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)

Our data confirms previous reports of intestinal and kidney compensatory growth, low plasma 1,25(OH)2D3 and up regulation of intestinal VDRs during untreated diabetes. All of these parameters were normalized in diabetic rats treated with exogenous insulin. There were no alterations in VDR numbers in kidneys or thymus of untreated diabetic animals, indicating that up-regulation of VDRs during untreated diabetes did not occur in all vitamin D target tissues. Compensatory growth of the intestine during untreated diabetes was associated with both hypertrophy and hyperplasia, whereas diabetic kidney growth appeared to be associated with hypertrophy without hyperplasia. Diabetes did not affect somatic index of thymus. The data suggests that the up regulation of VDRs during untreated diabetes may be unique to the intestine and further that VDR up regulation may be related to hyperplasia. Calbindin D-9K was significantly lower in diabetic intestine, suggesting that low circulating 1,25(OH)2D3 prevented amplification of 1,25(OH)2D3's action despite up regulation of intestinal VDRs.
Diabetes Res 1990 Dec
PMID:Vitamin D receptors in intestine, kidney and thymus of streptozotocin diabetic rats. 196 37

The physiological VDR ligand, 1 alpha,25-dihydroxyvitamin D3, acts upon a wide variety of tissues and cells, both related to and unrelated to calcium and phosphate homeostasis. The noncalcemic actions of natural and synthetic VDR ligands are exemplified by their potent anti-proliferative, prodifferentiative and immunomodulatory activities. As a result, a VDR ligand is an approved drug for the topical treatment of psoriasis. A plethora of actions of 1 alpha,25-dihydroxyvitamin D3 in various systems have suggested wide clinical applications of VDR ligands in such diverse disease states as inflammation (rheumatoid arthritis, psoriatic arthritis), dermatological indications (psoriasis, photoaging and skin rejuvenation), osteoporosis, cancers (breast, prostate, colon, leukemia and myelodysplastic syndrome) and autoimmune diseases (multiple sclerosis, type I diabetes and systemic lupus erythematosus). VDR ligands have shown therapeutic potential in limited human clinical trials as well as in animal models of these diseases. Some of the VDR ligands have shown not only potent preventive but also therapeutic anabolic activities in animal models of osteoporosis. However, the use of VDR in above mentioned indications as well as in oral therapy for psoriasis and even topical therapy for severe psoriasis is hampered by its associated toxicity, namely hypercalcemia. New VDR ligands have been synthesized which exhibit greater specificity by retaining desirable properties, but with reduced calcemic potential. The discovery of novel vitamin D3 analogs along with an increased understanding of the biological functions and mechanisms of action of VDR are likely to result in improved treatments for responsive indications.
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PMID:Vitamin D analogs: mechanism of action and therapeutic applications. 1156 85

Several studies suggested that part of the genetic susceptibility for Type 1 diabetes (T1DM) is encoded by some polymorphisms of CTLA-4 gene (2q33) and of Vitamin D Receptor gene (VDR; 12q12-14). Our aim was to assess their contribution to T1DM genetic susceptibility in the Romanian population. We typed CTLA-4 49 A/G and VDR FokI (F/f), ApaI (A/a) and TaqI (T/t) polymorphisms by Sequence Specific Primer PCR (SSP-PCR) in 204 Romanian diabetic families (756 individuals: 212 T1DM probands and 544 unaffected parents and siblings). We studied alleles transmission using the Transmission Disequilibrium Test (TDT). We found an increased transmission of CTLA-4 49G allele to diabetics (54.8%, p=0.11). The transmission of F (56.1%, p=0.063), a (55.7%, p=0.061) and T (51.8%, p=0.37) alleles of VDR gene to diabetics was increased but did not reach statistical significance. In conclusion we found the same increased transmission of CTLA-4 49 G allele to diabetics as previously reported. VDR FoqI F allele seems to be predisposing while TaqI T allele seems to be protective.
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PMID:The study of CTLA-4 and vitamin D receptor polymorphisms in the Romanian type 1 diabetes population. 1200 70

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 costimulatory 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 that 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 has also effects similar to 1,25(OH)(2)D(3) on DCs. Graft acceptance is associated with an increased percentage of CD4(+)CD25(+) regulatory cells in the spleen and in the draining lymph node that can protect 100% of syngeneic recipients from islet allograft rejection. CD4(+)CD25(+) cells, 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 1,25-dihydroxy-16,23Z-diene-26,27-hexafluoro-19-nor vitamin D(3) (BXL-698). 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 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 allograft rejection and autoimmune diseases. 1252 May 19

Chronic periodontitis (CP) is caused by enhanced resorption of the alveolar bone supporting the teeth and is associated with intraoral inflammation after infection with certain bacteria. The VDR gene polymorphism was reported recently to be deeply related to the occurrence of tuberculosis and infection of chronic hepatitis B virus. This may be interpreted to indicate a close relationship between VDR gene polymorphism and the immunological action, because vitamin D activates monocytes, stimulates cell-mediated immunity, and suppresses lymphocyte proliferation. The purpose of the present study was to clarify whether polymorphisms in VDR gene exons are associated with the incidence of CP. A case-controlled study was performed on a group of 168 unrelated Japanese subjects whose ages ranged from 35 to 65 years. The Taq I polymorphism in the VDR gene was found to be associated significantly with CP (X2=4.48, P=0.034). We performed multiple logistic regression analyses on the TT genotype, which was found to be associated with CP, and on well-recognized risk factors, smoking and diabetes. The odds ratio (OR) for the genotype (TT/Tt) was 2.73 (95% CI 1.11-6.68, P=0.028), being larger than the unadjusted value. This indicates that the VDR gene polymorphism (TT genotype) is a risk factor for CP, independently of smoking and diabetes.
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PMID:Vitamin D receptor gene polymorphism is associated with chronic periodontitis. 1457 74

Type 1 diabetes is an autoimmune disease with a complex polygenic inheritance. Until recently, only three susceptibility genes had been reproducibly identified, namely HLA, INS-VNTR, and CTLA4. During the past 7 years, a number of new putative susceptibility genes have been isolated from both human and animal models of the disease. We present eight genes implicated in type 1 diabetes etiology and discuss them in relation to the pathogenesis of the disease: VDR, IL6, IL12B, AIRE, FOXP3, B2m, Cblb, and Lyp/Ian4l1.
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PMID:New autoimmune genes and the pathogenesis of type 1 diabetes. 1503 74

We hypothesize that the peroxisome proliferator-activated receptor-gamma (PPARgamma) is associated with colorectal cancer given its association with insulin, diabetes, obesity, and inflammation. In this study, we evaluated the association between colorectal cancer and specific tumor mutations and the Pro12Ala (P12A) PPARgamma polymorphism. We also evaluated interactions between the PPARgamma gene and other insulin-related genes and use of aspirin and non-steroidal anti-inflammatory drug use. Data were available from 1,577 cases of colon cancer that were matched to 1,971 population-based controls and 794 cases of rectal cancer that were matched to 1,001 population-based controls. Colon tumors from the case subjects were evaluated for p53 and Ki-ras mutations and microsatellite instability (MSI). Insulin-related genes evaluated were the Bsm1, polyA, and Fok1 polymorphisms of the VDR gene; the G972R IRS1 polymorphism; the G1057D IRS2 polymorphism; the 19CA repeat polymorphism of the IGF1 gene; and the -200A>C IGFBP3 polymorphism. The odds ratio (OR) between the PA/AA genotypes and proximal tumors was 0.83 (95% CI: 0.69-1.01); for distal tumors was 1.00 (95% CI: 0.83-1.21); and for rectal tumors was 1.04 (95% CI: 0.86-1.25). Evaluation of specific types of tumor mutations showed that colon cancer cases with the PA or AA genotypes were less likely to have p53 tumor mutations (OR 0.78; 95% CI: 0.62-0.99), specifically transition mutations (OR 0.74; 95% CI: 0.56-0.97). Colon cancer cases also were less likely to have a tumor with MSI if they had the PA or AA PPARgamma genotype (OR 0.68; 95% CI: 0.47-0.98); differences in Ki-ras mutations were not seen in colon tumors by PPARgamma genotype. Those who did not take ibuprofen-type drugs and had the PA or AA genotypes were at a significantly greater risk of rectal cancer (OR 2.11; 95% CI: 1.52-2.92; p interaction 0.03) than people with the PP genotype regardless of ibuprofen-type drug use. There was a significant interaction between the -200A>C IGFBP3 polymorphism and the Pro12Ala PPARgamma polymorphism and risk of colon cancer (p for interaction = 0.02) with individuals being at significantly lower risk if they had both the CC IGFBP3 genotype and the PA/AA PPARgamma genotype. For rectal cancer there was a significant interaction between the Bsm1/polyA polymorphisms (p = 0.001) of the VDR gene and the PA/AA Pro12Ala PPARgamma polymorphism with the highest risk group being those with both the PA/AA Pro12Ala PPARgamma and the BB/SS VDR genotypes. These data suggest that PPARgamma may be associated with many aspects of colorectal cancer including insulin- and inflammation-related mechanisms.
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PMID:PPARgamma and colon and rectal cancer: associations with specific tumor mutations, aspirin, ibuprofen and insulin-related genes (United States). 1648 31

Type 2 diabetes mellitus (T2DM) is by far the most common type of diabetes and is characterized by insulin resistance and altered insulin secretion. Some genes, such as the vitamin D receptor gene (VDR, NM_001017535; GI: 7421), involved in its metabolic pathway have been regarded as good candidates for T2DM. In this study, we investigated whether there was an association of VDR: g.59979G>T or c.1025-49G>T (ApaIG>T) and g.60058T>C or c.1056T>C (TaqIT>C) polymorphisms in the 3' untranslated region of VDR with T2DM in a Turkish population. We collected blood samples from 241 individuals (72 patients with T2DM and 169 healthy individuals), and their DNA was isolated. Polymorphisms of the VDR were analyzed by DNA amplification with polymerase chain reaction and endonuclease digestion with ApaI and TaqI. Body mass index was higher in T2DM patients than in control individuals. However, the frequency of g.59979TT genotype in T2DM patients was not significantly increased compared to healthy subjects (37.5% vs. 36.1%, respectively). Although the VDR g.60058CC genotype in T2DM patients (19.4%) was higher than that in healthy individuals (11.2%), there was no significant difference. In the same way, there was no difference between the groups in allele frequencies. In conclusion, our study did not provide evidence for the association of two examined VDR polymorphisms with T2DM in a Turkish population.
J Diabetes Complications
PMID:Detection of VDR gene ApaI and TaqI polymorphisms in patients with type 2 diabetes mellitus using PCR-RFLP method in a Turkish population. 1918 74

Recent studies using genetically modified mice, such as FGF23-/- and Klotho-/- mice that exhibit altered mineral homeostasis due to a high vitamin D activity showed features of premature aging that include retarded growth, osteoporosis, atherosclerosis, ectopic calcification, immunological deficiency, skin and general organ atrophy, hypogonadism and short lifespan. The phenotype reversed by normalizing vitamin D and/or mineral homeostasis. Thus, hypervitaminosis D due to an increased 1alpha-hydroxylase activity seems to be a cause of the premature aging. In several studies, we have described that a complete or partial lack of vitamin D action (VDR-/- mice and CYP27B1-/-) show almost similar phenotype as FGF23-/- or Klotho-/- mice. VDR mutant mice have growth retardation, osteoporosis, kyphosis, skin thickening and wrinkling, alopecia, ectopic calcification, progressive loss of hearing and balance as well as short lifespan. CYP27B1-/- mice do not show alopecia nor balance deficit, which might be apoVDR-dependent or calcidiol-dependent. The features are typical to premature aging. The phenotype is resistant to a normalization of the mineral homeostasis by a rescue diet containing high calcium and phosphate. Taken together, aging shows a U-shaped dependency on hormonal forms of vitamin D suggesting that there is an optimal concentration of vitamin D in delaying aging phenomena. Our recent study shows that calcidiol is an active hormone. Since serum calcidiol but not calcitriol is fluctuating in physiological situations, calcidiol might determine the biological output of vitamin D action. Due to its high serum concentration and better uptake of calcidiol-DBP by the target cells through the cubilin-megalin system, calcidiol seems to be an important circulating hormone. Therefore, serum calcidiol might be associated with an increased risk of aging-related chronic diseases more directly than calcitriol. Aging and cancer seem to be tightly associated phenomena. Accumulation of damage on DNA and telomeres cause both aging and cancer, moreover the signalling pathways seem to converge on tumour suppressor protein, p53, which seems to be regulated by vitamin D. Also, the insulin-like growth factor signalling pathway (IGF-1, IGFBPs, IGFR) and fibroblast growth factor-23 (FGF-23) regulate growth, aging and cancer. Vitamin D can regulate these signalling pathways, too. Also NF-kappaB and telomerase reverse transcriptase (TERT) might be molecular mechanisms mediating vitamin D action in aging and cancer. Calcidiol serum concentrations show a U-shaped risk of prostate cancer suggesting an optimal serum concentration of 40-60 nmol/L for the lowest cancer risk. Therefore, it is necessary to study several common aging-associated diseases such as osteoporosis, hypertension and diabetes known to be vitamin D-dependent before any recommendations of an optimal serum concentration of calcidiol are given.
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PMID:Vitamin D and aging. 1944 37

Fair skin pigmentation has been associated with a higher risk of type 1 diabetes mellitus (T1DM). The aim is to compare children with T1DM directly to a sibling in relation to their skin pigmentation in sun-exposed and unexposed sites, past sun exposure and methylation of the VDR gene promoter. The sample consisted of children with T1DM attending a diabetes outpatient clinic and siblings (total n=42). Cutaneous melanin density was estimated using a spectrophotometer. Parental report on past sun exposure was obtained. DNA methylation analysis of the VDR gene promoter was conducted. Matched data analysis was performed comparing each case directly to their sibling. Cases were significantly more likely to have lighter skin pigmentation at the upper arm (AOR 0.69 [95% CI: 0.52, 0.90]; P=0.01). Low infant sun exposure was imprecisely associated with a two-fold increase in T1DM risk (AOR 2.43 [95% CI: 0.91, 6.51]; P=0.08 for under 1 h of winter sun exposure per leisure day). The VDR gene promoter was completely unmethylated in both cases and siblings. The previously demonstrated association between light skin pigmentation and T1DM risk was evident even in this comparison across sibling pairs. Further work on past UVR exposure and related factors such as skin pigmentation is required.
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PMID:A case-sibling assessment of the association between skin pigmentation and other vitamin D-related factors and type 1 diabetes mellitus. 1945 87


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