Olga Bradnova

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.

Physiological changes of adipokines during the menstrual cycle

Background . The cyclical effects of hormones during the menstrual cycle (MC) are responsible for driving ovulation. The information about roles of adipokines within the scope of MC are not definite. Leptin plays a role in sexual function and regulating the onset of puberty. Thin girls often fail to ovulate or release an egg from an ovary during menstruation cycles. Leptin also acts on specific receptors in the hypothalamus to inhibit appetite. Levels of leptin are increased in women suffering from premenstrual syndrome. Aim . The aim of our study was to describe physiological changes of selected steroids and adipokines at healthy women during the MC. Methods. Twenty-seven women with regular menstrual cycles were included in the study. Each sample was collected in cooled EDTA tubes, centrifuged at 2000 rpm in a refrigerated centrifuge, and stored at –80 °C. For all samples we measured luteinizing hormone (LH), follicularstimulating hormone (FSH), sex hormone-binding globulin (SHBG), testosterone, dehydroepiandrosterone (DHEA), estradiol, 7 α -DHEA, 7 β -DHEA, 7-oxoDHEA, 17-hydroxyprogesterone (17-OH P), progesterone, cortisol, adrenocorticotropic hormone (ACTH) by RIA and IRMA. Levels in plasma of hormones associated with food intake (c-peptide, ghreline, GIP, GLP, GLP-1, glucagon, insulin, leptin, PAI-1, resistin and visfatin) were measured using magnetic bead-based multiple assays (x-MAP technology, Luminex Corporation). Two kits were used: the 10-plex Bio-Plex Pro Human Diabetes assay and the 2-plex Bio-Plex Pro Human Adiponectin and Adipsin assay (both Bio-Rad Laboratories). Patient . Twenty-seven women with regular menstrual cycles (cycle length 28±2 days) were included in the study. The average age of the women was 31.8±3.56, and average BMI 22.9±2.8. The women used no hormonal contraceptives or other medicines influencing the production of steroid hormones, and were non-smokers. Before enrollment in the study, all signed informed consent that was approved by the local ethical committee of the Institute of Endocrinology. Intervention . Fasting blood samples were taken in the morning between 7 and 8 am. The first sampling was done at the start of the menstrual cycle (1st or 2nd day). Subsequent samples were taken at regular intervals every three days, for a total of 10 samples taken during the study. Main outcome measures. During the MC we found increased levels of testosterone, estradiol, progesterone, and 17-hydroxyprogesterone during ovulation. SHBG gradually increased after ovulation. There was a significant decrease in resistin levels during ovulation, followed by an increase in the latter part of the cycle. Adipsin showed a notable increase during ovulation, but this increase was not statistically significant. Results . Classical changes in gonadotropins, estrogens and progesterone during the menstrual cycle are accompanied by less striking but significant changes in 17-hydroxyprogesterone and testosterone. No significant changes show dehydroepiandrosterone and its 7-oxygenated metabolites. Adipokines show a tendency to increase during ovulation, while ghrelin and resistin decrease. There is also a remarkable association of sex hormone binging globuline (SHBG) on the day of the cycle. Conclusions . Our results demonstrate that changes to adipokines during the menstrual cycle are not substantial. Differing leptin levels are characteristic for premenstrual syndrome. Precise descriptions of physiological changes in healthy women are important in helping us understand the significance of the changes accompanying various pathological states.

Reply to Letter to the Editor by Dr. Dimitrios Tsamis

Dear Editor, I would like to comment on the objection of Dr. Dimitrios Tsamis to our study where we used mixed meal tolerance test. The amount of liquid used during the test meal is 300 mL which was consumed in a time interval of 10 min. The test meal was well tolerated by patients even after laparoscopic great curvature plication. We used mixed meal tolerance test because it is more similar to usual conditions and better tolerated than oGTT. Gastric bypass was not used in this group of patients. It was shown that sleeve gastrectomy is not so restrictive as bypass and we think that this is valid also for LGCP. Moreover, the test meal was used also to compare the differences in reactivity of diabetics and nondiabetic subjects after bariatric surgery [1] as well as in the evaluation of the effect of bariatric surgery and caloric restriction [2] and in many other studies.

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.