Marketa Vankova

Association of Insulin Gene VNTR Polymorphism with Polycystic Ovary Syndrome

Abstract: Variability in the number of tandem repeats of the insulin gene (INS VNTR) is known to influence several phenotypes, including polycystic ovary syndrome (PCOS), diabetes mellitus type 1, diabetes mellitus type 2, and birth weight. The presence of the class III allele of INS VNTR has been reported to be protective in diabetes mellitus type 1, but in contrary it increases the disease risk of PCOS and diabetes mellitus type 2. PCOS is a very common endocrinopathy in women of reproductive age. The etiology of PCOS is uncertain, but family history of this syndrome suggests a major genetic cause. The aim of this pilot study was to investigate the possible association of INS VNTR polymorphism with PCOS in Czech women. In PCOS, significantly higher WHR, BMI, G0, G180, I30, Cp0, Cp30, Cp60, AUC‐I, AUC‐Cp, and insulinogenic index and significantly lower AUC‐G/AUC‐I were found. No significant differences in INS VNTR genotype, phenotype, or allele frequencies were found between PCOS and controls. In spite of several differences in anthropometric and biochemical parameters (abdominal fat localization, increased β‐cell function, and lower insulin sensitivity in PCOS women), no effect of INS VNTR polymorphism was found on insulin secretion, insulin action, or any other screened parameter.

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.

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 β-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.

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 β-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.

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

Abstract 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/cm2) at the hip and in the spine (L1–L4) 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, p≤0.0027). We did not find any associations between LRP5 genotypes and bone or hormonal characteristics. Conclusions: VDR IVS8+443G>A 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. Clin Chem Lab Med 2006;44:1066–9.

SHBG Genetic Variability and Glucose Tolerance in T2DM Patients, Gestational Diabetics, and Women with PCOS in Comparison with the Control Czech Population Sample

Background: Sex hormone-binding globulin (SHBG) belongs to the factors contributing to the pathophysiology of type 2 diabetes mellitus (T2DM). We determined genotypic frequencies of the single nucleotide polymorphisms (SNPs) rs6259 and rs6257 in T2DM patients, offspring of T2DM patients, gestational diabetics, patients suffering from polycystic ovary syndrome (PCOS), and in healthy adult Czechs. 1687 volunteers entered the study. The aim was to compare genetic constellation between the groups and to study the possible association of the SNPs with biochemical and anthropometric markers of insulin sensitivity. Methods: TaqMan (LC480, Roche) was used for genotyping, statistical evaluation was carried out using Statgraphics Centurion version XVI and NCSS 2007. Results: The SNPs distribution was similar between the groups. We found lower SHBG concentrations in diabetics and PCOS patients. The rs6259 SNP was associated with SHBG levels: in the NN carriers, the concentration was significantly higher in comparison with DD and DN. Unexpected results were observed when association of the rs6259 SNP with insulin sensitivity was assessed. In spite of higher SHBG concentration, which is considered to be protective factor, the NN homozygotes exhibited systematically higher stimulated glucose levels during the 3-hour oral glucose tolerance test and lower Cederholm index of insulin sensitivity. Conclusions: Genetic analysis confirmed the association between rs6259 NN genotype and higher SHBG levels. Furthermore, the NN genotype showed higher stimulated glycemia and lower insulin sensitivity. This observation seems intriguing considering established protective effect of higher SHBG levels in relation to T2DM and should be verified on a larger group of probands.