Impact of glucocorticoid receptor gene (NR3C1) polymorphisms in Turkish patients with metabolic syndrome.

BACKGROUND: The metabolic syndrome (MetS) is characterized by a cluster of metabolic factors, including insulin resistance and type-2 diabetes, abdominal obesity, dyslipidemia, hypertension and microalbuminuria. Impaired glucocorticoid receptor (GR) activity also plays an important role in the etiology of MetS. The objective of our study is to evaluate the effects of GR gene polymorphisms (BclI, N363S, TthIII1 and ER22/23EK) in Turkish patients with MetS. MATERIALS AND METHODS: Seventy subjects with MetS and 185 healthy controls were enrolled in the study. PCR-RFLP analysis was used for genotyping. Results for each polymorphism have been verified by allele-specific oligonucleotide analysis. RESULTS: BclI GG genotype was significantly associated with an increased risk of MetS (p = 0.02). Also, only in women, the G allele carriers were significantly associated with higher C-peptide. T allele carriers of TthIII1 polymorphism were significantly associated with higher C-peptide, triglyceride, insulin and C-reactive protein (CRP, p value 0.048, 0.022, 0.005 and 0.022, respectively), and lower fasting blood glucose (FBG, p = 0.02). The combined carriers of BclI polymorphism G allele and TthIII1 polymorphism T allele were significantly associated with higher diastolic blood pressure in all patients, and lower FBG and postprandial blood glucose in only men. All the ER22/23EK polymorphisms coexisted with polymorphic variant of TthIII1 (p = 0.0058). CONCLUSION: The presence of homozygote polymorphic variant of BclI might be good predictive markers for the disease susceptibility. The BclI and the TthIII1 polymorphism are associated with sex-specific clinical parameters. Our findings also suggest that the combination of BclI and TthIII1 polymorphisms may play a protective role in blood glucose.

An amino-terminal DAX1 (NROB1) missense mutation associated with isolated mineralocorticoid deficiency.

CONTEXT: Mutations in DAX1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome gene 1; NR0B1) cause X-linked adrenal hypoplasia congenita, a disease characterized by primary adrenal failure, testicular dysgenesis, and gonadotropin deficiency. Most DAX1 mutations are deletions, nonsense, or frameshift mutations that markedly impair its transcriptional activity. Missense mutations have been restricted to the carboxy-terminal domain and are associated with more variable clinical phenotypes. OBJECTIVE: The objective was to identify novel clinical phenotypes associated with DAX1 missense mutations. PATIENTS AND DESIGN: We investigated the genetic basis of isolated mineralocorticoid deficiency in a patient who carries a unique missense mutation (W105C) in the amino-terminal region of DAX1. RESULTS: The W105C DAX1 mutation in the proband was present in three asymptomatic hemizygous males, but it was not detected in the general population. Using in vitro studies of DAX1 expression and function in transfected cells, we demonstrate that the mutant DAX1 protein exhibits mild loss of function, whether studied for genes it represses or for genes it activates. Structure-function studies suggest that the W105C and other mutations in the aminoterminus are compensated by the presence of repeated LXXLL motifs that mediate DAX1 interactions with other proteins. CONCLUSIONS: We describe the first missense mutation in the aminoterminus of DAX1 and conclude that mutations in this region may be partially compensated by redundant functional domains. Mild DAX1 mutations may be a cause of isolated mineralocorticoid deficiency.

[Analysis of choroidal thickness in AP-ROP, threshold disease and ROP without laser photocoagulation]. / Untersuchung der Aderhautdicke bei aggressiver posteriorer Retinopathia praematurorum, Threshold Disease und Frühgeborenenretinopathie ohne Laserphotokoagulation.

BACKGROUND: Enhanced depth imaging (EDI) and spectral domain optical coherence tomography (SD-OCT) provide high-definition cross-sectional images of the choroid. Information on alterations in choroidal thickness (CT) after laser photocoagulation (LC) in aggressive posterior retinopathy of prematurity (APROP) and threshold disease (TD) is rare. PATIENTS AND METHODS: A total of 75 eyes were retrospectively analyzed in 4 groups. Groups 1 and 2 included patients with APROP and TD, respectively, who underwent LC. Group 3 included ROP children who did not undergo LC and group 4 included full-term children. Infants aged ≥4 < 7, who had examination of subfoveal (SF) CT with SD-EDI-OCT, visual acuity (VA), spherical equivalent (SE), anterior segment and fundus examination, axial lenght (AXL) were included. The results of SFCT, VA and SE at the age of ≥ 4 < 7 years, AXL, gestational age (GA), birth weight (BW) and age at examination were compared between the groups. Potential risk factors (GA, BW, SE, AXL and SFCT) influencing visual acuity were evaluated by using multivariate linear regression analysis. RESULTS: The results of SFCT and AXL were not significantly different between groups 2 and 3 or between groups 3 and 4. There was a significant difference between the other groups for SFCT and AXL and VA was significantly different between all groups. The SE was not significantly different between groups 3 and 4 but there was a significant difference for SE, BW and GA between the groups. Age at examination was not significantly different between the groups. Multivariate linear regression analysis revealed SFCT for groups 1 and 2, GA for group 3 and GA, SFCT and AXL for group 4 as independent risk factors influencing visual acuity. CONCLUSION: The regression model used for groups 1-4 explains the variation of the dependent risk factor LogMar VA for groups 1-4 with 31.2 %, 43.5 %, 9.6 % and 69.4 %, respectively. These values expressed in percentage demonstrate that even more predictors may influence the dependent factor LogMar VA than evaluated in the study.

Improved glycemic control increases fasting plasma acylation-stimulating protein and decreases leptin concentrations in type II diabetic subjects.

Acylation-stimulating protein is an adipocyte-derived protein that has recently been suggested to play an important role in the regulation of triglyceride storage. To date, little information has been reported with regard to fasting acylation-stimulating protein levels and its relation to metabolic control, leptin, and/or lipids in subjects with diabetes mellitus. We therefore evaluated fasting acylation-stimulating protein, leptin, and lipid levels before and 4 months after improving glycemic control with sulfonylurea treatment in a group of poorly controlled obese women with type 2 diabetes and in age- and body mass index-matched nondiabetic obese women. Fasting plasma acylation-stimulating protein (49.67 +/- 19.73 vs. 48.49 +/- 20.70 nmol/liter) and leptin concentrations (33.7 +/- 23.2 vs. 26.2 +/- 10.6 ng/ml) were not significantly different between the groups. Improvement of glycemic control produced parallel falls in fasting blood glucose and hemoglobin A1c. Plasma leptin concentrations were also significantly reduced (33.69 +/- 23.2 vs. 22.73 +/- 11.26 ng/ml; P = 0.036), whereas fasting acylation-stimulating protein concentrations were significantly increased after treatment (48.49 +/- 20.70 vs. 72,82 +/- 29,72 nmol/liter; P = 0.004). Nevertheless, lipids and apolipoprotein B did not significantly improve. We could not find any correlation between elevated acylation-stimulating protein levels and changes in body mass index, glucose, insulin, hemoglobin A1c, leptin, or lipid levels. Similarly, the decrement in circulating leptin levels observed after treatment did not correlate with changes in the levels of glucose, insulin, hemoglobin A1c, or any lipid parameters. We conclude that improved glycemic control increases fasting acylation-stimulating protein and decreases leptin concentrations, but not corrects critical lipid abnormalities in type 2 obese diabetic subjects. Moreover, altered plasma acylation-stimulating protein levels are not associated with changes in body mass index or lipid, leptin, insulin, or glucose levels. Thus, our findings suggest that improved glycemic control or insulin resistance is not responsible for abnormal fatty acid trapping, and failure of lipids to improve after treatment in our patients is consistent with the acylation-stimulating protein resistance concept.

Plasma melatonin concentration before and during testosterone replacement in Klinefelter's syndrome: relation to hepatic indolamine metabolism and sympathoadrenal activity.

The mechanisms leading to alterations in plasma melatonin (MT) levels with testosterone replacement in Klinefelter's syndrome (KS) remain elusive. We investigated early morning plasma MT levels, urinary 6-sulfatoxymelatonin (6-SM) levels, and urinary catecholamine levels before and 6 months after testosterone treatment in 31 patients with KS and 20 healthy males to demonstrate whether alterations in plasma MT levels in such patients are due to subtle changes in sympathoadrenal activity and/or alterations in the hepatic indolamine metabolism influenced by testosterone replacement. The plasma MT level was measured by RIA. The sensitivity of the test was 10.7 pmol/L. The 6-SM level was measured by enzyme-linked immunosorbent assay. Urinary catecholamines were determined by high performance liquid chromatography. The pretreatment mean plasma MT level was insignificantly higher in the patient group than in the control group (72.57 +/- 74.82 vs. 42.37 +/- 29.02 pmol/L; z = -1.218; P = 0.223). The pretreatment urinary 6-SM and norepinephrine (NE) levels were significantly lower and, the epinephrine (E) and dopamine levels were insignificantly lower in the patient group than those in the control group [6-SM, 76.54 +/- 31.92 vs. 125.49 +/- 50.16 nmol/L (z = -3.727; P < 0.001); NE, 120.79 +/- 58.33 vs. 178.84 +/- 81.61 nmol/day (z = -2.585; P = 0.01); E, 31.27 +/- 27.42 vs. 34.65 +/- 28.33 nmol/day (z = -0.39; P: = 0.692); dopamine, 1577.02 +/- 863.02 vs. 1812.32 +/- 677.59 nmol/day (z = -1.03, P = 0.308)]. After testosterone replacement, plasma MT levels were significantly decreased (72.57 +/- 74.82 vs. 24.73 +/- 23.61 pmol/L; z = -4.29; P < 0.001), and urinary 6-SM, NE, E, and dopamine levels were significantly increased [6-SM, 25.04 +/- 10.44 vs. 40.05 +/- 17.65 ng/mL (z = -4.78; P < 0.001); NE, 120.78 +/- 58.33 vs. 154.08 +/- 61.35 nmol/day (z = -4.27; P < 0.001); E, 31.27 +/- 27.42 vs. 40.74 +/- 30.04 nmol/day (z = -4.22; P < 0.001); dopamine, 1577.02 +/- 863.02 vs. 2162.67 +/- 823.15 (z = -6.127; P < 0.001)]. There was no relation between plasma MT levels, urinary 6-SM, and catecholamine levels and levels of gonadotropins or gonadal steroids either before or after treatment. We demonstrate that in untreated KS, plasma MT levels tend to be higher than those in normal controls, whereas those of the melatonin metabolite 6-SM and those of NE in urine tend to be lower. After testosterone treatment, however, plasma MT levels fall significantly, whereas urinary levels of 6-SM and NE rise. Our data show that the effect of testosterone is mediated by enhanced metabolism of melatonin, not by any effect on net sympathetic outflow, and that the increase in plasma melatonin in untreated KS patients also results from an alteration in the rate of melatonin metabolism and not from increased net sympathetic activity.

The effects of thyroid status on plasma leptin levels in women.

Leptin, the product of the adipose specific ob gene, regulates food intake and energy expenditure. However, little is known about the effects of thyroid status on plasma leptin levels in women. We determined fasting plasma leptin levels before and 1 month after restoration of euthyroidism in 20 female patients with hypothyroidism, 20 female patients with hyperthyroidism and 20 age and BMI-matched female controls. To restore the normal thyroid function patients with hypothyroidism were treated with levothyroxine, whereas patients with hyperthyroidism were treated with propylthiouracil. Plasma leptin levels were measured by a RIA method with a sensitivity of 0.5 microgram/l. Leptin levels were significantly lower in patients with hypothyroidism before treatment (4.17 +/- 2.58 micrograms/l) than in patients with hyperthyroidism (6.80 +/- 4.3 micrograms/l; z = -2.06, p = 0.037). Leptin levels were significantly higher in hyperthyroid patients than in the control group (3.71 +/- 1.69 micrograms/l, z = -2.44, p = 0.014) whereas leptin levels in the hypothyroid patients were not significantly different from those in control subjects (z = -0.16, p = 0.87). Restoration of euthyroid state was not associated with a significant change in leptin levels either in the hypothyroid (from 4.17 +/- 2.58 to 5.22 +/- 3.4 micrograms/l; z = -1.74, p = 0.08) or in the hyperthyroid group (from 6.80 +/- 4.37 micrograms/l to 7.93 +/- 6.25 micrograms/l z = -0.89, p = 0.37), although a tendency for leptin to increase was observed in both groups. There was no correlation between plasma leptin and FT3, FT4, TSH, or BMI either before or after therapy in both groups. Leptin levels were significantly correlated with BMI in the control group (r = -0.53, p = 0.018). We conclude that plasma leptin levels are increased in hyperthyroidism and unchanged in hypothyroidism. Furthermore, our study demonstrates that mean plasma leptin levels are not influenced by short term restoration of euthyroidism in both hypothyroidism and hyperthyroidism, although an effect of long-term treatment may not be excluded.

Effects of gonadotropin and testosterone treatments on plasma leptin levels in male patients with idiopathic hypogonadotropic hypogonadism and Klinefelter's syndrome.

Since little is known about the effects of gonadotropin and testosterone treatment on leptin levels in male hypogonadism, we determined fasting plasma leptin levels before and 3 months after treatment in 21 patients with idiopathic hypogonadotropic hypogonadism (IHH), 16 patients with Klinefelter's syndrome and 20 male controls. Patients with IHH were treated with hCG/human menopausal gonadotropin, whereas patients with Klinefelter's syndrome received T treatment. Plasma leptin levels were measured by an RIA with a sensitivity of 0.5 microg/L. Mean leptin levels in patients with IHH before treatment (9.23+/-4.09 microg/L) were not significantly different from those in patients with Klinefelter's syndrome (7.29+/-5.05 microg/L; z=-1.41; P=0.15). Leptin levels in both IHH and Klinefelter's syndrome groups were, however, significantly higher than in the normal men (3.91+/-1.67 microg/L) (P<0.001 and P<0.01, respectively). Mean leptin levels did not change significantly 3 months after the initiation of gonadotropin (11.6+/-6.44 microg/L) or T (8.32+/-5.17 microg/L) treatment in either IHH or Klinefelter's syndrome. Our study demonstrated that mean plasma leptin levels are not influenced by short-term gonadotropin or T treatment in male hypogonadism.

Vitamin d-receptor gene polymorphisms and vertebral bone density in men with idiopathic hypogonadotrophic hypogonadism.

BACKGROUND: Optimal peak bone mass is closely related to sufficient and appropriately timed androgen release. However, attainment of peak bone mass in men, as in women, is under genetic control, as well as being subject to hormonal and mutational effects. With increasing recognition of osteoporosis and related fractures in men, it is of interest to consider whether there is relationship between bone density and vitamin D receptor (VDR) polymorphisms, as described in women. MATERIAL AND METHODS: To assess the influence of allelic variation in the VDR gene on vertebral bone density in men with idiopathic hypogonadrotrophic hypogonadism (IHH), 27 patients (mean age 21.4 +/- 0.4 yrs) and 25 age-and-BMI matched healthy males (mean age 21.2 +/- 0.3) were genotyped using three restriction enzymes (Apa I, Bsm I, and Taq I). Vertebral bone mineral density was measured using dual energy X-ray absorptiometry (DEXA). RESULTS: As expected, vertebral bone density was reduced significantly in patients with IHH (p < 0.001). Despite weak evidence for an association between Apa I polymorphism and vertebral bone density in the IHH group (r = 0.454, p = 0.017 and r2 = 0.20), VDR genotype was not associated with vertebral bone density in either group. When analyzing homozygous haplotypes, the probability of carrying the favorable BAt haplotype was greater in the control group (OR = 2.000 vs. 0.500). CONCLUSION: We conclude that VDR genotype has no influence on vertebral bone density in men with IHH. Thus, allelic variation in the VDR cannot help define those at increased risk for osteoporosis and related fractures among such patients.