Higher FG Research Articles

Genetic support of causal association between lipid and glucose metabolism and stress urinary incontinence in women: a bidirectional Mendelian randomization and multivariable-adjusted study.

Stress urinary incontinence (SUI) is a common condition characterized by urethral sphincter failure and urine leakage. Its prevalence in women is higher than in men, and estimates of crude prevalence rates vary widely due to factors such as research methodologies, study populations, and underreporting by patients. This variability hinders research and impacts patient diagnosis, treatment, and quality of life. The complex etiology of SUI is not fully understood, and previous studies have primarily focused on non-invasive indicators. While emerging observational research suggests a correlation between SUI in women and abnormalities in lipid and blood metabolism, the underlying biological mechanisms and causal relationships require further investigation. This study aims to explore the causalities between SUI in women and lipid and blood metabolism. Using bidirectional univariate Mendelian randomization (MR), we investigated the causal association between SUI liability in women (case/control = 5,924/399,509) from UK Biobank and lipid and glucose metabolism, indicated by total cholesterol (TC, N = 61,166), low-density lipoproteins (LDL, N = 58,381), high-density lipoproteins (HDL, N = 60,812), triglycerides (TG, N = 60,027), fasting glucose (FG, N = 19,745), and fasting insulin (FI, N = 38,238) from ENGAGE consortium. To account for potential confounding effects, multivariable MR (MVMR) analyses were performed, adjusting for body mass index (BMI) and separately among lipid and glucose metabolism. We found that increased genetically proxied TC, LDL, and HDL levels were associated with an elevated risk of SUI in women (OR: 1.090-1.117, all P < 0.05), These associations were further supported by MVMR analyses with adjustment for BMI (OR: 1.087-1.114, all P < 0.05). Conversely, increased FG and FI were associated with reduced SUI reliability in women (OR: 0.731-0.815, all P < 0.05). When adjusting among lipid and glucose metabolism, only HDL and FI demonstrated causal effects. Reverse MR analyses provided no genetic evidence supporting the causal effect of SUI in women on lipid and blood metabolism (all P > 0.05). Our results reported that increased TC, LDL, and HDL are linked to higher SUI susceptibility in women, while higher FG and FI levels have a protective effect. In overweight/obese women with metabolic abnormalities, the positive associations between TC, LDL, and HDL levels and SUI indicate a higher risk.

Risk Assessment of Diabetes Mellitus during and after Pregnancy in Women with Prolactinomas.

Prolactin (PRL) is a crucial mediator of gluco-insulinemic metabolism. Dissecting glucose metabolism during and after pregnancy in patients with prolactinomas. 52 patients treated with cabergoline (CAB) were evaluated before conception, during pregnancy and up to 10 years after delivery. During pregnancy, CAB was discontinued, while it was restarted in 57.7 % of patients after delivery, due to recurrent hyperprolactinemia (RH). Hormonal (serum PRL) and metabolic (HbA1c, fasting glucose/FG, glucose tolerance) parameters were assessed. During pregnancy, PRL gradually increased, while FG remained stable. An inverse correlation between PRL and FG was found in the first (p=0.032) and third (p=0.048) trimester. PRL percent increase across pregnancy was inversely correlated with third trimester FG. Serum PRL before conception emerged as predictive biomarker of third trimester FG (τ=2.603; p=0.048). Elderly patients with lower HbA1c at first trimester and lower FG at 3 years postpartum, delivered infants with reduced birth weight. Breastfeeding up to 6 months correlated with lower FG at 4 and 10 years postpartum. A positive correlation between BMI and FG at 10 years after delivery (p=0.03) was observed, particularly in overweight/obese patients requiring higher CAB doses. Patients with RH who had to restart CAB showed shorter breastfeeding duration and higher FG at 2 years postpartum. Low PRL levels before pregnancy may be detrimental to FG during pregnancy. CAB duration and dose may influence long-term glucose tolerance, besides family history and BMI. Pre-conceptional metabolic management should be recommended to reduce the risk of gestational and type 2 diabetes mellitus.

MO027: Clinical efficacy of treatment with tolvaptan in patients with autosomal dominant polycystic kidney disease

Abstract BACKGROUND AND AIMS Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. The only treatment approved today to slow its progression is tolvaptan (vasopressin antagonist). However, there is no clinical efficacy parameter for follow-up during treatment. To assess the clinical efficacy of treatment based on analytical (Fg) and radiological parameters: total kidney volume adjusted to height (TKV h). METHOD Retrospective observational study was undertaken of patients with ADPKD on treatment with tolvaptan after its approval in Spain in 2017. RESULTS Of the 182 ADPKD, 18% (n = 33) started treatment. The mean follow-up time of patients was 39.85 ± 10.04 months. Of the patients included; 60.6% (n = 20) were male, age 47.64 ± 8.64 years, a baseline glomerular filtration rate of 65.24 ± 20.14 mL/min and a height-adjusted total baseline renal volume of 1137.45 ± 667.58 mL. Baseline Mayo Clinic classification: 1C (72.7%), 1D (15.2%) and 1E (12.1%). Baseline CKD stages were as follows: 1: 15.2% (n = 5), 2:48.5% (n = 16), 3a:18.2% (n = 6), a 12.1% (n = 4) and 6.1% stage 4 (n = 2). The variation of Fg (mL/min), with respect to baseline was as follows: 1, 3, 6, 12, 24 and 36 months: (−4.26 ± 5.65; −3.54 ± 4.52; −1.68 ± 5.71, −10.89 ± 21.65, −10.54 ± 12.64, −8.08 ± 7.5). Fg decreased at months 1, 3, 6, 12, 12, 24 and 36 by 72.7%, 67.7%, 44.8%, 70.8%, 70.8%, 85% and 85.7%, the latter follow-up period being reached in 14 patients of the sample studied. Despite the decrease in Fg, 100% of the patients at 36 months had a higher Fg than expected according to the Mayo Clinic Fg prediction model, in accordance with their TKV at baseline. A mean decrease in TKVh was observed in annual control periods, the mean being as follows: −80.8 ± 290, −14.7 ± 187 and −82.8 ± 415.8 mL. In 100% of the patients with control at the third year (17 patients of the total sample), the percentage increase in TKV was lower than expected according to the Mayo Clinic model. CONCLUSION Although there is no efficacy parameter in the follow-up of treatment with tolvaptan in patients with ADPKD, our study shows an improvement in the expected value of both Fg and TKV; therefore, it could be considered an effective drug.

Observation of phenotypic variation among Indian women with polycystic ovary syndrome (PCOS) from Delhi and Srinagar

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder that demonstrates ethnic and regional differences. To assess the phenotypic variability among Indian PCOS women, we evaluated clinical, biochemical and hormonal parameters of these women being followed in two tertiary care institutions located in Delhi and Srinagar. A total of 299 (210 PCOS diagnosed by Rotterdam 2003 criteria and 89 healthy) women underwent estimation of T4, TSH, LH, FSH, total testosterone, prolactin, cortisol, 17OHP, and lipid profile, in addition to post OGTT, C-peptide, insulin, and glucose measurements. Among women with PCOS, mean age, age of menarche, height, systolic, diastolic blood pressure, and serum LH were comparable. PCOS women from Delhi had significantly higher BMI (26.99 ± 5.38 versus 24.77 ± 4.32 kg/m2; P = 0.01), glucose intolerance (36 versus 10%), insulin resistance as measured by HOMA-IR (4.20 ± 3.39 versus 3.01 ± 2.6; P = 0.006) and QUICKI (0.140 ± 0.013 versus 0.147 ± 0.015; P = 0.03) while PCOS from Srinagar had higher FG score (12.12 ± 3.91 versus 10.32 ± 2.22; P = 0.01) and serum total testosterone levels (0.65 ± 0.69 versus 0.86 ± 0.41 ng/ml; P = 0.01. Two clear phenotypes, i.e. obese hyperinsulinaemic dysglycemic women from Delhi and lean hyperandrogenic women from Srinagar are emerging. This is the first report on North Indian women with PCOS showing phenotypic differences in clinical, biochemical and hormonal parameters despite being in the same region.

Gene-Environment Interactions of Circadian-Related Genes for Cardiometabolic Traits.

OBJECTIVECommon circadian-related gene variants associate with increased risk for metabolic alterations including type 2 diabetes. However, little is known about whether diet and sleep could modify associations between circadian-related variants (CLOCK-rs1801260, CRY2-rs11605924, MTNR1B-rs1387153, MTNR1B-rs10830963, NR1D1-rs2314339) and cardiometabolic traits (fasting glucose [FG], HOMA-insulin resistance, BMI, waist circumference, and HDL-cholesterol) to facilitate personalized recommendations.RESEARCH DESIGN AND METHODSWe conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations and interactions between dietary intake/sleep duration and selected variants on cardiometabolic traits from 15 cohort studies including up to 28,190 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.RESULTSWe observed significant associations between relative macronutrient intakes and glycemic traits and short sleep duration (<7 h) and higher FG and replicated known MTNR1B associations with glycemic traits. No interactions were evident after accounting for multiple comparisons. However, we observed nominally significant interactions (all P < 0.01) between carbohydrate intake and MTNR1B-rs1387153 for FG with a 0.003 mmol/L higher FG with each additional 1% carbohydrate intake in the presence of the T allele, between sleep duration and CRY2-rs11605924 for HDL-cholesterol with a 0.010 mmol/L higher HDL-cholesterol with each additional hour of sleep in the presence of the A allele, and between long sleep duration (≥9 h) and MTNR1B-rs1387153 for BMI with a 0.60 kg/m2 higher BMI with long sleep duration in the presence of the T allele relative to normal sleep duration (≥7 to <9 h).CONCLUSIONSOur results suggest that lower carbohydrate intake and normal sleep duration may ameliorate cardiometabolic abnormalities conferred by common circadian-related genetic variants. Until further mechanistic examination of the nominally significant interactions is conducted, recommendations applicable to the general population regarding diet—specifically higher carbohydrate and lower fat composition—and normal sleep duration should continue to be emphasized among individuals with the investigated circadian-related gene variants.

Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=−0.09±0.01 mmol l−1, P=3.4 × 10−12), T2D risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early insulin secretion (β=−0.07±0.035 pmolinsulin mmolglucose−1, P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l−1, P=4.3 × 10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l−1, P=1.3 × 10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

Abstract P4-01-08: Effect of bilateral salpingo-oophrectomy on breast MRI fibroglandular volume and background parenchymal enhancement for BRCA 1/2 mutation carriers.

Abstract PURPOSE: Bilateral salpingo-oophrectomy (BSO) reduces breast cancer risk in women with BRCA1/2 mutations by approximately 50%. Annual screening for these high-risk women includes breast MRI and mammography. It is unknown whether BSO affects fibroglandular volume (FG) and background enhancement (BG) on breast MRI in this population. The purpose of this study is to assess the difference in FG and BG in BRCA1/2 mutation carriers before and after BSO on breast MRI. METHOD AND MATERIALS: We compared FG and BG on contrast-enhanced breast MRI before and after BSO. Two readers blinded to both clinical and imaging history scored FG according to the BI-RADS criteria from 1–4: fatty, scattered, heterogeneously dense, or extremely dense. BG was graded based on the MRI BI-RADS scale from 1–4: minimal, mild, moderate, and marked. Average BIRADS scores of each reader were used to calculate mean FG and BG (±SD) before and after BSO, and compared using a paired t-test for significance. RESULTS: We examined 60 women with BRCA1/2 mutations who underwent breast MRI before and after BSO from 2001–2011 at our institution. Five patients were excluded from the final analysis as they underwent mastectomy or bilateral radiation therapy before post-BSO MRI. Mean time to post-BSO MRI was 8.3 months ± 7 months. Mean pre- and post-operative FG were 2.64±0.78 and 2.58±0.75, respectively (p = 0.622). Mean pre- and post-operative BG were 2.46±0.93 and 1.87±0.81, respectively (p = 0.0001). Breast cancer was detected in 8 women at a median time of 3.4 years following BSO. In these 8 women, mean pre- and post-operative FG were 3.10±0.57 and 2.55±0.69, respectively. Mean pre- and post-operative BG were 3.20±0.67 and 2.35±0.71, respectively. CONCLUSION: In this population of 55 BRCA1/2 mutation carriers who underwent breast MRI before and after BSO, there was a significant reduction in BG following BSO. There was no difference in FG on MRI following BSO. For the 8 patients in this cohort who were diagnosed with breast cancer after BSO, there was a trend toward higher FG and BG both before and after BSO, in comparison to the patients who were not diagnosed with breast cancer, suggesting that rates of higher FG and BG may be associated with increased risk for developing breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-01-08.

The Effects of Satellite-Derived Vegetation Cover Variability on Simulated Land–Atmosphere Interactions in the NAMS

Abstract Substantial evolution of Normalized Difference Vegetation Index (NVDI)-derived vegetation cover (Fg) exists in the southwestern United States and Mexico. The intraseasonal and wet-/dry-year fluctuations of Fg are linked to observed precipitation in the North American monsoon system (NAMS). The manner in which the spatial and temporal variability of Fg influences the land–atmosphere energy and moisture fluxes, and associated likelihood of moist convection in the NAMS regions, is examined. For this, the regional climate model (RCM) is employed, with three different Fg boundary conditions to examine the influence of intraseasonal and wet-/dry-year vegetation variability. Results show that a strong link exists between evaporative fraction (EF), surface temperature, and relative humidity in the boundary layer (BL), which is consistent with a positive soil moisture feedback. However, contrary to expectations, higher Fg does not consistently enhance EF across the NAMS region. This is because the low soil moisture values simulated by the land surface model (LSM) yield high canopy resistance values throughout the monsoon season. As a result, the experiment with the lowest Fg yields the greatest EF and precipitation in the NAMS region, and also modulates regional atmospheric circulation that steers the track of tropical cyclones. In conclusion, the simulated influence of vegetation on land–atmosphere exchanges depends strongly on the canopy stress index parameterized in the LSM. Therefore, a reliable dataset, at appropriate scales, is needed to calibrate transpiration schemes and to assess simulated and realistic vegetation–atmosphere interactions in the NAMS region.

Slow-tonic muscle fibers and their potential innervation in the turtle,Pseudemys (Trachemys)scripta elegans

A description is provided of the ratio of slow-tonic vs. slow- and fast-twitch fibers for five muscles in the adult turtle, Pseudemys (Trachemys) scripta elegans. The cross-sectional area of each fiber type and an estimation of the relative (weighted) cross-sectional area occupied by the different fiber types are also provided. Two hindlimb muscles (flexor digitorum longus, FDL; external gastrocnemius, EG) were selected on the basis of their suitability for future motor-unit studies. Three neck muscles (the fourth head of testo-cervicis, TeC4; the fourth head of retrahens capitus collique, RCCQ4; transversalis cervicis, TrC) were chosen for their progressively decreasing oxidative capacity. Serial sections were stained for myosin adenosine triphosphatase (ATPase), NADH-diaphorase, and alpha-glycerophosphate dehydrogenase (alpha-GPDH). Conventional fiber-type classification was then performed using indirect markers for contraction speed and oxidative (aerobic) vs. glycolytic (anaerobic) metabolism: i.e., slow oxidative (SO, including slow-twitch and possibly slow-tonic fibers), fast-twitch, oxidative-glycolytic (FOG), and fast-twitch glycolytic (Fg) fibers. Slow-tonic fibers in the SO class were then revealed by directing the monoclonal antibody, ALD-58 (raised against the slow-tonic fiber myosin heavy chain of chicken anterior latissimus dorsi), to additional muscle cross sections. All five of the tested muscles contained the four fiber types, with the ATPase-stained fibers including both slow-tonic and slow-twitch fibers. The extreme distributions of SO fibers were in the predominately glycolytic TrC vs. the predominately oxidative TeC4 muscle (TrC-SO, 9%; FOG, 20%; Fg, 71% vs. TeC4-SO, 58%: FOG, 16%; Fg, 25%). Across the five muscles, the relative prevalence of slow-tonic fibers (4-47%) paralleled that of the SO fibers (9-58%). TeC4 had the highest prevalence of slow-tonic fibers (47%). The test muscles exhibited varying degrees of regional concentration of each fiber type, with the distribution of slow-tonic fibers paralleling that of the SO fibers. In the five test muscles, fiber cross-sectional area was usually ranked Fg > FOG > SO, and slow-twitch always > slow-tonic. In terms of weighted cross-sectional area, which provides a coarse-grain measure of each fiber type's potential contribution to whole muscle force, all five muscles exhibited a higher Fg and lower SO contribution to cross-sectional area than suggested by their corresponding fiber-type prevalence. This was also the case for the slow-twitch vs. slow-tonic fibers. We conclude that slow-tonic fibers are widespread in turtle muscle. The weighted cross-sectional area evidence suggested, however, that their contribution to force generation is minor except in highly oxidative muscles, with a special functional role, like TeC4. There is discussion of: 1) the relationship between the present results and previous work on homologous neck and hindlimb muscles in other nonmammalian species, and 2) the potential motoneuronal innervation of slow-tonic fibers in turtle hindlimb muscles.