Sex-Specific Associations of Testosterone With Metabolic Traits

Background: Testosterone levels are differentially linked with diabetes risk in men and women: lower testosterone levels in men and higher testosterone levels in women are associated with type 2 diabetes, though, the mechanisms are not fully clear. We addressed sex-specific links between testosterone and major pathogenetic mechanisms of diabetes.Methods: We analyzed data of 623 subjects (202 male, 345 female without, and 76 female with oral contraceptive therapy [OCT]) for whom insulin sensitivity and insulin secretion were assessed by oral glucose tolerance test. Body fat percentage was assessed by bioelectrical impedance. Testosterone was measured by enzyme-linked immunoassay; free testosterone and Framingham risk score were calculated.Results: There were significant interactions between testosterone and sex for all tested metabolic traits. Increasing testosterone was associated with less body fat, elevated insulin sensitivity, and reduced glycemia, independent of adiposity in men. In women without OCT, testosterone correlated with more body fat, insulin resistance, and higher glucose concentrations. Testosterone was not associated with insulin secretion in either sex, but with lower Framingham risk score in men and higher Framingham risk score in women.Conclusions: Similar to diabetes risk, insulin resistance has different association directions with testosterone levels in males and females. Insulin resistance could therefore constitute the best biological candidate linking testosterone levels and diabetes prevalence. The question of antiandrogen therapy being able to improve metabolism, glucose tolerance and cardiovascular risk in women was not clarified in our study but should be reviewed with higher numbers in a carefully matched study to reduce the influence of confounding variables

Gene x Gene Interactions Highlight the Role of Incretin Resistance for Insulin Secretion

Introduction: Genetic polymorphisms in TCF7L2 are the strongest common risk variants for type 2 diabetes mellitus (T2D). We and others have shown that genetic variation in TCF7L2 and WFS1 affect incretin-stimulated insulin secretion. A recent genome-wide association study discovered genetic variants associated with incretin levels. We hypothesized that these SNPs (single nucleotide polymorphisms) interact with the well-known TCF7L2 variant rs7903146 on insulin secretion due to their incretin altering effect.Methods: In this retrospective analysis, we used data from the cross-sectional TUEF-cohort (n = 2929) and a hyperglycemic clamp study using additional GLP-1 infusion at the end of the clamp (n = 76). Insulin secretion was measured by evaluating OGTT-derived indexes of insulin secretion and insulin/C-peptide levels during clamp. We genotyped rs7903146 in TCF7L2, rs10010131 in WFS1, and six SNPs associated with GLP-1 and GIP levels.Results: One of the six incretin-associated SNPs, rs17681684 in GLP2R, exhibited significant SNP x SNP interactions with rs7903146 in TCF7L2 on insulin secretion (p = 0.0024) after correction for multiple testing. Three further SNP‘s showed nominally significant interactions (p < 0.05). In the hyperglycemic clamp study, rs7903146 in TCF7L2 also interacted with rs17681684 on AUC C-peptide during the GLP-1 stimulation phase, thereby replicating the above finding.Conclusion: The findings exemplify the role of SNP x SNP interactions in the genetics of type 2 diabetes mellitus and corroborate the existence of clinically relevant differences in incretin sensitivity

Interaction between the obesity-risk gene FTO and the dopamine D2 receptor gene ANKK1/TaqIA on insulin sensitivity

Variations in FTO are the strongest common genetic determinants of adiposity, and may partly act by influencing dopaminergic signalling in the brain leading to altered reward processing that promotes increased food intake. Therefore, we investigated the impact of such an interaction on body composition, and peripheral and brain insulin sensitivity. Participants from the Tubingen Family study (n = 2245) and the Malmo Diet and Cancer study (n = 2921) were genotyped for FTO SNP rs8050136 and ANKK1 SNP rs1800497. Insulin sensitivity in the caudate nucleus, an important reward area in the brain, was assessed by fMRI in 45 participants combined with intranasal insulin administration. We found evidence of an interaction between variations in FTO and an ANKK1 polymorphism that associates with dopamine (D2) receptor density. In cases of reduced D2 receptor availability, as indicated by the ANKK1 polymorphism, FTO variation was associated with increased body fat and waist circumference and reduced peripheral insulin sensitivity. Similarly, altered central insulin sensitivity was observed in the caudate nucleus in individuals with the FTO obesity-risk allele and diminished D2 receptors. The effects of variations in FTO are dependent on dopamine D2 receptor density (determined by the ANKK1 polymorphism). Carriers of both risk alleles might, therefore, be at increased risk of obesity and diabetes.Peer reviewe

Disease heterogeneity of adult diabetes based on routine clinical parameters at diagnosis: Results from the German/Austrian DPV registry.

AIMS To cluster adults with diabetes using parameters from real-world clinical care at manifestation. MATERIALS AND METHODS We applied hierarchical clustering using Ward's method to 56,869 adults documented in the Prospective Diabetes Follow-up Registry (DPV). Clustering variables included age, sex, BMI, HbA1c, diabetic ketoacidosis (DKA), components of the metabolic syndrome (hypertension/dyslipidemia/hyperuricemia), and beta-cell antibody status. Time until use of oral antidiabetic drugs (OAD), use of insulin, chronic kidney disease (CKD), cardiovascular disease (CVD), retinopathy, or neuropathy were assessed using Kaplan Meier analysis and Cox regression models. RESULTS We identified eight clusters: Four clusters comprised early diabetes onset (median age between 40 and 50 years), but differed with regard to BMI, HbA1c, DKA and antibody positivity. Two clusters included adults with diabetes onset in their early 60s who met target HbA1c, but differed in BMI and sex distribution. Two clusters were characterized by late diabetes onset (median age 69 and 77 years) and relatively low BMI, but differences in HbA1c. Earlier insulin use was observed in adults with high HbA1c, and earlier OAD use was observed in those with high BMI. Time until CKD or CVD was shorter in those with late onset, whereas retinopathy occurred earlier in adults with late onset and high HbA1c, and in adults with early onset, but high HbA1c and high percentage of antibody positivity. CONCLUSIONS Adult diabetes is heterogeneous beyond classical type 1/type 2 diabetes, based on easily available parameters in clinical practice using an automated clustering algorithm which allows both continuous and binary variables. This article is protected by copyright. All rights reserved

Экскурсионная деятельность как актуальный способ развития туризма в г. Новосибирске

Последнее десятилетие в Российской Федерации возрос интерес правительства в комплексном развитии туризма: как во всем государстве, так и в отдельных регионах. Для качественного развития массового въездного и внутреннего туризма в регионах России, в частности в городе Новосибирске, необходимо уделить отдельное внимание экскурсионному обслуживанию. Именно обзорные экскурсии создают первое впечатление о городе у его гостей. От экскурсионной деятельности во многом зависит как воспримут туристы посещаемые места, захотят ли побывать в них еще раз. Поэтому целью моей работы является разработка пакета экскурсионных маршрутов по принципу Hop-on Hop-off для туристов по городу Новосибирску.The last decade in the Russian Federation has increased the interest of the government in the integrated development of tourism: both in the whole state and in certain regions. For the qualitative development of mass inbound and domestic tourism in the regions of Russia, in particular in the city of Novosibirsk, it is necessary to pay special attention to excursion services. It is the sightseeing tours that create the first impression of the city at its guests. From the excursion activity in many respects depends on how the tourists will perceive the places visited, whether they will want to visit them again. Therefore the purpose of my work is elaboration of a package of sightseeing routes on the principle of Hop-on Hop-off for tourists around the city of Novosibirsk

Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy

Peptides presented at the cell surface reflect the protein content of the cell; those on HLA class I molecules comprise the critical peptidome elements interacting with CD8 T lymphocytes. We hypothesize that peptidomes from ex vivo tumour samples encompass immunogenic tumour antigens. Here, we uncover >6000 HLA-bound peptides from HLA-A*02+ glioblastoma, of which over 3000 were restricted by HLA-A*02. We prioritized in-depth investigation of 10 glioblastoma-associated antigens based on high expression in tumours, very low or absent expression in healthy tissues, implication in gliomagenesis and immunogenicity. Patients with glioblastoma showed no T cell tolerance to these peptides. Moreover, we demonstrated specific lysis of tumour cells by patients' CD8+ T cells in vitro. In vivo, glioblastoma-specific CD8+ T cells were present at the tumour site. Overall, our data show the physiological relevance of the peptidome approach and provide a critical advance for designing a rational glioblastoma immunotherapy. The peptides identified in our study are currently being tested as a multipeptide vaccine (IMA950) in patients with glioblastom