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Biomedical subjects

Klaus Badenhoop

Publications and source records attributed to Klaus Badenhoop.

At least 19 recordsLinked to original sources
PubMed2007

CYP2R1-, CYP27B1- and CYP24-mRNA expression in German type 1 diabetes patients.

1,25(OH)(2)D(3) and 25(OH)D(3) have been associated with type 1 diabetes. Diverse enzymes are involved in the synthesis of these metabolites: the 25-Vitamin-D-hydroxylase (CYP2R1), the 25-hydroxyvitamin-D(3)-1-alpha-hydroxylase (CYP27B1) and the 25(OH)D(3)-24-hydroxylase (CYP24) among others. Serum levels of 25(OH)D(3) and 1,25(OH)(2)D(3) were investigated in type 1 diabetes patients (n=173) and the mRNA expression of the CYP2R1, CYP27B1 and CYP24 genes in type 1 diabetes patients (n=33) and healthy controls (n=23). These parameters were correlated with the -1260 (C/A) polymorphism in the CYP27B1 gene. Lower expression of CYP27B1 mRNA in comparison with healthy controls (1.7165 versus 1.7815, P=0.0268) was found. Additionally, patients carrying the genotype CC possessed a reduced amount of CYP27B1 mRNA compared to healthy controls (1.6855 versus 1.8107, respectively, P=0.0220). The heterozygosity rate of the -1260 C/A polymorphism was more frequent in patients with normal levels of 1,25(OH)(2)D(3) (> or =19.9 pmol/ml) than in whose with a level of less than 19.9 pmol/ml (46.7% versus 22.2%, P=0.0134). No correlation with serum levels of 25(OH)D(3) was found. Thus, CYP27B1 gene could play a functional role in the pathogenesis of type 1 diabetes through modulation of its mRNA expression and influence serum levels of 1,25(OH)(2)D(3) via the -1260 C/A polymorphism.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2006

DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis.

Hypophosphatemia is a genetically heterogeneous disease. Here, we mapped an autosomal recessive form (designated ARHP) to chromosome 4q21 and identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes. Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected individuals, providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels and suggesting that DMP1 may regulate FGF23 expression.

Adolescent↗
PubMed2006

Multicenter study on the diagnostic value of a new RIA for the detection of free plasma metanephrines in the work-up for pheochromocytoma.

Available laboratory test methods for the detection of elevated concentrations of catecholamines and their metabolites in urine and/or plasma are not always sensitive enough for the detection of pheochromocytoma. High-quality immunoassays for these compounds appear to be as accurate as high-pressure liquid chromatography (HPLC) or gas chromatography/mass spectrometry (GC-MS). Therefore, the current project aims to establish a new sensitive radioimmunoassay (RIA) for the measurement of free metanephrines in the plasma of patients in the work-up for pheochromocytoma. We report first results of an ongoing multicenter clinico-chemical evaluation study in hypertensive patients and normotensive volunteers. After an overnight fast plasma samples were collected on ice in EDTA- and heparin-coated tubes after insertion of an indwelling venous line and resting in the supine (patients) or sitting position (normal volunteers) for 30 min. Plasma metanephrines were measured by a newly developed RIA from IBL, Hamburg, Germany. Good agreement of the assay with the tandem mass spectrometry (LC-MS/MS) method for normetanephrine (r2=0.975) and for metanephrine (r2=0.985) could be demonstrated. Both specimens, EDTA and heparin plasma, can be used with the same results. The RIA has a good precision of <15% in the normal range and of <10% in the elevated concentration range. Our preliminary data suggest a high validity of the newly developed RIA for measuring free metanephrine and normetanephrine in hypertensive subjects in both EDTA and heparin plasma. Further work is required to determine the accuracy of the test in larger patient populations and in patients with pheochromocytoma.

Adrenal Gland Neoplasms↗
PubMed2006

Protection from type 1 diabetes by vitamin D receptor haplotypes.

Vitamin D has been involved in the modulation of calcium and bone metabolism as well as in the immune system, where it suppresses the proliferation of activated T cells. These effects are exerted via the vitamin D receptor (VDR). Polymorphisms within this gene have been exhaustively studied in diverse autoimmune diseases but with inconsistent results. We previously reported a positive association of polymorphisms within the VDR gene (Apa I, Taq I, Bsm I, and Fok I). In the present article we extended our previous reports to seven additional polymorphisms (rs757343, rs9729, rs2853559, rs1989969, rs3847987, rs2238135, and rs4516035) in a larger set of German simplex type 1 diabetes families. Additionally we correlated serum levels of 25(OH)D(3) and 1,25(OH)(2)D(3) with VDR genotypes and haplotypes. The haplotypes "CG" (Taq I-Apa I), "CGG" (Taq I-Apa I-Tru I), "CGC" (Taq I-Apa I-Fok I), "GCTG" (rs9729-Taq I-Apa I-Tru I), and "CGGC"(Taq I-Apa I, Tru I, Fok I) were less often transmitted, thus negatively associated with type 1 diabetes. Patients who carried the genotype "CC" of the rs3847987 polymorphism had higher median serum levels of 25(OH)D(3). Furthermore, the majority of patients with this genotype possessed normal serum levels of 25(OH)D(3). We conclude that variants of the VDR may confer a genetic protection from type 1 diabetes. Furthermore, normal serum levels of 25(OH)D(3) appear to correlate with a VDR genotype. This supports a role of vitamin D in the immune pathogenesis of type 1 diabetes.

Calcifediol↗
PubMed2005

Vitamin D and type 1 diabetes mellitus: state of the art.

Recent evidence suggests a role for vitamin D in pathogenesis and prevention of diabetes mellitus. Active vitamin D, 1alpha,25(OH)(2)D(3), prevents type 1 diabetes in animal models, modifies T-cell differentiation, modulates dendritic cell action and induces cytokine secretion, shifting the balance to regulatory T cells. High-dose vitamin D supplementation early in life protects against type 1 diabetes. 1alpha,25(OH)(2)D(3) activity is mediated through its receptor, and targets include transcriptional regulators; therefore, 1alpha,25(OH)(2)D(3) influences gene transcription. 1alpha,25(OH)(2)D(3) also affects pancreatic beta-cell function. Genomic variations of vitamin D metabolism and target cell action predispose to type 1 diabetes. Vitamin D deficiency in pregnancy probably increases the incidence of autoimmune diseases, such as type 1 diabetes, in genetically predisposed individuals. Pharmacotherapy with 1alpha,25(OH)(2)D(3) analogues might help prevent and treat diabetes.

Animals↗
PubMed2005

Vitamin D receptor polymorphisms are associated with Graves' disease in German and Polish but not in Serbian patients.

Diverse genes are candidates for susceptibility to Graves' disease, including the vitamin D receptor (VDR), which regulates the transcription of target genes in response to the active metabolite 1,25(OH)(2)D(3). We analyzed four polymorphisms of the VDR gene (ApaI, TaqI, BsmI, and FokI) in patients with Graves' disease (n = 789) and healthy controls (n = 823) from three European populations (German, Polish, and Serbian). The VDR ApaI (rs7975232) and TaqI (rs731236) polymorphisms showed no significant difference in any population. The BsmI (rs1544410) variant "b" was associated with Graves' disease in the Polish population (p = 0.0070). The FokI (rs10735810) variant "f " was found to be associated with Graves' disease in Germans and "F" in Polish patients (p = 0.0024 and 0.0049, respectively). Construction of haplotypes for TaqI, ApaI, and BsmI showed the haplotype "Tab" to be the most frequent in the German and Polish population as well as in the Serbian patients, while "tAB" in Serbian controls. Our results show an association of VDR gene polymorphisms in the German and Polish population but not in the Serbian. Furthermore, the VDR polymorphisms are differentially distributed in the three populations. Therefore, VDR polymorphisms analysis needs to be stratified according to the population background.

Adult↗
PubMed2005

Sex-specific association of PTPN22 1858T with type 1 diabetes but not with Hashimoto's thyroiditis or Addison's disease in the German population.

BACKGROUND: Endocrine autoimmune disorders share genetic susceptibility loci, causing a disordered T-cell activation and homeostasis (HLA class II genes, CTLA-4). Recent studies showed a genetic variation within the PTPN22 gene to be an additional risk factor. MATERIALS AND METHODS: Patients with type 1 diabetes (n = 220), Hashimoto's thyroiditis (n = 94), Addison's disease (n = 121) and healthy controls (n = 239) were genotyped for the gene polymorphism PTPN22 1858 C/T. RESULTS: Our study confirms a significant association between allelic variation of the PTPN22 1858 C/T polymorphism and type 1 diabetes mellitus (T1D). 1858T was observed more frequently in T1D patients (19.3% vs 11.3%, P = 0.0009; odds ratio for allele T = 1.88, 95% confidence interval [1.3-2.7]). Furthermore, we found a strong association in female patients with T1D (P = 0.0003), whereas there was no significant difference between male patients with type 1 diabetes and male controls. No significant difference was observed between the distribution of PTPN22 C/T in patients with Hashimoto's thyroiditis or Addison's disease and healthy controls. CONCLUSION: The PTPN22 polymorphism 1858 C/T may be involved in the pathogenesis of type 1 diabetes mellitus by a sex-specific mechanism that contributes to susceptibility in females.

Addison Disease↗
PubMed2004

CYP27B1 polymorphisms variants are associated with type 1 diabetes mellitus in Germans.

CYP27B1 (25-hydroxyvitamin D(3)-1alpha-hydroxylase) catalyzes the metabolization of 25-hydroxyvitamin D(3) to 1,25(OH)(2)D(3) the most active natural Vitamin D metabolite. 1,25(OH)(2)D(3) plays a role in the regulation of autoimmunity and cell proliferation and prevents the development of autoimmune diabetes mellitus in animal models besides other autoimmune disorders. One hundred and eighty-seven families with one offspring affected with type1diabetes mellitus were genotyped for the polymorphisms in the promoter region (-1260 C/A) and intron 6 (2338 T/C) of the CYP27B1 gene on chromosome 12 q13.1-13.3 and extended transmission disequilibrium tests (ETDT) were performed. The haplotype CT (-1260 A/2338 T) was significantly more often transmitted to affected offspring (96 transmitted (T) versus 63 not transmitted (NT), P = 0.0089). While the AT (-1260 C/2838 T) was significantly less often transmitted (37 T versus 60 NT, P = 0.0195). This study suggests that CYP27B1 haplotypes may confer susceptibility to type 1 diabetes mellitus in Germans.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2004

Thyroid fetal male microchimerisms in mothers with thyroid disorders: presence of Y-chromosomal immunofluorescence in thyroid-infiltrating lymphocytes is more prevalent in Hashimoto's thyroiditis and Graves' disease than in follicular adenomas.

The presence of fetal cells in a maternal compartment is defined as fetal-maternal microchimerism, which has been detected in thyroids of mothers suffering from autoimmunity. We analyzed the immunohistology of paraffin-embedded thyroid specimen taken at surgery from 49 women with Hashimoto's thyroiditis (n = 25), Graves' disease (n = 15), or nodular or diffuse follicular adenomas (n = 9), whose childbirth history was positive for sons. By fluorescence in situ hybridization we screened for X-chromosome- and Y-chromosome-specific staining and compared the finding with human leukocyte antigen (HLA) DQ types of the mothers and, where available, their offspring. In 23 thyroids we found Y-chromosome-specific staining, which was more frequent in thyroid autoimmune disease (60% Hashimoto's thyroiditis and 40% Graves' disease) than in follicular adenomas (22.2%). There was no significant difference for HLA DQ alleles among women whose thyroids showed Y-chromosome staining and those without. However, a subgroup of all investigated microchimerism-positive mother-child pairs and women with Hashimoto's thyroiditis and Graves' disease more often had the susceptibility alleles HLA DQA1*0501-DQB1*0201 or DQB1*0301. In conclusion, fetal microchimerism is observed in thyroids of mothers with sons, and this is found more frequently in thyroid autoimmune diseases.

Adenoma↗
PubMed2004

A promoter polymorphism of the CYP27B1 gene is associated with Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus in Germans.

BACKGROUND: CYP27B1 hydroxylase catalyzes the conversion of 25 hydroxyvitamin D(3) (25OHD(3)) to 1,25(OH)(2)D(3), the most active natural vitamin D metabolite, which plays a role in the regulation of immunity and cell proliferation. We therefore investigated two single nucleotide polymorphisms in the CYP27B1 hydroxylase gene for an association with Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus. METHODS: Patients with Addison's disease (n=124), Hashimoto's thyroiditis (n=139), Graves' disease (n=334), type 1 diabetes mellitus (n=252) and healthy controls (n=320) were genotyped for the promoter (-1260) C/A polymorphism and for the intron 6 (+2838) C/T polymorphism of the CYP27B1 gene. Patients and controls were compared using genotype-wise and allele-wise X(2) testing. RESULTS: A significant association was found between allelic variation of the promoter (-1260) C/A polymorphism and Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus (P=0.0062, P=0.0173, P=0.0094 and P=0.0028 respectively). Significant differences were also observed for the intron 6 (+2838) C/T polymorphism (P=0.0058) in Hashimoto's thyroiditis but not for the other autoimmune endocrine diseases. CONCLUSIONS: The CYP27B1 promoter (-1260) C/A polymorphism appears to be associated with endocrine autoimmune diseases but the CYP27B1 intron 6 (+2838) C/T polymorphism appears to be associated only with Hashimoto's thyroiditis. These results imply a regulatory difference of the CYP27B1 hydroxylase to predispose to endocrine autoimmunity.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2004

[Genetic markers in thyroid autoimmune diseases].

Autoimmune disorders of the thyroid such as Graves' disease and Hashimoto's thyroiditis are the most common autoimmune diseases in the Western world. The frequent occurrence of both diseases in members of the same family indicates the influence of common genetic factors generally predisposing to thyroid autoimmunity. Common susceptibility loci have been mapped to the HLA region on chromosome 6p21 (HLA DR, HLA DQ), to chromosome 2q33 (CTLA4) and possibly to chromosome 8q24 (thyroglobulin). Additional susceptibility is conferred by genomic variants of the vitamin D system (vitamin D receptor and CYP1 alpha hydroxylase). Since these polymorphisms prevail also in healthy relatives they are necessary but not sufficient cofactors. The higher prevalence of thyroid autoimmune disease in women cannot be explained by susceptibility genes. The observation of microchimerisms in thyroid tissue might explain that an immunisation by fetal-maternal interaction can lead to thyroid autoimmunity in HLA risk combinations.

Autoimmune Diseases↗
PubMed2003

The IDDM-associated solitary retroviral promoters DQ-LTR3 and DQ-LTR13 have a distinct impact on the expression of selected DQB1 genes in different cell lines in vitro.

The HLA complex on chromosome 6, especially of the HLA class II genes, plays an important role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). Three solitary long terminal repeats (LTRs) have been described in the vicinity of HLA DQ, two of them modifying the genetic susceptibility to type 1 diabetes on high-risk HLA DQ haplotypes. Therefore, we have investigated the putative regulatory properties of these retroviral promoters in different cell lines, including a number of B- and T-lymphoblastoid cell lines bearing different DQ haplotypes, employing a transient reporter gene assay. The transcriptional activity of appropriate constructs harboring an LTR linked to the luciferase reporter gene revealed different expression patterns which varied considerably between the investigated cell lines. DQ-LTR3 showed clear activities, whereby the levels of luciferase gene expression were also increased approximately 200-fold in the teratocarcinoma cell line GH. For the different B- and T-cell lines, no significant activity was detected for any of the investigated LTRs. Furthermore, we have analyzed the effect of DQ-LTR13 on distinct DQB1 promoters and could show an increased activity of the DQB1*0302 promoter under the influence of DQ-LTR13. It varied from 1.5- to 6-fold in different cell lines depending on the transcriptional orientation and position of the LTR and was independent of DQ-LTR3. Moreover, the impact of the LTR was different for the DQB1*0201 promoter demonstrating a decreasing effect. These data indicate that a DQ-LTR13-mediated impact on the DQB1 promoter activity exists which differs clearly between selected promoters.

Base Sequence↗
PubMed2003

[Two consecutive pregnancies in a type 1 diabetic under treatment with insulin Lispro].

BACKGROUND: Glucose control is mandatory in pregnant women with type 1 diabetes to keep the incidence of malformations and complications low. Insulin Lispro is a new and popular fast-acting insulin analog used for intensified insulin therapy. Although popular among young patients, this drug has not been licensed for use in pregnancy due to a possibly increased risk of fetal malformations. CASE REPORT: Retrospectively, the case of a 34-year-old woman with diabetes type 1, gravid III and para III, which carried her second and third child full time under Lispro treatment, was analyzed. We performed an interview of the patient and her doctors. Additionally, the pregnancy documents along with the examination documents of the children, our patient files, and the blood glucose documentation were investigated. Contrary to the first pregnancy which was carried out in the absence of Lispro (first degree hip dysplasia), both subsequent pregnancies were completely normal despite continuous Lispro therapy. HbA(1c) values in the range of 4.9-5.9% showed an adequate glucose control throughout these pregnancies. CONCLUSION: This case supports the hypothesis that insulin Lispro which is highly popular among young patients can safely and effectively be used in pregnancies. In order to be able to adequately assess possible risks associated with this application, additional cases need to be documented and analyzed.

Abnormalities, Drug-Induced↗
PubMed2003

[Glucocorticoid-induced insulin resistance and diabetes mellitus. Receptor-, postreceptor mechanisms, local cortisol action, and new aspects of antidiabetic therapy].

BACKGROUND: Glucocorticoids are frequently prescribed drugs. Nearly half of the patients treated with glucocorticoids over a longer period develop a deranged glucose metabolism. In about 50%, these disturbances persist despite reduction or even withdrawal of the drug. PATHOPHYSIOLOGY: Glucocorticoids antagonize the insulin-mediated inhibition of hepatic glucose release, decrease glucose utilisation in muscle, and reduce the binding affinity of insulin receptors. Therefore, glucocorticoid-induced diabetes mellitus is equivalent to unmasked type 2 diabetes. New studies presume that an increased endogenous production of glucocorticoids particularly in adipocytes could play a role in type 2 diabetes as well. THERAPY: Patients with glucocorticoid-induced diabetes bear, comparable to patients with other types of diabetes, a considerable risk of arteriosclerotic and cardiovascular diseases and should therefore receive an intensified treatment. Therapy of glucocorticoid-induced diabetes basically corresponds to that of type 2 diabetes. Applicable are oral antidiabetic drugs, particularly metformin and the glitazones as insulin sensitizers both requiring consideration of contraindications, or treatment with insulin.

Diabetes Mellitus, Type 2↗
PubMed2003

Fas ligand gene polymorphisms are not associated with Hashimoto's thyroiditis and Graves' disease.

Hashimoto's thyroiditis and Graves' disease represent the two most common autoimmune thyroid disorders. Whereas in Hashimoto's thyroiditis FasL expression causes thyrocytes to undergo apoptosis, additional anti-apoptotic molecules appear to protect these cells in Graves' disease. Mutations of the FasL gene were observed in systemic lupus erythematosus. Given its functional relevance for the pathogenesis of thyroid autoimmunity we wondered whether variants of the FasL gene play a role in Hashimoto's thyroiditis and Graves' disease. We genotyped families with at least one offspring affected by Hashimoto's thyroiditis (n = 86) and Graves' disease (n = 90) for two FasL gene polymorphisms (C -843 T in the promoter, A IVS2nt-124 G in intron 2). Extended transmission disequilibrium (ETDT) and chi(2) testing were performed. Neither polymorphism alone nor the promoter/intron 2 haplotypes (p = 0.91) were associated with Hashimoto's thyroiditis. No association with Graves' disease was observed for the promoter polymorphism (p = 0.91) and the intron 2 "A" allele (57.1%; p = 0.36) or the promoter/intron 2 haplotypes (p = 0.31). Moreover, intron 2 genotyping revealed no difference between an additional 251 patients with Graves' disease and 197 healthy controls (p = 0.37). Italian and German families did not differ for the studied polymorphisms. In conclusion, our data do not suggest common genetic FasL variants to significantly contribute to the pathogenesis of either Hashimoto's thyroiditis or Graves' disease.

Autoimmune Diseases↗