Lean Women Research Articles

Effect of Acute Walking on Endothelial Function and Postprandial Lipemia in South Asians and White Europeans.

South Asians (SAs) have an elevated risk of cardiovascular disease (CVD) compared with White Europeans (WEs). Postprandial endothelial function (flow-mediated dilatation (FMD%)) in SA women and SA men with central obesity has not been investigated. Research in other populations has highlighted that a 1% higher FMD% is associated with a ~13% lower risk of future CVD events. We investigated whether FMD% and lipemia, two markers for CVD risk, were higher in SAs versus WEs, whether walking improved FMD% and lipemia, and if there were ethnic differences in the response. Lean premenopausal women (study 1; 12 SA, 12 WE) and men with central obesity (study 2; 15 SA, 15 WE) completed two 2-d trials. On day 1, participants walked for 60 min at 60% of their peak oxygen uptake or rested. On day 2, participants rested and consumed two high-fat meals over 8 h. Repeated ultrasound assessments of endothelial function and venous blood samples for CVD risk markers were taken. Compared with WEs, SAs had lower postprandial FMD% (study 1, -1.32%; study 2, -0.54%) and higher postprandial triacylglycerol concentrations (study 1, 0.31 mmol·L -1 ·h -1 ; study 2, 0.55 mmol·L -1 ·h -1 ). Walking improved postprandial FMD% (study 1, 1.12%; study 2, 0.94%) and resulted in no significant change or small reductions in postprandial triacylglycerol concentrations (study 1, -0.01 mmol·L -1 ·h -1 ; study 2, -0.25 mmol·L -1 ·h -1 ). Exercise-induced changes in FMD% and triacylglycerol were consistent between ethnic groups. Walking mitigated the adverse postprandial effect of a high-fat diet on FMD% to a similar extent in SA and WE women and men, even with no/small improvements in triacylglycerol. This study highlights the importance of exercise to clinically improve FMD% in SAs and WEs.

Obesity downregulates lipid metabolism genes in first trimester placenta

Placentas of obese women have low mitochondrial β-oxidation of fatty acids (FA) and accumulate lipids in late pregnancy. This creates a lipotoxic environment, impairing placental efficiency. We hypothesized that placental FA metabolism is impaired in women with obesity from early pregnancy. We assessed expression of key regulators of FA metabolism in first trimester placentas of lean and obese women. Maternal fasting triglyceride and insulin levels were measured in plasma collected at the time of procedure. Expression of genes associated with FA oxidation (FAO; ACOX1, CPT2, AMPKα), FA uptake (LPL, LIPG, MFSD2A), FA synthesis (ACACA) and storage (PLIN2) were significantly reduced in placentas of obese compared to lean women. This effect was exacerbated in placentas of male fetuses. Placental ACOX1 protein was higher in women with obesity and correlated with maternal circulating triglycerides. The PPARα pathway was enriched for placental genes impacted by obesity, and PPARα antagonism significantly reduced 3H-palmitate oxidation in 1st trimester placental explants. These results demonstrate that obesity and hyperlipidemia impact placental FA metabolism as early as 7 weeks of pregnancy.

Associations between Overweight and Obesity and Common Mental Disorders and Eating Behaviors of Adult Women

Background: Obesity is a serious public health concern, challenging health professionals worldwide. Women with obesity have an increased risk of triggering psychological disorders, due to the weight stigma. Stigmatization of weight-related health correlates with behavior and contributes to a vicious cycle of obesogenic processes. Objective: Our objective is to analyze the association between the presence of mental suffering, risk of mental disorders, and eating behaviors in lean, overweight, and obese women. Methods: A total of 169 adult women aged between 20 and 39 years were included, and participants signed the informed consent, answered a questionnaire on eating habits, the Self Report Questionnaire (SRQ-20), the Scale of Depression, Anxiety and Stress (DASS-21), and the Three-Factor Eating Questionnaire—R21 (TFEQ-R21). Results: The presence of mental suffering was higher in the lean group (26.9%) compared to the overweight and obese group (57.8%). The overweight and obese group had significantly higher scores for the SRQ, DASS, and TFEQ-R21 (p = 0.001 for all analyses), except when evaluating cognitive restraint. Several correlations among scores were found and summarized. There was no significant effect of body mass index on emotional eating, albeit body mass index exerts effects on the DASS score and on binge eating behavior, both of which present mediation effects on emotional eating. Conclusions: These results support the connection between mental health status and the presence of overweight and obesity and emphasize that mental health risks also need specific targeting in public policy.

Genetic Polymorphisms in Polycystic Ovarian Syndrome

Polycystic ovarian syndrome can be defined as an endocrine disorder that most affects the reproductive system of women of childbearing age; its causes are not exactly known. However, the majority of the experts agree that it is a multifactorial entity with multiple factors. Genetics is becoming increasingly important. In recent years, several genes that are involved in the pathogenic processes of this syndrome have been identified. Within these, the most important ones are the ones that encode steroidogenesis enzymes and insulin receptors, as well as other hormones that are associated with the actions of insulin and gonadotropins and their receptors. The results obtained included 1) women with PCOS had significantly lower levels of adiponectin compared to controls. Adiponectin levels were significantly lower in both lean and obese women with PCOS compared to the control group. 2) PCOS women had significantly higher levels of LH, FSH, LH/FSH ratio, and total testosterone compared to controls. 3) Both lean and obese PCOS women had significantly higher levels of LH, LH/FSH ratio, and total testosterone compared to the control group, however, FSH levels were significantly increased only in obese PCOS women compared to controls. 4) PCOS women had significantly higher levels of total cholesterol, triglycerides, LDL cholesterol, VLDL cholesterol, and lower levels of HDL-cholesterol compared to controls. 5) Both lean and obese PCOS women had significantly higher levels of total cholesterol, triglycerides, LDL cholesterol, and VLDL cholesterol compared to controls. Only obese PCOS women had significantly lower levels of HDL-cholesterol compared to the controls. 6) The genotype analysis of FSHR gene polymorphism showed that the heterozygote Ala/Thr genotype was significantly more frequent in PCOS patients than in controls (64.1% versus 40%).

Maternal obesity: new placental paradigms unfolded.

The prevalence of maternal obesity is increasing at an alarming rate, and is providing a major challenge for obstetric practice. Adverse effects on maternal and fetal health are mediated by complex interactions between metabolic, inflammatory, and oxidative stress signaling in the placenta. Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are common downstream pathways of cell stress, and there is evidence that this conserved homeostatic response may be a key mediator in the pathogenesis of placental dysfunction. We summarize the current literature on the placental cellular and molecular changes that occur in obese women. A special focus is cast onto placental ER stress in obese pregnancy, which may provide a novel link for future investigation.

Investigation of Transcriptome Patterns in Endometrial Cancers from Obese and Lean Women.

Endometrial cancer is the most common gynaecological malignancy in developed countries. One of the largest risk factors for endometrial cancer is obesity. The aim of this study was to determine whether there are differences in the transcriptome of endometrial cancers from obese vs. lean women. Here we investigate the transcriptome of endometrial cancer between obese and lean postmenopausal women using rRNA-depleted RNA-Seq data from endometrial cancer tissues and matched adjacent non-cancerous endometrial tissues. Differential expression analysis identified 12,484 genes (6370 up-regulated and 6114 down-regulated) in endometrial cancer tissues from obese women, and 6219 genes (3196 up-regulated and 3023 down-regulated) in endometrial cancer tissues from lean women (adjusted p-value < 0.1). A gene ontology enrichment analysis revealed that the top 1000 up-regulated genes (by adjusted p-value) were enriched for growth and proliferation pathways while the top 1000 down-regulated genes were enriched for cytoskeleton restructure networks in both obese and lean endometrial cancer tissues. In this study, we also show perturbations in the expression of protein coding genes (HIST1H2BL, HIST1H3F, HIST1H2BH, HIST1H1B, TTK, PTCHD1, ASPN, PRELP, and CDH13) and the lncRNA MBNL1-AS1 in endometrial cancer tissues. Overall, this study has identified gene expression changes that are similar and also unique to endometrial cancers from obese vs. lean women. Furthermore, some of these genes may serve as prognostic biomarkers or, possibly, therapeutic targets for endometrial cancer.

Maternal Cardiac Changes in Women With Obesity and Gestational Diabetes Mellitus.

We investigated if women with gestational diabetes mellitus (GDM) in the third trimester of pregnancy exhibit adverse cardiac alterations in myocardial energetics, function, or tissue characteristics. Thirty-eight healthy, pregnant women and 30 women with GDM were recruited. Participants underwent phosphorus MRS and cardiovascular magnetic resonance for assessment of myocardial energetics (phosphocreatine [PCr] to ATP ratio), tissue characteristics, biventricular volumes and ejection fractions, left ventricular (LV) mass, global longitudinal shortening (GLS), and mitral in-flow E-wave to A-wave ratio. Participants were matched for age, gestational age, and ethnicity. The following data are reported as mean ± SD. The women with GDM had higher BMI (27 ± 4 vs. 33 ± 5 kg/m2; P = 0.0001) and systolic (115 ± 11 vs. 121 ± 13 mmHg; P = 0.04) and diastolic (72 ± 7 vs. 76 ± 9 mmHg; P = 0.04) blood pressures. There was no difference in N-terminal pro-brain natriuretic peptide concentrations between the groups. The women with GDM had lower myocardial PCr to ATP ratio (2.2 ± 0.3 vs. 1.9 ± 0.4; P < 0.0001), accompanied by lower LV end-diastolic volumes (76 ± 12 vs. 67 ± 11 mL/m2; P = 0.002) and higher LV mass (90 ± 13 vs. 103 ± 18 g; P = 0.001). Although ventricular ejection fractions were similar, the GLS was reduced in women with GDM (-20% ± 3% vs. -18% ± 3%; P = 0.008). Despite no prior diagnosis of diabetes, women with obesity and GDM manifest impaired myocardial contractility and higher LV mass, associated with reductions in myocardial energetics in late pregnancy compared with lean women with healthy pregnancy. These findings may aid our understanding of the long-term cardiovascular risks associated with GDM.

Inflammatory markers in lean Polycystic Ovary Syndrome subjects are not associated with the spectrum of dyslipidemia

HIGHLIGHTS 1. Polycystic ovarian syndrome (PCOS) might be a condition of chronic low degree inflammation and dyslipidemia.2. Association between inflammation markers and dyslipidemia in PCOS patients was investigated.3. Dyslipidemia and chronic low degree inflammation were present in lean PCOS patients, but inflammation markers related insignificantly with dyslipidemia. ABSTRACT Objectives: This study aimed to address the detailed lipid profile in lean woman with PCOS and investigate the relationship between chronic low grade inflammation (using NLR, PLR, and monocyte/HDL ratio) and dyslipidemia (defined as total cholesterol level &gt; 190 mg/dL). Materials and Methods: This study was a cross-sectional study conducted from June – December 2020 at the Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia, involving 45 women aged 18 – 35 years old, diagnosed as having PCOS with normal BMI (18.5 – 22.9 kg/m2). To compare quantitative variables, data analysis was carried out using the t-test or Mann-Whitney U test as appropriate; whereas, to compare categorical variables, the Chi-square test was used. Results: We found that although the median BMI was within normal limits at 21.48 kg/m2, the mean values of the lipid profiles were found to be either abnormal or borderline, indicating the high possibility of dyslipidemia. No statistically association between NLR, PLR and MHR with dyslipidemia. Conclusion: Dyslipidemia and chronic low-grade inflammation were found in lean PCOS subjects, but there was no significant association between inflammation markers (NLR, PLR and MHR) and dyslipidemia. Further studies should investigate other factors that cause the inflammation.

Possible mediators of metabolic endotoxemia in women with obesity and women with obesity-diabetes in The Gambia

Aims/hypothesisTranslocation of bacterial debris from the gut causes metabolic endotoxemia (ME) that results in insulin resistance, and may be on the causal pathway to obesity-related type 2 diabetes. To guide interventions against ME we tested two hypothesised mechanisms for lipopolysaccharide (LPS) ingress: a leaky gut and chylomicron-associated transfer following a high-fat meal.MethodsIn lean women (n = 48; fat mass index (FMI) 9.6 kg/m2), women with obesity (n = 62; FMI 23.6 kg/m2) and women with obesity-diabetes (n = 38; FMI 24.9 kg/m2) we used the lactulose-mannitol dual-sugar permeability test (LM ratio) to assess gut integrity. Markers of ME (LPS, EndoCAb IgG and IgM, IL-6, CD14 and lipoprotein binding protein) were assessed at baseline, 2 h and 5 h after a standardised 49 g fat-containing mixed meal. mRNA expression of markers of inflammation, macrophage activation and lipid metabolism were measured in peri-umbilical adipose tissue (AT) biopsies.ResultsThe LM ratio did not differ between groups. LPS levels were 57% higher in the obesity-diabetes group (P < 0.001), but, contrary to the chylomicron transfer hypothesis, levels significantly declined following the high-fat challenge. EndoCAb IgM was markedly lower in women with obesity and women with obesity-diabetes. mRNA levels of inflammatory markers in adipose tissue were consistent with the prior concept that fat soluble LPS in AT attracts and activates macrophages.Conclusions/interpretationRaised levels of LPS and IL-6 in women with obesity-diabetes and evidence of macrophage activation in adipose tissue support the concept of metabolic endotoxemia-mediated inflammation, but we found no evidence for abnormal gut permeability or chylomicron-associated post-prandial translocation of LPS. Instead, the markedly lower EndoCAb IgM levels indicate a failure in sequestration and detoxification.

The Associations Between Alanine Aminotransferase and Other Biochemical Parameters in Lean PCOS

To explore the associations of alanine aminotransferase in lean women of polycystic ovary syndrome (PCOS) with other biochemical parameters and the potential risk factors. This is a retrospective cohort study with lean PCOS (n = 91) and healthy controls (n = 45); we reviewed the electrical records and databases of the PCOS patients in our infertility clinic between January 2019 and September 2021; independent t-test, linear correlation analysis, and multiple linear regression were used to explore the associations. Higher levels of luteinizing hormone, total testosterone, thyroid stimulating hormone, platelet count, lymphocyte count, homocysteine, alanine aminotransferase (ALT), and uric acid were identified in lean PCOS patients, while follicle-stimulating hormone level was lower in in lean PCOS as expected (P < 0.05). Of note, the linear correlation showed that BMI, total testosterone, white blood cell count, lymphocyte count, aspartate aminotransferase, and uric acid were positively associated with alanine aminotransferase (r = 0.232, 0.318, 0.218, 0.388, 0.602, 0.353 respectively, P < 0.05). After multiple linear regression was performed, total testosterone and aspartate aminotransferase were independently and positively correlated with alanine aminotransferase in lean PCOS (B = 0.251, 0.605 respectively, P < 0.05). Higher level of ALT was identified in the lean PCOS. BMI, white blood cell count, lymphocyte count, aspartate aminotransferase, uric acid, and total testosterone were positively correlated with ALT in lean PCOS. Total testosterone and aspartate aminotransferase were independently and positively associated with ALT in lean PCOS after multiple linear regression. There might exist a potential risk of afflicting liver impairment for the lean PCOS women in the earlier period. Early examination and intervention might be necessary to prevent or delay the progression of the liver disease as soon as the diagnosis of PCOS.

MPA alters metabolic phenotype of endometrial cancer-associated fibroblasts from obese women via IRS2 signaling.

Obese women have a higher risk of developing endometrial cancer (EC) than lean women. Besides affecting EC progression, obesity also affects sensitivity of patients to treatment including medroxprogesterone acetate (MPA). Obese women have a lower response to MPA with an increased risk for tumor recurrence. While MPA inhibits the growth of normal fibroblasts, human endometrial cancer-associated fibroblasts (CAFs) were reported to be less responsive to MPA. However, it is still unknown how CAFs from obese women respond to progesterone. CAFs from the EC tissues of obese (CO) and non-obese (CN) women were established as primary cell models. MPA increased cell proliferation and downregulated stromal differentiation genes, including BMP2 in CO than in CN. Induction of IRS2 (a BMP2 regulator) mRNA expression by MPA led to activation of glucose metabolism in CO, with evidence of greater mRNA levels of GLUT6, GAPDH, PKM2, LDHA, and increased in GAPDH enzymatic activity. Concomitantly, MPA increased the mRNA expression of a fatty acid transporter, CD36 and lipid droplet formation in CO. MPA-mediated increase in glucose metabolism genes in CO was reversed with a progesterone receptor inhibitor, mifepristone (RU486), leading to a decreased proliferation. Our data suggests that PR signaling is aberrantly activated by MPA in CAFs isolated from endometrial tissues of obese women, leading to activation of IRS2 and glucose metabolism, which may lead to lower response and sensitivity to progesterone in obese women.

Nonalcoholic Fatty Liver Disease and Risk of Early-Onset Vasomotor Symptoms in Lean and Overweight Premenopausal Women.

The role of nonalcoholic fatty liver disease (NAFLD) in vasomotor symptom (VMS) risk in premenopausal women is unknown. We examined the prevalence of early-onset VMSs according to NAFLD status in lean and overweight premenopausal women. This cross-sectional study included 4242 premenopausal Korean women (mean age 45.4 years). VMSs (hot flashes and night sweats) were assessed using the Korean version of the Menopause-Specific Quality of Life questionnaire. Hepatic steatosis was determined using liver ultrasound; lean was defined as a body mass index of <23 kg/m2. Participants were categorized into four groups: NAFLD-free lean (reference), NAFLD-free overweight, lean NAFLD, and overweight NAFLD. Compared with the reference, the multivariable-adjusted prevalence ratios (PRs) (95% confidence intervals (CIs)) for VMSs in NAFLD-free overweight, lean NAFLD, and overweight NAFLD were 1.22 (1.06–1.41), 1.38 (1.06–1.79), and 1.49 (1.28–1.73), respectively. For moderate-to-severe VMSs, the multivariable-adjusted PRs (95% CIs) comparing NAFLD-free overweight, lean NAFLD, and overweight NAFLD to the reference were 1.38 (1.10–1.74), 1.73 (1.16–2.57), and 1.74 (1.37–2.21), respectively. NAFLD, even lean NAFLD, was significantly associated with an increased risk of prevalent early-onset VMSs and their severe forms among premenopausal women. Further studies are needed to determine the longitudinal association between NAFLD and VMS risk.

Metformin Versus Insulin in the Managment of Gestational Diabetes Mellitus

Background: Insulin and metformin have been used extensively in the management of gestational diabetes mellitus (GDM).Insulin has been the primary medical treatment if maternal glucose targets are not achieved by dietary therapy.Insulin is safe for the fetus, because it does not normally cross the placenta. oral antidiabetic agents, glibenclamideand metformin are the most studied agents to treat GDM patients.Objective: To examine If oral metformln Is as effective as Insulin ln the prevention of fetal macrosomy lnpregnancies complicated with gestational diabetes mellitus.Method: This study is an open -labeled prospective randomized controlled study that was carried out in Basramaternity-outpatient clinics in the tertiary level hospital ln Basra. One hundred women with GDM who didnot attain euglycaemia with diet participated. Women were randomized to therapy with insulin n= 50 or oralmetformin n=50. Incidence of macrosomia in infants and neonatal morbidity was measured.Results: There were no statistically significant differences tn the incidence of macrosomia (16°/o versus 20°/o), and neonatal morbidity between insulin and metformtn group. Around 15 (30°/o) of the metformin treatedwomen needed supplemental insulin. They were more obese,(36.2 versus 30.6) kg/m2 bad higher fasting bloodglucose level (7.4mmol/L versus 6.1 mmol/L) and needed medical treatment for GDM earlier ( 27 versus 32 wks )than women who were normoglycemic with metformin alone. There was a tendency to a higher rate of caesareansections in the metformin group than in the insulin group.Conclusion: Metformin seems to be suitable for the prevention of fetal macrosomia , especially in lean or moderatelyoverweight women developing GDM in late pregnancy Women with considerable obesity, high fasting bloodglucose and an early need for pharmacological treatment may be more suitable for insulin therapy.

MRI thigh measurements predict whole‐body skeletal muscle mass in patients with type 2 diabetes: a comparison with DXA

AbstractBackgroundSarcopenia is an age‐related loss of skeletal muscle mass (SMM) and function, associated with falls, frailty, and functional decline. It is more prevalent and often accelerated in people with Type 2 diabetes (T2D), especially when co‐existing with obesity (sarcopenic obesity). Accurate whole‐body SMM measurement, feasible using dual‐energy X‐ray absorptiometry (DXA) or magnetic resonance imaging (MRI), has utility both in clinical practice and in epidemiological and mechanistic research, considering the dual mechanical and metabolic function of skeletal muscle. Compared with MRI, DXA may underestimate age‐related muscle mass by up to 30%, and so direct comparison of DXA/MRI‐derived SMM measurements may be invalid in patients with obesity and T2D, who have potentially even more pronounced sarcopenia/sarcopenic obesity. We aimed to validate single‐slice or multiple‐slice measures of SMM, using MRI, with whole‐body SMM measures derived from DXA scans of appendicular lean soft tissue, specifically in patients with obesity and T2D.MethodsWe undertook a cross‐sectional study in which we performed paired DXA and whole‐body 3.0‐T MRI on 36 people with T2D and obesity (body mass index [BMI] &gt; 30 kg/m2). Single‐slice and seven‐slice estimates of muscle mass, taken from mid‐thigh/thigh MRI images, respectively, were determined, and compared with whole‐body SMM derived from DXA scans of appendicular lean soft tissue, in men and women separately.ResultsSeventeen men (age 48.4 ± 8.2 years, BMI 37.5 ± 5.1 kg/m2, body fat 39.1 ± 6.0%) and 19 women (age 51.8 years ± 9.7, BMI 37.8 ± 5.8 kg/m2, body fat 47.6 ± 5.1%) were recruited. Whole‐body SMM estimated by seven‐slice thigh MRI correlated strongly with DXA‐derived SMM in both men (r = 0.94, P &lt; 0.001) and women (r = 0.94, P &lt; 0.001). Single‐slice thigh estimates of whole‐body SMM by MRI also showed strong relationships to DXA‐derived SMM in both men (r = 0.88, P &lt; 0.001) and women (r = 0.87, P &lt; 0.001). There was no evidence of a statistically significant difference when comparing the performance of using single‐slice vs. multiple‐slices to determine SMM (P = 0.10 for males and P = 0.13 for females).ConclusionsThis study demonstrates that accurate determination of whole‐body SMM is possible using either single‐slice mid‐thigh or seven‐slice thigh MRI in men and women with obesity and T2D in whom there may be significant alterations in body composition. Its application may be of use clinically and in obesity‐related, metabolic, and gerontological research where accurate assessments of body composition add mechanistic insight.

Prospective Risk of Type 2 Diabetes in Normal Weight Women with Polycystic Ovary Syndrome.

Background: Polycystic ovary syndrome (PCOS) is associated with obesity and increased risk for type 2 diabetes (T2D). However, the prospective risk of T2D in normal weight women with PCOS is debated, together with the relevant prospective screening programs for T2D in normal weight women with PCOS. Aim: To review and discuss prospective risk of T2D in normal weight women with PCOS, and to give recommendations regarding prospective screening for T2D in normal weight women with PCOS. Methods: Systematic review. Results: A systematic literature search resulted in 15 published prospective studies (10 controlled studies and 5 uncontrolled studies) regarding risk of T2D in study cohorts of PCOS, where data from normal weight women with PCOS were presented separately. In controlled studies, higher risk of T2D in normal weight women with PCOS compared to controls was reported in 4/10 studies, which included one study where T2D diagnosis was based on glucose measurement, two register-based studies, and one study where diagnosis of T2D was self-reported. Six of the 10 controlled studies reported no increased risk of T2D in normal weight women with PCOS. Four of these studies based the diagnosis of T2D on biochemical measurements, which supported the risk of surveillance bias in PCOS. In uncontrolled studies, 2/5 reported a higher risk of T2D in lean women with PCOS compared to the general population. We discuss the evidence for insulin resistance and β-cell dysfunction in normal weight women with PCOS, and aggravation in the hyperandrogenic phenotype, ageing women, and women with Asian ethnicity. Impaired glucose tolerance could be an important metabolic and vascular risk marker in PCOS. Conclusions: The risk of T2D may be increased in some normal weight women with PCOS. Individual risk markers such as hyperandrogenism, age >40 years, Asian ethnicity, and weight gain should determine prospective screening programs in normal weight women with PCOS.

Sex-specific modulation of circulating growth differentiation factor-15 in patients with type 2 diabetes and/or obesity.

ObjectiveGrowth differentiation factor-15 (GDF15), a key metabolic regulator, is associated with obesity and diabetes in which sex-specific differences have been reported. Thus, we assessed whether GDF15 could be dependent on sex in diabetes and/or obesity groups.MethodsWe measured serum GDF15 levels by ELISA in eight lean women and men (n = 16), eight women and eight men having obesity (n = 16), eight women and eight men with type 2 diabetes (T2D, n = 16), and seven women and nine men with both diabetes and obesity (n = 16). Estimation of the difference in the means of each group was performed by two-way ANOVA. The interdependence of the different variates was addressed by multivariate analysis. Correlations between GDF15 levels and HOMA-IR, HbA1c, triglycerides, HDL, and LDL were explored by linear regression.ResultsBeing a woman and having obesity alone or in combination with diabetes decreased GDF15 serum levels (β = −0.47, CI = −0.95, 0.00, P = 0.052; β = −0.45, CI = −0.94, 0.05, P= 0.075). Diabetes independently of metformin treatment and obesity were not predictive of low GDF15 levels (β = 0.10, CI = −0.36, 0.57, P = 0.7). Correlation analysis showed that HOMA-IR (r = 0.45, P = 0.008) and triglycerides (r = 0.41, P = 0.017) were positively correlated and HDL (r = −0.48, P = 0.005) was negatively correlated with GDF15 levels in men.Conclusions/interpretationGDF15 level was significantly different between men and women, as well as between the groups. Sex and group interaction revealed that being a woman and having obesity alone or in combination with diabetes decreased GDF15 levels.

Vitamin D supplementation inhibits NF-kß signaling pathway in lean and obese women with PCOS.

This study aims at investigating the effect of vitamin D (VD) replacement therapy on serum nuclear factor-kappa β (NF-kβ) levels in both lean and obese women with Polycystic Ovary Syndrome (PCOS). 50 women with PCOS with VD levels lower than 20 ng/mL were included in the study. Participants were equally divided into two groups, as lean and overweight/obese PCOS, according to their body mass index (BMI) values. Patients in both groups received 2000 IU/day oral VD replacement for two months. Serum NF-kβ, VD, demographic and hormonal values of the patients were recorded before and after VD replacement therapy. Serum insulin and homeostatic model assessment (HOMA-IR) values of overweight/obese women with PCOS were significantly higher than lean women with PCOS. Pre-replacement NF-kβ levels were found to be significantly higher in the overweight/obese PCOS group (3.22 ± 1.09 ng/mL) than in the lean PCOS group (1.22 ± 0.43 ng/mL) (p < 0.03). Serum NF-kβ levels of the patients in the overweight/obese group (1.10 ± 0.30 ng/mL) and the lean group (0.83 ± 0.10 ng/mL) decreased significantly after VD replacement. No significant difference was found between the groups in terms of HOMA-IR, insulin, and total testosterone levels at the end of VD replacement therapy. VD replacement therapy contributes to the improvement of subfertility and metabolic imbalance by reducing serum NF-kβ levels in both lean and obese women with PCOS.

1125-P: Obstructive Sleep Apnea and Insomnia Are Highly Prevalent in Monogenic Diabetes

Background: Sleep disorders are highly common in type 1 and type 2 diabetes with important cardiometabolic implications. Maturity Onset Diabetes of the Young (MODY) has unique features compared to type 1 or type 2 diabetes, such that patients are generally lean and not using insulin. Objective: To evaluate primary sleep disorders in patients with MODY. Methods: Participants were recruited from the Monogenic Diabetes Registry at the University of Chicago. The presence and severity of obstructive sleep apnea (OSA) was objectively assessed by a validated home OSA screening device (WatchPAT) . Insomnia was assessed by a validated survey, the Insomnia Severity Index. Results: Demographic characteristics are shown in Table 1. The majority of the patients were white lean women, not using insulin with no diabetic complications. Among all patients (n=24) , OSA was found in 58% (64% had mild OSA, 22% had moderate OSA, 14% had severe OSA) . Among lean patients (n=15) , 53% had mild-to-moderate OSA and 47% had no OSA. Based on the Insomnia Severity Index score, 71% of patients had some degree of insomnia (17% clinical insomnia, 54% subthreshold insomnia) and 29% no insomnia. Conclusion: OSA and insomnia were highly prevalent in MODY patients despite their lack of most traditional risk factors for sleep disorders. Given their unique characteristics, further research should investigate the pathophysiology of sleep disorders in this population. Disclosure M.A.Arosemena: None. K.Wroblewski: None. E.Tasali: None. L.H.Philipson: Advisory Panel; Nevro Corp., Research Support; Dompé, Novo Nordisk, provention BIo.

Application of a Physiologically Based Pharmacokinetic Model to Predict Cefazolin and Cefuroxime Disposition in Obese Pregnant Women Undergoing Caesarean Section.

Intravenous (IV) cefuroxime and cefazolin are used prophylactically in caesarean sections (CS). Currently, there are concerns regarding sub-optimal dosing in obese pregnant women compared to lean pregnant women prior to CS. The current study used a physiologically based pharmacokinetic (PBPK) approach to predict cefazolin and cefuroxime pharmacokinetics in obese pregnant women at the time of CS as well as the duration that these drug concentrations remain above a target concentration (2, 4 or 8 µg/mL or µg/g) in plasma or adipose tissue. Cefazolin and cefuroxime PBPK models were first built using clinical data in lean and in obese non–pregnant populations. Models were then used to predict cefazolin and cefuroxime pharmacokinetics data in lean and obese pregnant populations. Both cefazolin and cefuroxime models sufficiently described their total and free levels in the plasma and in the adipose interstitial fluid (ISF) in non–pregnant and pregnant populations. The obese pregnant cefazolin model predicted adipose exposure adequately at different reference time points and indicated that an IV dose of 2000 mg can maintain unbound plasma and adipose ISF concentration above 8 µg/mL for 3.5 h post dose. Predictions indicated that an IV 1500 mg cefuroxime dose can achieve unbound plasma and unbound ISF cefuroxime concentration of ≥8 µg/mL up to 2 h post dose in obese pregnant women. Re-dosing should be considered if CS was not completed within 2 h post cefuroxime administration for both lean or obese pregnant if cefuroxime concentrations of ≥8 µg/mL is required. A clinical study to measure cefuroxime adipose concentration in pregnant and obese pregnant women is warranted.

Adipocytokines and Insulin Resistance: Their Role as Benign Breast Disease and Breast Cancer Risk Factors in a High-Prevalence Overweight-Obesity Group of Women over 40 Years Old.

Insulin levels, adipocytokines, and inflammatory mediators trigger benign breast disease (BBD) and breast cancer (BC). The relationship between serum adipocytokines levels, overweight-obesity, metabolic disturbs, and BC is unclear. Methods: To analyze the serum levels of the adipocytokines, insulin, and the HOMA IR in women without breast disease, with BBD or BC, and the role of these as risk factors for benign breast disease or breast cancer. Results: Adipsin values > 0.91 and visfatin levels > 1.18 ng/mL represent a risk factor to develop BBD in NBD lean women (OR = 18; and OR = 12). Data in overweight-obese women groups confirm the observation due to insulin levels > 2.6 mU/mL and HOMA IR > 0.78, with OR = 60.2 and 18, respectively; adipsin OR = 26.4, visfatin OR = 12. Breast cancer risk showed a similar behavior: Adipsin risk, adjusted by insulin and visfatin OR = 56 or HOMA IR and visfatin OR = 22.7. Conclusion: Adipose tissue is crucial for premalignant and malignant tissue transformation in women with overweight-obesity. The adipocyte–breast epithelium interaction could trigger a malignant transformation in a continuum, starting with BBD as premalignant disease, especially in overweight-obese women.