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)

It is now recognized that it is casual exposure to sunlight that provides most humans with their vitamin D requirement. During exposure to sunlight, the high energy ultraviolet B photons (290-315 mm) photolyzes cutaneous stores of 7-dehydrocholesterol to previtamin D3. Once formed, previtamin D3 undergoes a thermal isomerization that results in the formation of vitamin D3. Vitamin D3 is biologically inert and requires successive hydroxylations in the liver and kidney to form its biologically active hormone 1,25-dihydroxyvitamin D3. The major physiologic function of 1,25-dihydroxy-vitamin D3 is to maintain blood calcium in the normal range. It accomplishes this by increasing the efficiency of intestinal calcium absorption and mobilizing stem cells to become osteoclasts which, in turn, remove calcium from the bone. It is now recognized that there are a variety of calcium metabolic disorders that are related to defects in the synthesis and metabolism of vitamin D. Chronic granulomatous disorders are often associated with hypercalciuria and hypercalcemia. The mechanism by which this occurs is that activated macrophages within granulomatous tissue, in an unregulated manner, convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Besides its calcemic activity 1,25-dihydroxyvitamin D3 is a potent antiproliferative factor for cells and tissues that possess its vitamin D receptor. This has clinical utility in that 1,25-dihydroxyvitamin D3 and its analogs have been successfully used for the treatment of the hyperproliferative skin disease psoriasis.
Exp Clin Endocrinol Diabetes 1995
PMID:Defects in the synthesis and metabolism of vitamin D. 758 27

Vitamin D has been discovered at the beginning of this century. 7-Dehydrocholesterol is converted to vitamin D3 in the skin and after several hydroxylations it is further converted to the active hormonal form, 1 alpha,25-(OH)2D3. Vitamin D stimulates the absorption of calcium and phosphate and is an essential link in bone resorption and formation and calcium metabolism. 1 alpha,25-(OH)2D3 acts through a vitamin D receptor. These receptors are not only present in clinical target organs (kidney, gut, liver) but can also be found in a wide variety of "non-classical" tissues (keratinocytes, cells belonging to the immune system). Moreover, numerous cells (keratinocytes, macrophages) can locally synthetize or can be induced to synthetize 1 alpha,25-(OH)2D3 and these cells are responsive to its action. When these data are combined, a possible paracrine function of 1 alpha,25-(OH)2D3 can be suspected. Via this paracrine function 1 alpha,25-(OH)2D3 can suppress the cellular and humoral immunity. Based on the discovery of these effects on immune cells in vitro it became clear that 1 alpha,25-(OH)2D3 might be an interesting molecule to prevent autoimmune diseases and organ transplantation. This has already been shown in several animal models (Heymann nephritis, diabetes mellitus, experimental allergic-encephalomyelitis, lupus). 1 alpha,25-(OH)2D3 demonstrates however some side-effects (hypercalciuria, hypercalcemia, bone resorption) and for this reason 1 alpha,25-(OH)2D3-analogs are developed with dissociated effects i.e. an activity profile that allows a specific action on non-classical tissues without calcemic effects. Some chemical modifications of the side chain, A and/or CD-ring results in "superanalogs" with 10 to 100-fold more activity on cell differentiation and the immune system then 1 alpha,25-(OH)2D3 but with less calcemic activity in vivo. These biological effects can be explained by differences in pharmacokinetics (low affinity for the plasma vitamin D-binding protein and short extracellular half-life) and increased intracellular activation and gen transactivation. Preclinical research must still be done to select the most potent superanalogs and to find the exact protocols for the prevention and treatment of autoimmune diseases and rejection of transplanted organs.
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PMID:[Immune modulation by vitamin D analogs in the prevention of autoimmune diseases]. 857 69

Polymorphisms at the vitamin D receptor (VDR) gene have been reported to mediate important differences in bone mineral density (BMD) and bone metabolism. In this longitudinal study we examined the relationships between VDR genotypes and bone metabolism, changes in BMD and changes in ultrasound transmission velocity in a population of healthy unrelated German women. The study population comprised 50 physically active women (aged 43.3 to 62.8 years, 14 premenopausal, 36 postmenopausal) with a daily calcium intake of (mean +/- SD) 1045 +/- 338 mg, who had earlier participated in a longitudinal study on the association of physical activity and bone density and bone turnover. Each participant was genotyped for the BsmI polymorphism at the VDR gene locus. Markers of bone turnover (alkaline phosphatase, osteocalcin, procollagen type I C-terminal propeptide, collagen type I C-terminal telopeptide, tartrate-resistant acid phosphatase) were measured at baseline. BMD (determined by peripheral quantitative computed tomography at the distal radius) and ultrasound transmission velocity through bone (at calcaneus, patella and thumb) were analysed at baseline and 15 months later. The genotypic groups did not differ significantly (p > 0.05) in any of the parameters determined at baseline. Neither were there any differences between these groups in the changes of BMD or ultrasound transmission velocity during the study period. Thus, we conclude that in physically active German women with a relatively high calcium intake the impact of VDR genotypic polymorphisms on bone density, bone metabolism and changes in bone density may be of limited importance.
Exp Clin Endocrinol Diabetes 1997
PMID:Vitamin D receptor genotypes and changes of bone density in physically active German women with high calcium intake. 913 41

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

Adynamic bone disease unrelated to aluminum deposition, with low parathyroid hormone (PTH) levels, has increased in patients with end-stage renal failure. Some patients present with severe secondary hyperparathyroidism despite calcitriol administration and phosphate restriction. Because therapeutic and environmental factors are now similar among hemodialyzed patients, the variable incidence of secondary hyperparathyroidism may be caused by genetic heterogeneity. To examine this possibility, we analyzed restriction fragment length polymorphisms of the vitamin D receptor (VDR) gene in 877 Japanese hemodialysis patients. VDR allelic polymorphism was determined by the method of Morrison et al. Polymerase chain reaction (PCR) amplification and a BsmI endonuclease restriction site at the 5' end of the VDR gene defined BB (absence of restriction site on both alleles), Bb (heterozygous), or bb (restriction site on both alleles). The mean serum PTH level was lower in BB patients (86 +/- 102 pg/mL) than in bb patients (148 +/- 217 pg/mL; P < 0.05). The serum osteocalcin level was also lower in BB than in bb patients (P < 0.05). If results were re-analyzed excluding patients with a history of dialysis exceeding 10 years or those with non-insulin-dependent diabetes mellitus (NIDDM) or who had undergone parathyroidectomy, the differences in serum PTH levels were greater. However, there was no significant difference in serum PTH levels among the VDR genotypes, only for patients with NIDDM. The present study shows that patients with the b allele for the VDR gene have more severe secondary hyperparathyroidism than patients without the b allele. However, NIDDM or a long history of hemodialysis has a stronger power to influence PTH secretion.
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PMID:Vitamin D receptor gene polymorphisms affect secondary hyperparathyroidism in hemodialyzed patients. 974 Jan 63

Patients with insulin-dependent diabetes mellitus (IDDM) are at higher risk of developing osteoporosis. Among the genetic factors related to the development of osteoporosis, a possible association between vitamin D receptor (VDR) gene polymorphism and bone mineral density (BMD) has been described in some populations. We characterized the VDR gene polymorphism in a healthy adult Brazilian population and in a group of patients with IDDM and correlated these findings with densitometric values in both groups. The Brazilian population is characterized by an important racial heterogeneity and therefore is considered an ethnically heterogeneous population. We recruited 94 healthy adult Brazilian volunteers (63 women and 31 men), mean (+/- SD) age 32.4 +/- 6.5 years (range 18-49 years), and 78 patients with IDDM (33 women and 45 men) diagnosed before 18 years of age, mean (+/- SD) age 23.3 +/- 5.5 years (range 18-39 years). VDR genotype was assessed by polymerase chain reaction amplification followed by BsmI digestion on DNA isolated from peripheral blood leukocytes. Statistical analysis included Bonferroni t-test to compare densitometric values within different genotypes in both groups and multiple regression analysis of bone density adjusted for potential confounding factors. The IDDM group had a lower BMD compared with the control group. The VDR genotype distribution in the control group was 43 Bb (45.7%), 39 bb (41.5%) and 12 BB (12.8%). This distribution did not differ from that observed in the IDDM group: 39 Bb (50%), 26 bb (33.3%) and 13 BB (16.7%). In the IDDM group, patients with the Bb genotype had a higher body weight when compared with the BB genotype (p = 0.02). However, when diabetic patients were controlled for age, sex and body mass index, BB genotype was associated with a lower mean BMD at lumbar spine and femoral neck than in Bb and bb patients. BB patients had a shorter duration of IDDM than bb and Bb patients. These findings suggest a small influence of VDR gene polymorphism on BMD of a racially heterogeneous population with IDDM.
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PMID:Vitamin D receptor gene polymorphism: correlation with bone mineral density in a Brazilian population with insulin-dependent diabetes mellitus. 979 3

We studied by PCR-RFLP 6 polymorphisms in these 5 candidate genes: Ala54Thr in the fatty acid binding protein 2 gene (FABP2), A to G substitution in the uncoupling protein type 1 gene (UCP1), Asp905Tyr in the protein phosphatase type 1 gene (PP1G), Trp64Arg in the human beta 3 adrenergic receptor gene (beta 3AR) and 2 RFLP sites of the vitamin D receptor (VDR) gene (VDRTaq1 and VDRApa1). This study was conducted among 89 cases and 100 controls matched according to age, gender and absence of first degree family link (11 triplets with 2 controls for 1 case and 78 pairs with 1 control for 1 case). Cases and controls were taken among a sample of 429 individuals selected for the study of the prevalence of diabetes in this ethnic group from Guadeloupe. By conditional logistic regression analysis, there was a significant relation (p = 0.02) between the Ala54Thr FABP2 polymorphism and Type 2 DM. Multivariate analysis discriminate the FABP2 polymorphism (p = 0.10), a triglyceridemia over 2 g/l (p < 10(-3)) and high blood pressure (p = 10(-2)) as variables associated with Type 2 DM in this population. These findings suggest that FABP2 does not represent a major gene for Type 2 DM in this migrant Indian population living in Guadeloupe, but seems to be related to the metabolic insulin resistance syndrome.
Diabetes Metab 1999 Jun
PMID:Type 2 diabetes mellitus: association study of five candidate genes in an Indian population of Guadeloupe, genetic contribution of FABP2 polymorphism. 1044 26

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.
Diabetes 2000 Mar
PMID:Vitamin D receptor allele combinations influence genetic susceptibility to type 1 diabetes in Germans. 1086 75

Recent studies have shown that related genetic influences on bone mineral density (BMD) and bone turnover are related to allelic variations in the vitamin D receptor (VDR) gene. Osteoporosis as a complication of hyperthyroidism is characterized by increased rates of both bone formation and bone resorption. In addition, VDR gene polymorphism influences susceptibility to some autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM) and multiple sclerosis (MS). In the gene encoding the VDR, we investigated the distribution of a VDR-FokI polymorphism that changes the predicted protein sequence. The subjects were 131 female Japanese patients with Graves' disease and 150 female controls. The distribution of genotype frequencies differs between Graves' disease and controls (chi2 = 5.99, degrees of freedom = 2, p = 0.0386). We found overexpression of F allele (69% vs. 61%, p = 0.0472) and homozygote FF (48% vs. 33%, p = 0.0118) in Graves' disease patients compared with controls. We also correlated a VDR-FokI polymorphism with BMD in the distal radius and biochemical markers of bone turnover in patients with Graves' disease in remission. Although generally no significant association was seen between age-adjusted BMD and genotype, patients in remission for >5 years showed significantly lower age-adjusted BMD in Ff heterozygotes than in ff homozygotes (Z = 1.14 ff vs. Z = -0.43 Ff, p < 0.05). Moreover, serum concentrations of bone alkaline phosphatase were significantly greater in Ff homozygotes than in FF homozygotes (78 +/- 12 vs. 59 +/- 10, p < 0.05). The genotypes did not differ in serum concentrations of osteocalcin, urinary hydroxyproline, or urinary deoxypyridinoline. Our results indicate, for the first time, an association between Graves' disease and a VDR polymorphism in the Japanese and suggest that a VDR-FokI polymorphism may affect bone mineral metabolism and can predict risk of osteoporosis as a complication of Graves' disease in patients in remission.
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PMID:Vitamin D receptor initiation codon polymorphism in Japanese patients with Graves' disease. 1088 83

Recent studies have shown that related genetic influences on bone mineral density (BMD) and bone turnover are related to allelic variations in the vitamin D receptor (VDR) gene. Osteoporosis as a complication of hyperthyroidism is characterized by increased rates of both bone formation and bone resorption. In addition, VDR gene polymorphism influences susceptibility to some autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM) and multiple sclerosis (MS). In the gene encoding the VDR, we investigated the distribution of a VDR-FokI polymorphism that changes the predicted protein sequence. The subjects were 131 female Japanese patients with Graves' disease and 150 female controls. The distribution of genotype frequencies differs between Graves' disease and controls (chi2 = 5.99, degrees of freedom = 2, p = 0.0386). We found overexpression of F allele (69% vs. 61%, p = 0.0472) and homozygote FF (48% vs. 33%, p = 0.0118) in Graves' disease patients compared with controls. We also correlated a VDR-FokI polymorphism with BMD in the distal radius and biochemical markers of bone turnover in patients with Graves' disease in remission. Although generally, no significant association was seen between age-adjusted BMD and genotype, patients in remission for fewer than 5 years showed significantly lower age-adjusted BMD in Ff heterozygotes than in ff homozygotes (z = 1.14 ff vs. z = -0.43 Ff, p < 0.05). Moreover, serum concentrations of bone alkaline phosphatase were significantly greater in Ff homozygotes than in FF homozygotes (78 +/- 12 vs. 59 +/- 10, p < 0.05). The genotypes did not differ in serum concentrations of osteocalcin, urinary hydroxyproline, or urinary deoxypyridinoline. Our results indicate, for the first time, an association between Graves' disease and a VDR polymorphism in the Japanese and suggest that a VDR-FokI polymorphism may affect bone mineral metabolism and can predict risk of osteoporosis as a complication of Graves' disease in patients in remission.
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PMID:Vitamin D receptor initiation codon polymorphism in Japanese patients with Graves' disease. 1090 90


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