Low-dose spironolactone reduces plasma fibulin-1 levels in patients with type 2 diabetes and resistant hypertension.

Diabetic patients with hypertension are at particularly high risk of vascular damage and consequently cardiovascular and renal disease. Fibulin-1, an extracellular matrix glycoprotein, is increased in arterial tissue and plasma from individuals with type 2 diabetes. This study aimed to evaluate whether antihypertensive treatment with spironolactone changes plasma fibulin-1 levels. In a multicenter, double-blind, randomized, placebo-controlled study, 119 patients with type 2 diabetes and resistant hypertension were included. A dose of spironolactone 25 mg or matching placebo was added to previous treatment at randomization. Blood pressure (BP) and plasma fibulin-1 were measured at baseline and at 16 weeks follow-up. Overall, 112 patients completed the study. All measures of BP were reduced in the spironolactone group at follow-up. Plasma fibulin-1 was significantly reduced after spironolactone treatment (P=0.009), but increased after placebo (P=0.017). Baseline plasma fibulin-1 correlated with BP and estimated glomerular filtration rate. Increased levels of plasma fibulin-1 (P=0.004) were observed in diabetic participants reporting erectile dysfunction as compared with participants who did not. Treatment with low-dose spironolactone reduced plasma fibulin-1 levels in patients with type 2 diabetes and resistant hypertension. This supports the hypothesis that the antihypertensive effect of the mineralocorticoid receptor blocker in part may be due to regression of vascular remodeling.

Near-diploid karyotypes with recurrent chromosome abnormalities characterize early-stage endometrial cancer.

Cytogenetic investigation was attempted on 15 endometrial tumors. Whenever possible, a combination of direct harvesting and short-term culture (with or without prior methotrexate synchronization) was used. The analysis was successful in 13 cases: 12 carcinomas of stage I and one atypical hyperplasia. Clonal abnormalities were found in 10 tumors, whereas the remaining three showed a normal karyotype. The modal chromosome number was near-diploid. The abnormal karyotypes contained relatively simple numerical or structural aberrations in all but one tumor, a serous papillary carcinoma with multiple complex changes as well as cytogenetic evidence of intratumor heterogeneity. Gain of 1q, trisomy for chromosomes 2, 7, 10 (this trisomy was shown by in situ hybridization to be present also in a large number of interphase cells), and 12, and loss of chromosome 22 were recurrent aberrations; these are also the cytogenetic anomalies that have been consistently associated with endometrial carcinomas in previous studies. The utilization of both direct harvesting and short-term culture in several cases increased the frequency with which abnormal karyotypes were found; sometimes aberrations were found by the first method but not by the other, and vice versa. Never were different clonal anomalies found by the two approaches in the same case. Synchronization of the cultures generally led to chromosome preparations with more mitoses and of better quality. Again, no different anomalies were found in synchronized and standard cultures from the same tumor.

[Interphase cytogenetics--a new technique for analysis of acquired genetic changes in tumor cells]. / Interfasecytogenetik--ny teknologi til analyse af erhvervede genetiske forandringer i tumorceller.

Newer genetic investigations of solid tumours by means of in situ hybridization (ISH) is reviewed. In situ hybridization, ISH, is a relatively new molecular biological method which can be used as a supplement to analysis of chromosome aberrations in tumour cells. Labelled DNA or RNA sequences (probes) are bound to specific sequences on cell chromosomes. After hybridization, the complementary sequences of the probe can be visualized and observed in a microscope. In contrast to classical cytogenetics where the chromosomes are studied in the mitosis, ISH can also be carried out on non-mitotic cells. The term "interphase cytogenetics" refers to this application of ISH, which can demonstrate the distribution of cells with different genotype without previous cell culturing. Interphase cytogenetics has been used for the analysis of several different tumour types where it gives fast and reliable information about specific cytogenetic aberrations in tumour cells. It is to be anticipated that this laboratory technique will be employed increasingly in the diagnosis and follow-up of certain malignancies.

Are there common genetic and environmental factors behind the endophenotypes associated with the metabolic syndrome?

AIMS/HYPOTHESIS: The cluster of obesity, insulin resistance, dyslipidaemia and hypertension, called the metabolic syndrome, has been suggested as a risk factor for cardiovascular disease and type 2 diabetes. The aim of the present study was to evaluate whether there are common genetic and environmental factors influencing this cluster in a general population of twin pairs. MATERIALS AND METHODS: A multivariate genetic analysis was performed on nine endophenotypes associated with the metabolic syndrome from 625 adult twin pairs of the GEMINAKAR study of the Danish Twin Registry. RESULTS: All endophenotypes showed moderate to high heritability (0.31-0.69) and small common environmental variance (0.05-0.21). In general, genetic and phenotypic correlations between the endophenotypes were strong only within sets of physiologically similar endophenotypes, but weak to moderate for other pairs of endophenotypes. However, moderate correlations between insulin resistance indices and either obesity-related endophenotypes or triacylglycerol levels indicated that some common genetic backgrounds are shared between those components. CONCLUSIONS/INTERPRETATION: We demonstrated that, in a general population, the endophenotypes associated with the metabolic syndrome apparently do not share a substantial common genetic or familial environmental background.

Twin study of genetic and environmental influences on glucose tolerance and indices of insulin sensitivity and secretion.

AIMS/HYPOTHESIS: Family and twin studies have reported different estimates of the relative contribution of genetic and environmental factors to the quantitative traits glucose tolerance, insulin secretion, and insulin sensitivity. Our aims were to estimate these relative influences in a large sample of twins from the population and to assess the effect of age. METHODS: In this population-based, cross-sectional study we gave an oral glucose tolerance test to 317 women and 290 men who were same-sex healthy twin pairs between 18 to 67 years of age. The genetic, common environmental and individual environmental variance components for fasting and 120-min glucose and for fasting and 30-min insulin as well as the linear effects of age on these components were estimated by multivariate analysis (using the software FISHER). RESULTS: In women and men the heritability for fasting glucose was 12 and 38%, for 120-min glucose it was 38 and 43%, for fasting insulin it was 54 and 37%, and for 30-min insulin it was 57 and 47%, respectively. Under the assumption of no non-additive genetic effects (no intra- or inter-gene interaction) there was no strong evidence for common environmental effects, barring significant effects for fasting glucose in women. Heritability decreased with age for 120-min glucose in women and fasting insulin in men, whereas it increased for 120-min glucose in men. CONCLUSION/INTERPRETATION: This study indicates a limited additive genetic influence on the result of an OGTT, possibly with sex-specific age effects, and generally little or no influence of the common environment. Accordingly, there is a considerable individual environmental variation.

Reproducibility of S-insulin and B-glucose responses in two identical oral glucose tolerance tests.

Recently, the diagnostic criteria for type 2 diabetes mellitus have been changed, but there are disagreements about which measurements should be used. In contrast to the American Diabetes Association (ADA), The World Health Organization (WHO) still recognizes fasting and 2-h glucose concentrations measured on either plasma or whole blood as diagnostic tools. Insulin sensitivity and insulin secretion are both assumed to be involved in the pathogenesis of type 2 diabetes. The oral glucose tolerance test (OGTT) for estimating insulin sensitivity and secretion is increasingly used, e.g. in intervention trials. The objectives of this study were to estimate the coefficients of intra-individual variation (CVw) of blood glucose and serum insulin concentrations from an OGTT as well as indices of insulin sensitivity (HOMA) and insulin secretion (delta insulin30/delta glucose30) derived from this test. Following duplicate OGTTs with a median interval of 13 days (range 1-87 days), the analytical, inter-individual, and intra-individual coefficients of variation were calculated by nested ANOVA. The CVw for fasting blood glucose (7%) was considerably lower than that for 2-h post-load glucose (15%), which was again lower than for the insulin concentrations and indices of insulin sensitivity and secretion. In conclusion, the intra-individual variation is larger for 2-h post-load glucose than for fasting glucose and may question the continued use of the 2-h post-load glucose value in the diagnosis of type 2 diabetes.

Twin study of genetic and environmental influences on adult body size, shape, and composition.

OBJECTIVE: To investigate the genetic and environmental influences on adult body size, shape, and composition in women and men, and to assess the impact of age. MATERIALS AND METHODS: In this cross-sectional study of 325 female and 299 male like-sex healthy twin pairs, on average 38 y old (18-67 y), we determined zygosity by DNA similarity, and performed anthropometry and bioelectrical impedance analysis of body composition. The contribution to the total phenotypic variance of genetic, common environment, and individual environment was estimated in multivariate analysis using the FISHER program. Further, these variance components were analysed as linear functions of age. RESULTS: In both women and men genetic contributions were significant for all phenotypes. Heritability for body mass index was 0.58 and 0.63; for body fat%, 0.59 and 0.63; for total skinfolds, 0.61 and 0.65; for extremity skinfolds 0.65 and 0.62; for truncal skinfolds, 0.50 and 0.69; for suprailiac skinfolds, 0.49 and 0.48; for waist circumference, 0.48 and 0.61; for hip, 0.52 and 0.58; for lean body mass/height2, 0.61 and 0.56; and for height, 0.81 and 0.69, respectively. There was no strong evidence of common environmental effects under the assumptions of no nonadditive effect. The pattern of age trends was inconsistent. However, when significant there was a decrease in heritability with advancing age. DISCUSSION: These findings suggest that adult body size, shape, and composition are highly heritable in both women and men, although a decreasing tendency is seen with advancing age.