rather than by a single marker. The consequences of the increased transmission of a low Th2 expressing genotypes together with a normal Th1 profile may result in a net proinflammatory cytokine expression pattern.
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PMID:Functional genetic polymorphisms in cytokines and metabolic genes as additional genetic markers for susceptibility to develop type 1 diabetes. 1473 47

Several reports have found a relation between polymorphisms of the vitamin D receptor gene (VDR) and the development of type 1 diabetes. We have examined the association of three VDR polymorphism with type 1 diabetes in 59 Chilean case-parents trios. Genotyping for Bsm1, Apal and Taq1 polymorphism were performed. Transmission/ disequiibrium tests were used to assess gene-disease associations through the evaluation of allelic transmission to affected offspring. Non-significant increased transmissions of B allele (probability of transmission = 52.5%, p = 0.69), A allele (probability of transmission = 58.4%, p = 0.17) and T allele (probability of transmission = 52.0%, p = 0.77) were estimated in Bsml, Apal and Taql sites, respectively. Haplotype-based analyses showed non-significant preferential transmissions (global p = 0.52). The present study does not support the hypothesis of a significant contribution of VDR alleles in the etiology of type 1 diabetes of Chilean cases.
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PMID:Vitamin D receptor polymorphism and susceptibility to type 1 diabetes in Chilean subjects: a case-parent study. 1567 87


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