The Glycemic Curve during the Oral Glucose Tolerance Test: Is It Only Indicative of Glycoregulation?

The shape of the glycemic curve during the oral glucose tolerance test (OGTT), interpreted in the correct context, can predict impaired glucose homeostasis. Our aim was to reveal information inherent in the 3 h glycemic trajectory that is of physiological relevance concerning the disruption of glycoregulation and complications beyond, such as components of metabolic syndrome (MS). METHODS: In 1262 subjects (1035 women, 227 men) with a wide range of glucose tolerance, glycemic curves were categorized into four groups: monophasic, biphasic, triphasic, and multiphasic. The groups were then monitored in terms of anthropometry, biochemistry, and timing of the glycemic peak. RESULTS: Most curves were monophasic (50%), then triphasic (28%), biphasic (17.5%), and multiphasic (4.5%). Men had more biphasic curves than women (33 vs. 14%, respectively), while women had more triphasic curves than men (30 vs. 19%, respectively) (p < 0.01). Monophasic curves were more frequent in people with impaired glucose regulation and MS compared to bi-, tri-, and multiphasic ones. Peak delay was the most common in monophasic curves, in which it was also most strongly associated with the deterioration of glucose tolerance and other components of MS. CONCLUSION: The shape of the glycemic curve is gender dependent. A monophasic curve is associated with an unfavorable metabolic profile, especially when combined with a delayed peak.

The Role of Steroidomics in the Diagnosis of Alzheimer's Disease and Type 2 Diabetes Mellitus.

Epidemiological studies suggest an association between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). This study aimed to investigate the pathophysiological markers of AD vs. T2DM for each sex separately and propose models that would distinguish control, AD, T2DM, and AD-T2DM comorbidity groups. AD and T2DM differed in levels of some circulating steroids (measured mostly by GC-MS) and in other observed characteristics, such as markers of obesity, glucose metabolism, and liver function tests. Regarding steroid metabolism, AD patients (both sexes) had significantly higher sex hormone binding globulin (SHBG), cortisol, and 17-hydroxy progesterone, and lower estradiol and 5α-androstane-3α,17ß-diol, compared to T2DM patients. However, compared to healthy controls, changes in the steroid spectrum (especially increases in levels of steroids from the C21 group, including their 5α/ß-reduced forms, androstenedione, etc.) were similar in patients with AD and patients with T2DM, though more expressed in diabetics. It can be assumed that many of these steroids are involved in counter-regulatory protective mechanisms that mitigate the development and progression of AD and T2DM. In conclusion, our results demonstrated the ability to effectively differentiate AD, T2DM, and controls in both men and women, distinguish the two pathologies from each other, and differentiate patients with AD and T2DM comorbidities.

The rs10830963 Polymorphism of the MTNR1B Gene: Association With Abnormal Glucose, Insulin and C-peptide Kinetics.

Background: The MTNR1B gene encodes a receptor for melatonin, a hormone regulating biorhythms. Disruptions in biorhythms contribute to the development of type 2 diabetes mellitus (T2DM). Genetic studies suggest that variability in the MTNR1B gene affects T2DM development. Our aim was to compare the distribution of the genetic variant rs10830963 between persons differing in glucose tolerance in a sample of the Czech population (N=1206). We also evaluated possible associations of the polymorphism with insulin sensitivity, beta cell function, with the shape of glucose, insulin and C-peptide trajectories measured 7 times during a 3-hour oral glucose tolerance test (OGTT) and with glucagon response. In a subgroup of 268 volunteers we also evaluated sleep patterns and biorhythm. Results: 13 persons were diagnosed with T2DM, 119 had impaired fasting blood glucose (IFG) and/or impaired glucose tolerance (IGT). 1074 participants showed normal results and formed a control group. A higher frequency of minor allele G was found in the IFG/IGT group in comparison with controls. The GG constellation was present in 23% of diabetics, in 17% of IFG/IGT probands and in 11% of controls. Compared to CC and CG genotypes, GG homozygotes showed higher stimulated glycemia levels during the OGTT. Homozygous as well as heterozygous carriers of the G allele showed lower very early phase of insulin and C-peptide secretion with unchanged insulin sensitivity. These differences remained significant after excluding diabetics and the IFG/IGT group from the analysis. No associations of the genotype with the shape of OGTT-based trajectories, with glucagon or with chronobiological patterns were observed. However, the shape of the trajectories differed significantly between men and women. Conclusion: In a representative sample of the Czech population, the G allele of the rs10830963 polymorphism is associated with impaired early phase of beta cell function, and this is evident even in healthy individuals.

Thyroid Cancer Detection in a Routine Clinical Setting: Performance of ACR TI-RADS, FNAC, and Molecular Testing in Prospective Cohort Study.

The aim of our study was to address the potential for improvements in thyroid cancer detection in routine clinical settings using a clinical examination, the American College of Radiology Thyroid Imaging Reporting and Database System (ACR TI-RADS), and fine-needle aspiration cytology (FNAC) concurrently with molecular diagnostics. A prospective cohort study was performed on 178 patients. DNA from FNA samples was used for next-generation sequencing to identify mutations in the genes BRAF, HRAS, KRAS, NRAS, and TERT. RNA was used for real-time PCR to detect fusion genes. The strongest relevant positive predictors for malignancy were the presence of genetic mutations (p < 0.01), followed by FNAC (p < 0.01) and ACR TI-RADS (p < 0.01). Overall, FNAC, ACR TI-RADS, and genetic testing reached a sensitivity of up to 96.1% and a specificity of 88.3%, with a diagnostic odds ratio (DOR) of 183.6. Sensitivity, specificity, and DOR decreased to 75.0%, 88.9%, and 24.0, respectively, for indeterminate (Bethesda III, IV) FNAC results. FNA molecular testing has substantial potential for thyroid malignancy detection and could lead to improvements in our approaches to patients. However, clinical examination, ACR TI-RADS, and FNAC remained relevant factors.

Altered Steroidome in Women with Gestational Diabetes Mellitus: Focus on Neuroactive and Immunomodulatory Steroids from the 24th Week of Pregnancy to Labor.

Gestational diabetes mellitus (GDM) is a complication in pregnancy, but studies focused on the steroidome in patients with GDM are not available in the public domain. This article evaluates the steroidome in GDM+ and GDM- women and its changes from 24 weeks (± of gestation) to labor. The study included GDM+ (n = 44) and GDM- women (n = 33), in weeks 24-28, 30-36 of gestation and at labor and mixed umbilical blood after delivery. Steroidomic data (101 steroids quantified by GC-MS/MS) support the concept that the increasing diabetogenic effects with the approaching term are associated with mounting progesterone levels. The GDM+ group showed lower levels of testosterone (due to reduced AKR1C3 activity), estradiol (due to a shift from the HSD17B1 towards HSD17B2 activity), 7-oxygenated androgens (competing with cortisone for HSD11B1 and shifting the balance from diabetogenic cortisol towards the inactive cortisone), reduced activities of SRD5As, and CYP17A1 in the hydroxylase but higher CYP17A1 activity in the lyase step. With the approaching term, the authors found rising activities of CYP3A7, AKR1C1, CYP17A1 in its hydroxylase step, but a decline in its lyase step, rising conjugation of neuroinhibitory and pregnancy-stabilizing steroids and weakening AKR1D1 activity.

Recurrence of Graves' Disease: What Genetics of HLA and PTPN22 Can Tell Us.

Background: Approximately half of patients diagnosed with Graves' disease (GD) relapse within two years of thyreostatic drug withdrawal. It is then necessary to decide whether to reintroduce conservative treatment that can have serious side effects, or to choose a radical approach. Familial forms of GD indicate a significant genetic component. Our aim was to evaluate the practical benefits of HLA and PTPN22 genetic testing for the assessment of disease recurrence risk in the Czech population. Methods: In 206 patients with GD, exon 2 in the HLA genes DRB1, DQA1, DQB1 and rs2476601 in the gene PTPN22 were sequenced. Results: The risk HLA haplotype DRB1*03-DQA1*05-DQB1*02 was more frequent in our GD patients than in the general European population. During long-term retrospective follow-up (many-year to lifelong perspective), 87 patients relapsed and 26 achieved remission lasting over 2 years indicating a 23% success rate for conservative treatment of the disease. In 93 people, the success of conservative treatment could not be evaluated (thyroidectomy immediately after the first attack or ongoing antithyroid therapy). Of the examined genes, the HLA-DQA1*05 variant reached statistical significance in terms of the ability to predict relapse (p=0.03). Combinations with either both other HLA risk genes forming the risk haplotype DRB1*03-DQA1*05-DQB1*02 or with the PTPN22 SNP did not improve the predictive value. Conclusion: the DQA1*05 variant may be a useful prognostic marker in patients with an unclear choice of treatment strategy.

FADS1 gene polymorphism(s) and fatty acid composition of serum lipids in adolescents.

Polyunsaturated fatty acids (PUFA) influence many physiological functions. Associations have been found between single nucleotide polymorphisms (SNP) in the FADS1 (Fatty acid desaturase 1) gene and the relative abundance of PUFA in serum lipids. This study examines the relationship between two SNPs in the FADS1 gene (rs174546, rs174537) and the fatty acid (FA) composition of serum lipids in adolescents (13-18 years). We used DNA samples (670 children; 336 girls and 334 boys) from the Childhood Obesity Prevalence and Treatment (COPAT) project. Genomic DNA was extracted from peripheral blood leukocytes in whole blood samples. For genotype analysis, TaqMan SNP Genotyping assays (Applied Biosystems) were used. Fatty acid composition of serum lipids was assessed using gas chromatography. The T-statistic and regression were used for statistical evaluations. Minor allele T carriers in both SNPs had significant lower level of palmitic acid (16:0, phospholipids) and arachidonic acid (20:4[n-6], phospholipids) in both sexes. In girls, we found a significant positive association between minor allele T carriers and eicosadienoic acid (20:2[n-6], cholesteryl esters) in both SNPs. Being a minor allele T carrier was significantly positively associated with dihomo-γ-linolenic acid (20:3[n-6], phospholipids) in boys in both SNPs. SNPs (including rs174546, rs174537) in the FADS gene cluster should have impacted desaturase activity, which may contribute to different efficiency of PUFA synthesis.

Regulated upon activation, normal T cell expressed and secreted (RANTES) levels in the peripheral blood of patients with Alzheimer's disease.

Alzheimer's disease (AD) is the most common type of dementia, but it is very difficult to diagnose with certainty, so many AD studies have attempted to find early and relevant diagnostic markers. Regulated upon activation, normal T cell expressed and secreted (RANTES, also known as C-C chemokine ligand) is a chemokine involved in the migration of T cells and other lymphoid cells. Changes in RANTES levels and its expression in blood or in cerebrospinal fluid have been reported in some neurodegenerative diseases, such as Parkinson's disease and multiple sclerosis, but also in metabolic diseases in which inflammation plays a role. The aim of this observational study was to assess RANTES levels in peripheral blood as clinical indicators of AD. Plasma levels of RANTES were investigated in 85 AD patients in a relatively early phase of AD (median 8.5 months after diagnosis; 39 men and 46 women; average age 75.7 years), and in 78 control subjects (24 men and 54 women; average age 66 years). We found much higher plasma levels of RANTES in AD patients compared to controls. A negative correlation of RANTES levels with age, disease duration, Fazekas scale score, and the medial temporal lobe atrophy (MTA) score (Scheltens's scale) was found in AD patients, i.e., the higher levels corresponded to earlier stages of the disease. Plasma RANTES levels were not correlated with cognitive scores. In AD patients, RANTES levels were positively correlated with the levels of pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-α, which is consistent with the well-known fact that AD is associated with inflammatory processes. RANTES levels were also positively correlated with insulin levels in AD patients, with insulin resistance (HOMA-R) and pancreatic beta cell function (HOMA-F). This study evaluated several clinical and metabolic factors that may affect plasma levels of RANTES, but these factors could not explain the increases in RANTES levels observed in AD patients. Plasma levels of RANTES appear to be an interesting peripheral marker for early stages of AD. The study was approved by the Ethics Committee of Institute of Endocrinology, Prague, Czech Republic on July 22, 2011.

The relationship between adolescent obesity and pelvis dimensions in adulthood: a retrospective longitudinal study.

BACKGROUND: The effect of fat tissue on a developing individual is fundamentally different from the effect on an adult. Several changes caused by obesity during sexual maturation have an irreversible and severe negative effect (lower fertility, reduced final height, type 2 diabetes mellitus) even for those who have subsequently lost weight. Our study was focused on monitoring the skeletal structure substantially influenced by sex hormones-the pelvis. The adult pelvis is strongly sexually dimorphic, which is not the case for the juvenile pelvis; skeletal differences between sexes are not so prominent and start to manifest with the onset of puberty. Evidence from animal models and case studies of treatment of gender dysphoria suggests that estrogens have a stimulatory effect on the growth plates present on the pelvis, leading to morphological change. Male obesity, especially in puberty, is connected with hypogonadism, manifesting in low levels of testosterone, and high levels of estrogens. The goal of our study was to evaluate the influence of obesity during adolescence on the morphology of the adult pelvis in the context of androgen and estrogen status. SAMPLE AND METHODS: Our sample consists of 238 individuals (144 females, 94 males) observed after an 8 year follow-up (mean age during enrollment 15.2 years, follow-up 23.3 years). Anthropometry and body composition using bioimpedance analysis (BIA) were obtained. During the follow-up, saliva samples from male participants were also collected to estimate testosterone and estradiol levels using the salivary ELISA kit (Salimetrics LLC, State College, PA, USA). RESULTS: The body fat (percentage of body fat estimated using BIA) was strongly positively associated with relative pelvic breadths in adulthood (males r = 0.64; females r = 0.56, both with p < 0.001). Adulthood pelvic breadth was a highly sensitive (0.81) and specific (0.74) retrospective marker of obesity during adolescence. The complex regression model (with reduction of dimensionality) including testosterone, estradiol to testosterone ratio and body fat (adolescent and adulthood) was able to describe 54.8% variability of pelvic breadth among males. DISCUSSION: We observed that adults with a history of obesity from adolescence tend to have a wider dimension of the bony pelvis in adulthood. Based on the parameters of the adult pelvis, the history of obesity can be determined with satisfactory sensitivity and specificity (<70%). One of the explanations for this observation can be the influence of relatively elevated estrogens levels connected with excessive adiposity leading to a wider pelvis. However, the biomechanical stress connected with elevated body mass also has to be considered, as does the influence of physical activity and gait pattern on the skeletal build.

Preliminary evidence of altered steroidogenesis in women with Alzheimer's disease: Have the patients "OLDER" adrenal zona reticularis?

Alzheimer's disease (AD) represents more than half of total dementias. Various factors including altered steroid biosynthesis may participate in its pathophysiology. We investigated how the circulating steroids (measured by GC-MS and RIA) may be altered in the presence of AD. Sixteen women with AD and 22 age- and BMI-corresponding controls aged over 65 years were enrolled in the study. The steroid levels (47 steroids and steroid polar conjugates) and their ratios in AD female patients indicated increased CYP11A1 activity, weakened activity of the CYP17A1C17,20 lyase metabolic step and attenuated sulfotransferase SULT2A1 activity at higher activity of the CYP17A1 17-hydroxylase step. The patients showed diminished HSD3B2 activity for C21 steroids, abated conversion of 17-hydroxyprogesterone to cortisol, and significantly elevated cortisol. The women with AD had also attenuated steroid 7α-hydroxylation forming immunoprotective Δ(5)-C19 steroids, attenuated aromatase activity forming estradiol that induces autoimmunity and a shift from the 3ß-hydroxy-5α/ß-reduced C19 steroids to their neuroinhibitory and antiinflammatory GABAergic 3α-hydroxy- counterparts and showed higher levels of the 3α-hydroxy-5α/ß-reduced C21 steroids and pregnenolone sulfate (improves cognitive abilities but may be both protective and excitotoxic). Our preliminary data indicated functioning of alternative "backdoor" pathway in women with AD showing higher levels of both 5α/ß-reduced C21 steroids but reduced levels of both 5α/ß-reduced C21 steroids, which implied that the alternative "backdoor" pathway might include both 5α- and 5ß-reduced steroids. Our study suggested relationships between AD status in women based on the age of subjects and levels of 10 steroids measured by GC-MS.

[Genetic background in common forms of obesity - from studies on identical twins to candidate genes of obesity]. / Genetické pozadí bezných forem obezity - od studií identických dvojcat po studium kandidátních genu obezity*

Common obesity is a result of interaction between genes and environmental/lifestyle factors, with heritability estimates 40-70%. Not only the susceptibility to obesity but also the success of weight management depends on the genetic background of each individual. This paper summarizes the up-to-date knowledge on genetic causes of common obesities. Introduction of genome-wide association studies (GWAS) led to an identification of a total of 32 variants associated with obesity/BMI and 14 with body fat distribution. Further, a great progress in revealing the mechanisms regulating the energy balance was also noted. However, the proportion of explained variance for BMI is still low, suggesting other mechanisms such as gene-gene and gene-environment interactions, rare gene variants, copy number variants polymorphisms, or epigenetic modifications and microRNAs regulating gene transcription. In summary, we present results of our studies on obesity risk variants in Czech adults, children and adolescents including those evaluating the influence of selected gene variants on the outcomes of weight management.

MTNR1B Genetic Variability Is Associated with Gestational Diabetes in Czech Women.

The gene MTNR1B encodes a receptor for melatonin. Melatonin receptors are expressed in human ß-cells, which implies that genetic variants might affect glucose tolerance. Meta-analysis confirmed that the rs10830963 shows the most robust association. The aim of the study was to assess the rs10830963 in Czech GDM patients and controls and to study relations between the SNP and biochemical as well as anthropometric characteristics. Our cohort consisted of 880 women; 458 were diagnosed with GDM, and 422 were normoglycemic controls without history of GDM. Despite similar BMI, the GDM group showed higher WHR, waist circumference, abdominal circumference, and total body fat content. The risk allele G was more frequent in the GDM group (38.3 versus 29.4% in controls, OR 1.49 CI95% [1.22; 1.82]; P OR = 0.0001). In spite of higher frequency, the G allele in the GDM group was not associated with any markers of glucose metabolism. In contrast, controls showed significant association of the allele G with FPG and with postchallenge glycemia during the oGTT. Frequency analysis indicates that rs10830963 is involved in gestational diabetes in Czech women. However, the association of the SNP with glucose metabolism, which is obvious in controls, is covert in women who have experienced GDM.

Steroids and insulin resistance in pregnancy.

Metabolism of glucose during pregnancy reflects the equilibrium between lactogenic hormones stimulating insulin production and counterregulatory hormones inducing insulin resistance. In physiological pregnancies, insulin-mediated glucose uptake is substantially decreased and insulin secretion increased to maintain euglycemia. This common state of peripheral insulin resistance arises also due to steroid spectra changes. In this review article, we have focused on the role of steroid hormones (androgens, estrogens, gestagens, mineralocorticoids, glucocorticoids, as well as secosteroid vitamin D) in the impairment of glucose tolerance in pregnancy and in the pathogenesis of gestational diabetes mellitus. This article is part of a Special Issue entitled 'Pregnancy and Steroids'.

[(TTTTA), polymorphism in the promoter of the CYP11A1 gene in the pathogenesis of polycystic ovary syndrome]. / Promotorový polymorfismus (TTTTA)n genu CYP11A1 v patogenezi syndromu polycystických ovarií.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrinopathy which is characterized by ovarian androgen excess. PCOS has a strong genetic component but the pathogenetic mechanisms responsible for hyperandrogenemia are still unknown. The CYP11A1 encodes the cholesterol side-chain cleavage enzyme that catalyzes the first and rate-limiting step of steroidogenesis. A promoter polymorphism (TTTTA)n CYP11A1 has been reported to be related to the risk of PCOS but the results were controversial. METHODS AND RESULTS: We determined this polymorphism in a cohort of 256 PCOS and 109 healthy control women. Using two models (dominant model for allele with 4 repeats and dominant model for long alleles, i.e. 7 and more repeats) we did not find either the difference in allele and genotype distribution between PCOS and controls or the influence of polymorphism on serum testosterone and androstendione levels. However, the PCOS carriers of long alleles had lower FSH, total- and LDL-cholesterol compared to the carriers of short alleles (p = 0.007; p = 0.02; p = 0.02, ANOVA). In controls, the non-carriers of allele with 4 repeats had significantly higher DHEA-S (p = 0.02, ANOVA) levels than the carriers of allele with 4 repeats. CONCLUSIONS: Despite of some associations found, it seems that the promoter variability of CYP11A1 does not play a key role in the pathogenesis of PCOS.

[Relation between insulin secretion and action--study of genetic determination]. / Vztah sekrece a pusobení inzulínu--studium genetické determinace.

BACKGROUND: The disposition index represents insulin secretion related to the degree of insulin sensitivity, being constant for given degree of glucose tolerance. The aim of this study is to discern genetic determinants influencing the value of disposition index, e.g. predisposition to glucose intolerance. METHODS AND RESULTS: Two hundred and four non-diabetic subjects with varied glucose tolerance were divided into groups according to the values of disposition index. Glucose and lipid metabolism, anthropometric parameters and family history of type 2 diabetes mellitus (DM2) were examined. The genotype frequency of candidate genes was compared between the groups of individuals within the lowest (Q1) and the highest (Q4) quartiles of the disposition index values. Those groups were not different concerning age and female to male ratio. Fasting and stimulated parameters of glucose metabolism and lipid profile were worse in group Q1 compared to group Q4. Group Q1 is characterized with higher number of individuals with metabolic syndrome and family history of DM2. The examination of candidate genes revealed the differences in genotype frequency of B2AR (rs1042714), PPARA (rs1800206), KCNJ11 (rs5219), and SLC30A8 (rs13266634) between groups Q1 and Q4. CONCLUSIONS: Low value of disposition index is related to the deterioration of glucose tolerance and other signs of metabolic syndrome. It is associated with genes affecting insulin secretion and genes related to energy metabolism and obesity.

Beta cell function and insulin sensitivity in women with polycystic ovary syndrome: influence of the family history of type 2 diabetes mellitus.

AIM: To study the impact of family history (FH) of type 2 diabetes mellitus on beta-cell compensatory mechanism in women with polycystic ovary syndrome (PCOS). SUBJECTS AND METHODS: A total of 70 women with PCOS, 14 with first-degree relative with type 2 diabetes mellitus (T2DM) (FH+), 56 with negative FH of T2DM (FH-) and 72 age and BMI matched control healthy women (CNT) underwent oral glucose tolerance test (OGTT). Insulin resistance was evaluated as oral glucose index (OGIS); insulin and C-peptide secretion as the insulinogenic index in 30th min of OGTT. RESULTS: Fasting blood glucose levels were significantly higher in FH+ than in FH- (p < 0.05). Fasting insulin was higher in FH+ than in CNT (p < 0.05). Fasting C-peptide was significantly higher in both FH- and FH+ than in CNT (p < 0.05 and p < 0.01, respectively). OGIS was lower in FH+ than in FH- or in CNT (p < 0.05). Insulinogenic index calculated from C-peptide values (II-Cp) was lower in FH+ than in CNT (p < 0.05). Adaptation index calculated from the values of OGIS and insulinogenic index was significantly lower in FH+ than in CNT or in FH- (p < 0.0001 and p < 0.01, respectively). CONCLUSIONS: Insulin resistance and defective early-phase insulin secretion is present only in those PCOS-affected subjects who had positive FH of T2DM.

Low-density lipoprotein receptor-related protein-5 C/T polymorphism in exon 18 is associated with C peptide and proinsulin levels in control women and patients with polycystic ovary syndrome.

OBJECTIVE: To assess the previously unstudied potential role of C/T (A1330V) polymorphism of the low-density lipoprotein receptor-related protein-5 gene in insulin sensitivity and secretion in polycystic ovary syndrome. The low-density lipoprotein receptor-related protein-5 gene has been found to play a role in determining insulin secretion in animal models. DESIGN: Case-control study. SETTING: Tertiary outpatient clinic. PATIENT(S): Women with polycystic ovary syndrome (n = 299; age, 27.5 +/- 7.1 y [mean +/- SD]), according to the European Society of Human Reproduction and Embryology criteria, as well as healthy control women (n = 187, age, 28.9 +/- 9.8 y). INTERVENTION(S): Oral glucose tolerance test, blood sampling. MAIN OUTCOME MEASURE(S): Glucose, insulin, C peptide, proinsulin during oral glucose tolerance tests, and lipids. Genotyping of C/T (A1330V) polymorphism by polymerase chain reaction-restriction fragment length polymorphism. RESULT(S): There was no difference in the frequency of genotypes between women with polycystic ovary syndrome (CC/CT/TT: 80.3%, 18.4%, 1.3%) and the control women (79.1%, 19.8%, and 1.1%). Carriers of the T allele had statistically significantly higher basal and stimulated C peptide and proinsulin levels than CC homozygotes, both basally and at the 180th minute. Regarding insulin sensitivity, there was no difference between T carriers and CC homozygotes. CONCLUSION(S): Polymorphism of C/T in the low-density lipoprotein receptor-related protein-5 gene is associated with C-peptide and proinsulin secretion but does not influence insulin sensitivity in either healthy women or women with polycystic ovary syndrome.

Role of D327N sex hormone-binding globulin gene polymorphism in the pathogenesis of polycystic ovary syndrome.

SHBG (sex hormone-binding globulin) is a transport protein specific for dihydrotestosterone, testosterone and estradiol. The missense mutation in exon 8 (GAC-->AAC) causing the amino acid exchange Asp-->Asn in codon 327 (D327N) correlates according to the published data with increased SHBG levels. We studied possible association of this polymorphism with polycystic ovary syndrome (PCOS) and anthropometric and biochemical parameters in 248 PCOS patients and 109 healthy control women. The D327N polymorphism (wild-type and variant allele) was detected using PCR-RFLP method (restriction enzyme Bbs-I). For statistical evaluation chi(2) test, Mann-Whitney test, ANCOVA, ANOVA (NCSS 2004, Statgraphics Plus v.5.1, USA) were used. There was no significant difference in genotype distribution between PCOS and controls (chi(2)=1.03, p=0.59). Moreover, we did not find an association of the variant allele with plasma SHBG level, steroid hormones, or screened parameters of lipid and glucose metabolism. In conclusion, the D327N polymorphism of the SHBG gene does not influence susceptibility to PCOS.

Low-density lipoprotein receptor-related protein 5 and vitamin D receptor gene polymorphisms in relation to vitamin D levels in menopause.

BACKGROUND: The low-density lipoprotein receptor-related protein 5 (LRP5) gene has been recently identified as a novel candidate for osteoporosis. The c.4037C>T polymorphism in the LRP5 gene has been associated with bone mass variance in general population. In contrast, the IVS8+443G>A polymorphism in the vitamin D receptor gene (VDR) has not been investigated in relation to bone metabolism. The aim of the present study was to determine VDR IVS8+443G>A and LRP5 c.4037C>T polymorphisms in a cohort of 165 perimenopausal women and to associate the genotypes with biochemical and densitometric bone parameters in a subset of 112 postmenopausal women. METHODS: Both polymorphisms were assessed by restriction analysis of the PCR product. Calcium, parathyroid hormone, vitamin D metabolites and bone mineral density (BMD, g/cm(2)) at the hip and in the spine (L(1)-L(4)) were examined. RESULTS: The genotype frequencies of both IVS8+443G>A (UU 75.2%, Uu 23%, uu 1.8%) and c.4037C>T (CC 73.9% TC 23.6%, TT 2.4%) were comparable to other Caucasian female cohorts. Serum 25OH vitamin D levels, assessed in only 63 probands, were significantly associated with VDR genotypes (ANCOVA, pA polymorphism was significantly associated with circulating 25OH vitamin D in postmenopausal Caucasian women. The role of candidate gene polymorphisms in the vitamin D metabolic pathway requires further investigation.

Determinants of circulating adiponectin in women with polycystic ovary syndrome.

BACKGROUND AND AIM: Adiponectin is regarded as a possible link between adiposity and insulin resistance. Ghrelin and leptin are considered as signals of energy status. We evaluated the relationships between these peptides, androgens and insulin sensitivity in women affected by polycystic ovary syndrome. METHODS: Thirty-six women with PCOS were examined with euglycemic hyperinsulinemic clamp (to determine M/I, index of insulin sensitivity). Leptin, ghrelin, adiponectin, androgens, and SHBG were determined. Statistics was done using correlation analysis and backward stepwise multiple regression. RESULTS: The positive correlation of adiponectin with testosterone remains significant even after adjustment for BMI (p = 0.01), M/I (p = 0.009) and for both M/I and BMI (p = 0.02). In multiple regression with testosterone, M/I, leptin and ghrelin as independent variables, the model including testosterone (p = 0.03) and ghrelin (p = 0.002) explained 49% of the variability (p < 0.0012) of adiponectin. CONCLUSIONS: Both adiponectin and ghrelin can be involved in the pathophysiology of PCOS but their relation must be delineated further.