Insulin Resistance In Women Research Articles

High-protein diet with excess leucine prevents inactivity-induced insulin resistance in women

Background and aimsMuscle inactivity leads to muscle atrophy and insulin resistance. The branched-chain amino acid (BCAA) leucine interacts with the insulin signaling pathway to modulate glucose metabolism. We have tested the ability of a high-protein BCAA-enriched diet to prevent insulin resistance during long-term bed rest (BR). MethodsStable isotopes were infused to determine glucose and protein kinetics in the postabsorptive state and during a hyperinsulinemic-euglycemic clamp in combination with amino acid infusion (Clamp+AA) before and at the end of 60 days of BR in two groups of healthy, young women receiving eucaloric diets containing 1 g of protein/kg per day (n=8) or 1.45 g of protein/kg per day enriched with 0.15 g/kg per day of BCAAs (leucine/valine/isoleucine=2/1/1) (n=8). Body composition was determined by Dual X-ray Absorptiometry. ResultsBR decreased lean body mass by 7.6±0.3% and 7.2±0.8% in the groups receiving conventional or high protein-BCAA diets, respectively. Fat mass was unchanged in both groups.At the end of BR, percent changes of insulin-mediated glucose uptake significantly (p=0.01) decreased in the conventional diet group from 155±23% to 84±10% while did not change significantly in the high protein-BCAA diet group from 126±20% to 141±27% (BR effect, p=0.32; BR/diet interaction, p=0.01; Repeated Measures ANCOVA). In contrast, there were no BR/diet interactions on proteolysis and protein synthesis Clamp+AA changes in the conventional diet and the high protein-BCAA diet groups. ConclusionA high protein-BCAA enriched diet prevented inactivity-induced insulin resistance in healthy women.

Exercise to Combat the Effect of Insulin Resistance in PCOS: A Narrative Review

Abstract: PCOS is a complex multigenic condition influenced by significant epigenetic and environmental variables, including nutrition and lifestyle. IR is found in roughly 80% of obese women with PCOS and 30–40% of lean women. IR is an impairment of insulin to mediate metabolism in skeletal muscle, adipocytes and liver. Following weight gain, the severity of IR in women with PCOS increases. IR affects many PCOS women who are not overweight, and minor weight loss improves clinical results in those with near-normal body weight. The effect of exercise on IS is optimized through glucose transport and metabolism. Exercise is the first-line treatment for PCOS. Moderate intensity (60–70% VO2max; comparable to 75–80% HRmax) and high-intensity aerobic exercise (heart rate >80%) improves IR in women with PCOS. These exercises are performed for at least 30 minutes per session and 3–5 days per week. A single bout of exercise (2–72 hours postexercise) can improve IS immediately. Exercise improves IS and glycemic management as well as helps in lowering the abdominal fat. Therefore, exercise performed on a regular basis can help improve insulin resistance in women with PCOS.

Yoga Exercises in Reduce Homa-Ir and Insulin Levels in Polycystic Ovarium Syndrome (PCOS) Insulin Resistant

Background: Polycystic Ovary Syndrome (PCOS), an endocrine disease that causes infertility in reproductive women, characterized by hyperandrogenemia, chronic anovulation, and Polycystic Ovary Morphology (PCOM), most PCOS women have metabolic disorders. The HOMA-IR can be used as a clinical index that is easy and sensitive to assess ovarian function in insulin-resistant PCOS women. The HOMA-IR examination has never been performed on obese PCOS patients in Madurese and Indonesia, it was carried out in Madura because it has the potential for obesity with unfavorable lifestyles such as consuming high carbohydrates and a tendency to obesity in PCOS patients. Purpose: The aim of this study was to analyze yoga exercises in reducing HOMA-IR and Insulin Levels in insulin-resistant polycystic ovary syndrome (PCOS) in the Madurese. Methods: Analytic observational study with a case-control study design, a sample of 50 patients (cases of PCOS) and 50 healthy women (non-PCOS) in the Madurese tribe, serum was taken to check HOMA-IR and insulin levels, which were examined in the laboratory. Chi-square statistical test with significance 0.05. Results: The results Chi-square statistical test with significance 0.05 showed that the case group before being given Yoga exercises the average HOMA-IR results were 40.97 and insulin levels were 61.38?l/ml while in the control group the average HOMA-IR results were 1.54 and average insulin levels were 2.9-21?l /ml, after doing Yoga exercises for 12 times and 2 times a week. Conclusion: There is a decrease in the HOMA-IR value and insulin levels. The HOMA-IR values and insulin levels decreased between before and after being given gymnastics in the case group.

Perinatal Plasma Carotenoids and Vitamin E Concentrations with Glycemia and Insulin Resistance in Women during and after Pregnancy.

We examined the associations of perinatal plasma carotenoids and E vitamers concentrations with glycemia, insulin resistance, and gestational and type 2 diabetes mellitus during pregnancy and post-pregnancy in GUSTO women. Plasma carotenoid and E vitamer concentrations were measured at delivery, and principal component analysis was used to derive the patterns of their concentrations. Fasting and 2 h glucose levels and fasting insulin were measured at 26-28 weeks gestation and 4-6 years post-pregnancy, with the derivation of homeostatic model assessment for insulin resistance (HOMA-IR). In 678 women, two carotenoid patterns (CP1: α- and β-carotene and lutein; CP2: zeaxanthin, lycopene, and β-cryptoxanthin) and one E vitamer pattern (VE: γ-, δ-, and α-tocopherols) were derived. A higher CP1 score (1-SD) was associated with lower gestational fasting glucose (β (95%CI): -0.06 (-0.10, -0.02) mmol/L) and lower gestational (-0.17 (-0.82, 0.01) mmol/L, p = 0.06) and post-pregnancy HOMA-IR (-0.11 (-0.15, -0.08) mmol/L). A higher VE score (1 SD) was associated with higher gestational and post-pregnancy fasting and 2 h glucose (gestational: 0.05 (0.01, 0.08) and 0.08 (0.01, 0.16); post-pregnancy: 0.19 (0.07, 0.31) and 0.24 (0.06, 0.42) mmol/L). Higher α- and β-carotene and lutein may be beneficial for gestational fasting glycemia, but higher vitamin E may increase gestational and post-pregnancy glycemia, although these findings require confirmation in cohorts with prospective longitudinal measurements of these vitamins.

FRI131 Abrogation Of Transglutaminase 2 In Myeloid Cells Ameliorates Angiotensin II Induced Vascular Stiffness In Female Mice

Abstract Disclosure: H. Naz: None. A.R. Aroor: None. A.T. Whaley-Connell: None. J. Guanghong: None. J.L. Hulse: None. C.M. Manrique Acevedo: None. G. Lastra: None. Introduction: Chronic low-grade inflammation and vascular stiffening contribute to cardiovascular disease (CVD) in obese and insulin-resistant women. Under these conditions, inappropriate activation of the renin angiotensin aldosterone system (RAAS) stimulates Transglutaminase 2 (TG2), a ubiquitously expressed enzyme that promotes vascular stiffening and remodeling. Additionally, Th17 cells contribute to CVD development in the setting of RAAS activation. However, it is unclear how TG2 activation mediates maladaptive immune responses associated with vascular stiffening in women. In this study, we hypothesize that TG2 abrogation inhibits Ang II-induced vascular stiffness in females by modulating Th17 immunity. Methods: 12-week-old female mice lacking TG2 expression (MyTG2KO) in myeloid cells, and control littermates (LM) were infused with Ang-II (1.4 mg/kg/day) for 2 weeks (n=4-8 per group). Prior to sacrifice, systolic blood pressure (SBP) was measured by tail-cuff method. Aortic stiffness was assessed by atomic force microscopy of thoracic aorta explants, and TG2 activity was examined by Alexa FluorTM 488 cadaverine. Analysis of Th17 cells in blood, spleen and epididymal fat (epi-fat) was done by flow cytometry. Cytokine bead array was used to measure cytokine levels in serum, RT-PCR was used to analyze cytokines in aortic tissue and TG2 knockdown efficiency in myeloid cells. Immunohistochemistry was used to examine fibrosis in aorta. Results: SBP was decreased in MyTG2KO-Ang-II as compared to LM-Ang-II cohort (129.6±5.6 vs 152.5 ±2 mmHg; p=0.04). TG2 mRNA expression in macrophages was lower in MyTG2KO mice as compared to LM (p=0.002). TG2 activity in aortic tissue increased in LM-Ang-II as compared to LM-saline (p=0.004) but was significantly lower in MyTG2KO-Ang-II mice (p=0.02). Aortic stiffness was lower in MyTG2KO-Ang-II mice relative to LM-Ang-II (4.0±0.6 vs 10.3±2.4 kPa; p=0.02). Compared to LM-Ang-II, MyTG2KO-Ang-II mice also had decreased Th17 lymphocytes (CD4+IL-17A+) in blood (3.5±0.2 vs 5.8 ±0.4 %; p=<0.0001), spleen (4.7±0.4 vs 7.1 ±0.5 %; p=0.004) and epi-fat (4.7±0.6 vs 6.8 ±0.5 %; p=0.02). MyTG2KO-Ang II mice also had significant lower levels of proinflammatory cytokines (TNF-a, IL6, IL17A, INF-g) in serum and mRNA expression of proinflammatory cytokines compared to LM-Ang-II mice and decreased total macrophage infiltration (CD68+) in the aorta. Ang-II treated MyTG2KO mice group also exhibited reduced fibrosis in the aorta relative to LM-Ang-II (p=0.003). Conclusion: The results demonstrate that abrogating TG2 in myeloid cells in female mice substantially reduces blood pressure, proinflammatory cytokines, and Th17 immune responses induced by Ang-II. Our findings have potential clinical implications for the prevention and management of CVD in women. Presentation: Friday, June 16, 2023

FRI393 Mapping Endometrial Cell-type-specific Disease Signatures A nd Endometrial Organoids In Polycystic Ovary Syndrome

Abstract Disclosure: G. Eriksson: None. C. Li: None. S. Risal: None. H. Pui: None. S. Torstensson: None. A. Linden Hirschberg: None. S. Petropoulos: None. Q. Deng: None. E. Stener-Victorin: None. Women with polycystic ovary syndrome (PCOS) suffer from reduced fertility linked to implantation failure and miscarriage, as well as endometrial cancer, all associated with endometrial dysfunction. We hypothesize that cell-type-specific endometrial dysfunction in insulin-resistant and hyperandrogenic women with PCOS contributes to the observed endometrial dysfunction and that treatment aimed at improving insulin sensitivity and decreasing androgen excess has the potential to reverse identified alterations.To uncover cell-type-specific disease signatures and molecular pathways for PCOS-specific endometrial dysfunction, we first extracted single-nuclei (sn) from frozen endometrial biopsies taken in the proliferative phase (day 7-10) from controls (n=5) and women with PCOS (n=10) at baseline and in PCOS after 16 weeks of metformin (n=7) or lifestyle management (n=3) for snRNA-sequencing. The 10x Genomics protocol allowed us to sequence ≈10,000 nuclei/sample and ≈20,000 reads/nuclei. A total of 248,694 nuclei were captured and 6 major cell types were identified. The 3 largest cell clusters were i) stromal cells (124,055 nuclei), ii) epithelial cells (105,095 nuclei) and iii) immune cells (13,596), whilst iv) uterine smooth muscle cells, v) endothelial and vi) lymphoid cell clusters consisted of <3000 nuclei. Subsetting the epithelial cells revealed the functional luminal, glandular and ciliated cell types as well as proliferative cells. In the immune cell cluster, both myeloid and lymphoid lineage cells were identified, of which uterine NK-cells (uNK) and macrophages (uM) were the largest populations. Several differentially expressed genes (DEGs) of the epithelial subtypes, uNKs, uMs and stromal cells were identified in women with PCOS compared with controls. DEGs in cell types between PCOS cases and controls were enriched in pathways related to cilium organization in the ciliated epithelium, extracellular matrix structure in stromal cells, and cysteine-type endopeptidase activity in uM type 1. Of note, both 16-week of metformin treatment or lifestyle management restored multiple DEGs in each subtype. Second, to validate the identified molecular target, we have established 3D endometrial organoids (EOs) from fresh endometrial biopsies of control and PCOS women. After several passages, EOs were cryopreserved to create a biobank for future functional analyses of the molecular targets. The EOs can be re-established after thawing and immunofluorescence staining shows that the EOs consist of an intact proliferative basolateral epithelial membrane. This rigorous mapping of the human PCOS endometrium improves our understanding of cellular complexity and specific cell types. It provides new mechanistic insights into disease-specific endometrial dysfunction(s), and several of the identified dysfunctions can be reversed by current first-line interventions. Presentation: Friday, June 16, 2023

Neck Circumference as a Predictor of Insulin Resistance in People with Non-alcoholic Fatty Liver Disease.

Insulin resistance is common in individuals with non-alcoholic fatty liver disease (NAFLD). Because insulin resistance is a predictive factor for advanced liver diseases in people with NAFLD, efforts have been made to predict it through anthropometric variables. Recently, neck circumference (NC) has been regarded as a reliable alternative marker for metabolic disorders. This study verified the association between NC and insulin resistance in patients with NAFLD. We analyzed data from 847 people with NAFLD who participated in the 2019 Korean National Health and Nutrition Examination Survey. NAFLD was defined by a hepatic steatosis index score of ≥36 points, and insulin resistance was defined by a homeostatic model assessment of insulin resistance score of ≥2.5 points. Participants were divided according to sex-specific NC tertiles (T1, lowest; T2, middle; T3, highest). In the analysis of the area under the receiver operating characteristic curve (AUC), NC displayed a greater predictive power than body mass index (BMI) for insulin resistance in women (AUC of NC=0.625 vs. AUC of BMI=0.573, P=0.035). NC and the odds ratio (OR) for insulin resistance showed a cubic relationship in both men and women. In the weighted multiple logistic regression analysis, the ORs with 95% confidence intervals for insulin resistance in people with NAFLD in T2 and T3 compared to the reference tertile (T1) were 1.06 (0.47-2.41) and 1.13 (0.41-3.11), respectively, in men and 1.12 (0.64-1.97) and 2.54 (1.19-5.39), respectively, in women, after adjusting for confounding factors. NC was positively correlated with insulin resistance in women with NAFLD.

Evaluation of Necrotumic Factor, Fasting Diabetes, Fasting Insulin and Insulin Resistance Levels in Women with Gestational Diabetes

This study aims to examine the concentrations of tumor necrosis factor-α, endothelial growth factors, fasting insulin, fasting blood glucose, and insulin resistance, in 70 women with gestational diabetes in the city of Kirkuk for the period between November 2022 and April 2023 in Kirkuk General Hospital and the medical and specialized clinics. The age of these women ranges between 20-40 years who were divided into two age groups: (20-29) and (30-40). Each group included (35). In addition, the control group included 20 healthy people who did not suffer from any symptoms. After obtaining blood serum, physiological and biochemical tests were conducted. The results show a significant increase (p≤0.01) in the concentration of tumor necrosis factor-α (TNF-α), in the level of fasting insulin, fasting blood sugar, and insulin resistance in women with gestational diabetes when compared with the control group. However, both groups of patients (20-29) and (30-40) showed no significant difference in the variables of the study.

Differences in DNA methylation of HAMP in blood cells predicts the development of type 2 diabetes

ObjectivesBetter disease management can be achieved with earlier detection through robust, sensitive, and easily accessible biomarkers. The aim of the current study was to identify novel epigenetic biomarkers determining the risk of type 2 diabetes (T2D). MethodsLivers of 10-week-old female New Zealand Obese (NZO) mice, slightly differing in their degree of hyperglycemia and liver fat content and thereby in their diabetes susceptibility were used for expression and methylation profiling. We screened for differences in hepatic expression and DNA methylation in diabetes-prone and -resistant mice, and verified a candidate (HAMP) in human livers and blood cells. Hamp expression was manipulated in primary hepatocytes and insulin-stimulated pAKT was detected. Luciferase reporter assays were conducted in a murine liver cell line to test the impact of DNA methylation on promoter activity. ResultsIn livers of NZO mice, the overlap of methylome and transcriptome analyses revealed a potential transcriptional dysregulation of 12 hepatokines. The strongest effect with a 52% decreased expression in livers of diabetes-prone mice was detected for the Hamp gene, mediated by elevated DNA methylation of two CpG sites located in the promoter. Hamp encodes the iron-regulatory hormone hepcidin, which had a lower abundance in the livers of mice prone to developing diabetes. Suppression of Hamp reduces the levels of pAKT in insulin-treated hepatocytes. In liver biopsies of obese insulin-resistant women, HAMP expression was significantly downregulated along with increased DNA methylation of a homologous CpG site. In blood cells of incident T2D cases from the prospective EPIC-Potsdam cohort, higher DNA methylation of two CpG sites was related to increased risk of incident diabetes. ConclusionsWe identified epigenetic changes in the HAMP gene which may be used as an early marker preceding T2D.

Blood orange juice intake changes specific bacteria of gut microbiota associated with cardiometabolic biomarkers.

Blood orange juice is an important source of flavanones and anthocyanins, mainly hesperidin, narirutin, and cyanidin-3-O-glucoside. The benefits of these bioactive compounds have been reported, but the mechanistic details behind their biological effects are not well established. This study investigated the effects of Moro orange (Citrus sinensis L. Osbeck) juice (MOJ) on gut microbiota composition and cardiometabolic biomarkers in overweight women. In this study, 12 overweight women (BMI from 25.0 to 29.9 kg/m2), aged 18-37 years, consumed 500 mL of MOJ every day for 4 weeks. We assessed the gut microbiota composition, levels of short-chain fatty acids (SCFAs), cardiometabolic biomarkers, and insulin resistance (HOMA-IR) at baseline and after 2 weeks and 4 weeks of MOJ intake. The results suggested that MOJ intake affected the abundance of specific operational taxonomic units (OTUs) of the gut microbiota but did not significantly alter the diversity and general composition of the gut microbiota. However, MOJ intake increased the production of SCFAs, especially propionic and isobutyric acids, and significantly improved cardiometabolic biomarkers such as blood pressure and plasma VCAM-1 levels in the overweight women. Additionally, we observed significant associations between gut microbiota OTUs belonging to the Bacteroidetes phyla and Prevotella 9 genera and the cardiometabolic biomarkers. Furthermore, MOJ reduced fasting glucose and insulin levels and HOMA-IR values, thereby enhancing insulin sensitivity in the insulin-resistant overweight women. Finally, we highlighted the importance of orange juice intake duration because some beneficial changes such as blood pressure improvements were evident at the 2-week time interval of the intervention, but other changes became significant only at the 4-week interval of MOJ intake. In conclusion, our study demonstrated that changes in specific OTUs of the gut microbiota in response to MOJ intake were associated with significant improvements in some cardiometabolic biomarkers and SCFA levels in overweight women with insulin resistance.

The Effect and Safety Assessment of Metformin and DLBS3233 (A Bioactive Fraction of Lagerstroemia speciosa and Cinnamomum burmannii) on Improving Metabolic Parameters in Women with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) can lead to compensatory hyperinsulinemia with consequent metabolic abnormalities in women. In this study, DLBS3233 and Metformin were used to be tested. DLBS3233 itself is the new insulin-sensitizing drug, a combination-bioactive-fraction derived from two Indonesian herbals, Lagerstroemia speciosa and Cinnamomum burmannii. DLBS3233 alone and in combination with metformin were evaluated for efficacy and safety in insulin-resistant women with polycystic ovary syndrome (PCOS). A randomized, double-blind, 3-arm, double-dummy, non-inferiority, and also a controlled clinical study was conducted at the Dr. Kariadi Hospital, Indonesia, between October 2014 and February 2019. The study involved 60 female subjects (with 20 female subjects in each group) that had polycystic ovary syndrome (PCOS).Treatment I consists of one placebo capsule twice per day and one 100 mg DLBS3233 capsule once per day. Treatment II consists of one placebo caplet once per day and one 750 mg Metformin XR caplet twice per day. Treatment III consists of one 750 mg Metformin XR caplet twice per day and one 100 mg DLBS3233 capsule once per day. In treatment I, the homeostatic model assessment for insulin resistance (HOMA-IR) levels were 3.55, 3.59, and 3.80 at pretest, 3 months, and 6 months after intervention, respectively. In treatment II, the HOMA-IR level were 4.00, 2.21, and 4.40 at pretest, 3 months, and 6 months after intervention respectively. In treatment III, the HOMA-IR levels were 3.30, 2.86, and 3.12 at pretest, 3 months, and 6 months after intervention, respectively. There was no apparent difference existed in the fasting plasma glucose (FPG), high-density lipoprotein (HDL), triglycerides, ferriman-gallwey scores (FGS), and safety assessment on vital signs and laboratory examinations (liver function and renal function) in all groups. Either DLBS3233 alone or the DLBS3233/Metformin combination showed no significant efficacy and did not negatively affect cardiovascular function, liver and kidney function in PCOS subjects. NCT01999686 Date: 3rd of December, 2013.

Retraction.

Hamed, H.O., Hasan, A.F., Ahmed, O.G. and Ahmed, M.A. (2010), Metformin versus laparoscopic ovarian drilling in clomiphene- and insulin-resistant women with polycystic ovary syndrome. International Journal of Gynecology & Obstetrics, 108: 143-147. https://doi.org/10.1016/j.ijgo.2009.08.033 The above article, published online on 4 November 2009 on Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal's Editor-in-Chief, Professor Michael Geary, the International Federation of Gynecology and Obstetrics and John Wiley & Sons Ltd. The journal's Editor-in-Chief was contacted by a third party who raised concerns about the article. Following review, the journal's research integrity team found substantial errors in the study's reported results. Thus, they consider the article's conclusions unreliable.

P-643 The effect of hyperinsulinemia on FSH-mediated signalling pathways in granulosa cells - implications for follicle growth in women with PCOS

Abstract Study question Does in vitro exposure of granulosa cells (GC) to an equivalent hyperinsulinemic (HI) dose of insulin alter key signalling pathways, potentially slowing follicle growth? Summary answer Exposure of GC to HI dose of insulin down-regulated FSH-mediated phosphorylation of AKT and ERK proteins, which was reversed by metformin but not myoinositol treatment What is known already Antral follicles utilise glycolytic methods of energy production releasing the metabolites pyruvate and lactate, which are then secreted into the follicular fluid or passed directly to the oocyte via gap junctions. Insulin increases GC glucose uptake and cross-talks with FSH-mediated intracellular pathways that determine follicle growth and glucose utilisation. We and others have shown that there is significant perturbation in glucose metabolism (as measured by reduced lactate production) in cultured luteinised GC (GLC) from women with anovulatory PCOS, compared to those with normal ovaries or polycystic ovarian morphology (PCOM), that represents both attenuated glucose uptake and reduced glycolytic activity. Study design, size, duration KGN-GC were exposed to 1000ng/ml insulin for 48h (mimicking prolonged HI in vivo) with/without metformin [10-7M] or myo-inositol [25mM]; followed by acute stimulation with FSH (10ng/ml at 15 and 30 mins) (n = 4-5). GLCs obtained from women with normal ovaries (n = 5), PCOM (n = 7) and PCOS (n = 2) were serum-starved and exposed acutely to insulin (10ng/ml for 30mins), glucose starved (20mins) and treated with a radiolabelled 2-deoxy-glucose mix. Fasting serum glucose and insulin were measured in PCOS women. Participants/materials, setting, methods Western blotting on proteins from KGN-GC was performed using antibodies against total and phosphorylated forms of AKT and ERK. Densitometry measurements of phospho:total forms were taken from individual treatments, normalised to loading controls (either β-actin/Vinculin) and then untreated controls. GLCs were lysed and uptake of 14C-2DG (non-metabolised) measured and expressed as percentage uptake of 14C-2DG in the insulin-treated normalised to untreated/control cells (100%). Insulin resistance (IR) was calculated from fasting glucose and insulin using HOMA2. Main results and the role of chance Chronic exposure of KGNs to high dose insulin significantly down-regulated acute FSH-mediated phosphorylation of AKT and ERK (ANOVA *p=0.03, multiple post-hoc t-tests p < 0.05, two-tailed), without altering insulin receptor levels. Addition of metformin to FSH treatment, significantly reversed the HI-induced reduction in pAKT levels and enhanced it further (*p=0.02) but had no effect on pERK levels. Myoinositol had no effect on either pAKT or pERK levels. These findings demonstrated that HI directly inhibited FSH signalling events downstream of the insulin receptor in GC, but that metformin could counteract some of these detrimental effects. The 2-deoxy form of glucose is taken up into the cell but not metabolised further. Measurement of 14C-2DG showed that acute stimulation with post-prandial levels of insulin of GLCs taken from normal and PCOM women significantly increased glucose uptake (*p<0.05, ratio of paired t-test, 2-tailed); whereas GLCs from women with PCOS and insulin resistance were unable to respond to insulin and take up glucose. Therefore, GLCs from insulin resistant women with PCOS retain their phenotype in vitro and this is not an artefact, since GLCs from normal and PCOM also subjected to the same stimulation regime were able to take up glucose in response to insulin stimulation. Limitations, reasons for caution A clear limitation is the small number of insulin resistant women with PCOS. In addition, human GLCs were collected after hormonal stimulation. Wider implications of the findings Women with IR, HI and PCOS undergoing ART may require extra gonadotrophin stimulation to grow and mature sufficient eggs. Additionally, the oocyte quality maybe compromised, as indicated by reduced glucose uptake. Treatment of women with metformin but not myoinositol may improve the dysregulated FSH-signalling pathways brought about by HI. Trial registration number not applicable

Testosterone-associated blood pressure dysregulation in women with androgen excess polycystic ovary syndrome.

We tested the hypothesis that hyperandrogenemia in androgen excess polycystic ovary syndrome (AE-PCOS) is a primary driver in blood pressure (BP) dysregulation via altered sympathetic nervous system activity (SNSA), reduced integrated baroreflex gain and increased renin-angiotensin system (RAS) activation. We measured resting SNSA (microneurography), integrated baroreflex gain, and RAS with lower body negative pressure in obese insulin-resistant (IR) women with AE-PCOS [n = 8, 23 ± 4 yr; body mass index (BMI) = 36.3 ± 6.4 kg/m2] and obese IR controls (n = 7, control, 29 ± 7 yr; BMI = 34.9 ± 6.8 kg/m2), at baseline (BSL), after 4 days of gonadotropin-releasing hormone antagonist (ANT, 250 μg/day) and 4 days of ANT + testosterone (ANT + T, 5 mg/day) administration. Resting BP was similar between groups for systolic blood pressure (SBP; 137 ± 14 vs. 135 ± 14 mmHg, AE-PCOS, control) and diastolic BP (89 ± 21 vs. 76 ± 10 mmHg, AE-PCOS, control). BSL integrated baroreflex gain was similar between groups [1.4 ± 0.9 vs. 1.0 ± 1.3 forearm vascular resistance (FVR) U/mmHg], but AE-PCOS had lower SNSA (10.3 ± 2.0 vs. 14.4 ± 4.4 burst/100 heartbeats, P = 0.04). In AE-PCOS, T suppression increased integrated baroreflex gain, which was restored to BSL with ANT + T (4.3 ± 6.5 vs. 1.5 ± 0.8 FVR U/mmHg, ANT, and ANT + T, P = 0.04), with no effect in control. ANT increased SNSA in AE-PCOS (11.2 ± 2.4, P = 0.04). Serum aldosterone was greater in AE-PCOS versus control (136.5 ± 60.2 vs. 75.7 ± 41.4 pg/mL, AE-PCOS, control, P = 0.04) at BSL but was unaffected by intervention. Serum angiotensin-converting enzyme was greater in AE-PCOS versus control (101.9 ± 93.4 vs. 38.2 ± 14.7 pg/mL, P = 0.04) and reduced by ANT in AE-PCOS (77.7 ± 76.5 vs. 43.4 ± 27.3 µg/L, ANT, and ANT + T, P = 0.04) with no impact on control. Obese, IR women with AE-PCOS showed decreased integrated baroreflex gain and increased RAS activation compared with control.NEW & NOTEWORTHY Here we present evidence for an important role of testosterone in baroreflex control of blood pressure and renal responses to baroreceptor unloading in women with a common, high-risk androgen excess polycystic ovary syndrome (AE-PCOS) phenotype. These data indicate a direct effect of testosterone on the vascular system of women with AE-PCOS independent of body mass index (BMI) and insulin-resistant (IR). Our study indicates that hyperandrogenemia is a central underlining mechanism of heightened cardiovascular risk in women with PCOS.

Serum HMGB1 levels are independently associated with glucose clamp-derived measures of insulin resistance in women with PCOS

PurposePCOS is associated with low grade inflammation which could play a role in insulin resistance and ovarian dysfunction. Preliminary findings suggested that serum levels of HMGB1, a cytokine involved in inflammation, might be altered in women with PCOS. Primary aim of this study was to assess whether HMGB1 serum concentrations are associated with PCOS and with the state of insulin resistance of these women.MethodsSixty women with PCOS, selected to have a similar proportion of subjects with altered or normal insulin sensitivity, and 29 healthy controls were studied. Serum HMGB1 levels were compared in subgroups of PCOS women and controls. In PCOS women, insulin sensitivity was assessed by the glucose clamp technique and HMGB1 was measured at baseline and after acute hyperinsulinemia.ResultsHMGB1 levels were similar in women with PCOS and controls and no elements used for diagnosing PCOS were associated with serum HMGB1. However, HMGB1 concentrations were higher in insulin-resistant vs insulin-sensitive PCOS women (p = 0.017), and inversely associated with insulin-induced total and non-oxidative glucose metabolism. In both subgroups of PCOS women, serum HMBG1 levels significantly increased after acute hyperinsulinemia.ConclusionsThese data suggest that HMGB1 levels are not associated with PCOS per se, but with insulin resistance. Further research should establish the underlying nature of this relationship, and whether this protein might play a role in the metabolic complications of PCOS.

Metformin inhibits ovarian granular cell pyroptosis through the miR-670-3p/NOX2/ROS pathway

Recent studies have demonstrated that ovarian granular cells (OGCs) pyroptosis is present in the ovaries of polycystic ovary syndrome (PCOS) mice and that NLRP3 activation destroys follicular functions. Metformin has been shown to protect against PCOS by reducing insulin resistance in women, whereas its role in OGC pyroptosis is unknown. This study aimed to investigate the impact of metformin on OGC pyroptosis and the underlying mechanisms. The results showed that treating a human granulosa-like tumor cell line (KGN) with metformin significantly decreased LPS-induced expression of miR-670-3p, NOX2, NLRP3, ASC, cleaved caspase-1, and GSDMD-N. Cellular caspase-1 activity; ROS production; oxidative stress; and the secretion of IL-1β, IL-6, IL-18, and TNF-α were also diminished. These effects were amplified by adding N-acetyl-L-cysteine (NAC), a pharmacological inhibitor of ROS. In contrast, metformin's anti-pyroptosis and anti-inflammatory effects were robustly ameliorated by NOX2 overexpression in KGN cells. Moreover, bioinformatic analyses, RT-PCR, and Western blotting showed that miR-670-3p could directly bind to the NOX2 (encoded by the CYBB gene in humans) 3'UTR and decrease NOX2 expression. Metformin-induced suppression of NOX2 expression, ROS production, oxidative stress, and pyroptosis was significantly alleviated by transfection with the miR-670-3p inhibitor. These findings suggest that metformin inhibits KGN cell pyroptosis via the miR-670-3p/NOX2/ROS pathway.

Association between serum leptin concentrations and homeostasis model assessment-insulin resistance of 2.5 and higher in normal weight Japanese women

Normal weight insulin resistant phenotype was characterized in 251 Japanese female university students using homeostasis model assessment-insulin resistance. Birth weight, body composition at age 20, cardiometabolic traits and dietary intake were compared cross-sectionally between insulin sensitive (< 1.6, n = 194) and insulin resistant (2.5 and higher, n = 16) women. BMI averaged < 21 kg/m2 and waist < 72 cm and did not differ between two groups. The percentage of macrosomia and serum absolute and fat-mass corrected leptin concentrations were higher in insulin resistant women although there was no difference in birth weight, fat mass index, trunk/leg fat ratio and serum adiponectin. In addition, resting pulse rate, serum concentrations of free fatty acids, triglycerides and remnant-like particle cholesterol were higher in insulin resistant women although HDL cholesterol and blood pressure did not differ. In multivariate logistic regression analyses, serum leptin (odds ratio:1.68, 95% confidential interval:1.08–2.63, p = 0.02) was associated with normal weight insulin resistance independently of macrosomia, free fatty acids, triglycerides, remnant-like particle cholesterol and resting pulse rate. In conclusion, normal weight IR phenotype may be associated with increased plasma leptin concentrations and leptin to fat mass ratio in young Japanese women, suggesting higher leptin production by body fat unit.

Association between polycystic ovarian morphology and insulin resistance in women with polycystic ovary syndrome.

The aim of the present study was to determine whether polycystic ovarian morphology (PCOM) is related to insulin resistance in women with polycystic ovary syndrome (PCOS). A total of 147 Korean women aged 18 to 35 years and diagnosed with PCOS were included in this study. Fasting blood tests and standard 2-hour 75-g oral glucose tolerance tests were performed for all participants. PCOM-related parameters including total antral follicle count (TFC) and total ovarian volume (TOV) were assessed using transvaginal or transrectal ultrasonography. Correlation analysis was conducted to assess the relationships of TFC and TOV with insulin resistance-related clinical and biochemical parameters using Spearman rank correlation coefficients and linear regression analysis, with partial correlations used to control for the effects of confounding covariates. Fasting insulin levels, low-density lipoprotein levels, and insulin sensitivity assessment indices (ISAIs) were significantly correlated with TFC, but neither postprandial blood glucose levels nor insulin levels were significantly associated with TFC. No insulin resistance-related parameter was significantly correlated with TOV. These results did not change after adjustments for other anthropometric covariates. Fasting insulin and some ISAIs differed significantly between groups categorized by the median TFC value (TFC ≤54 and TFC >54). TFC, but not TOV, was found to be related to fasting insulin resistance-related parameters in women with PCOS.

Serum AMH levels and insulin resistance in women with Hashimoto thyroiditis

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Testosterone effects on autonomic function in women with androgen excess polycystic ovary syndrome

Women with androgen excess-polycystic ovarian syndrome (AE-PCOS) present with increased blood pressure (BP) and impaired cardiovascular autonomic control. We tested the hypothesis that androgens play an obesity-independent role in impaired baroreflex (BR) sensitivity and renin-angiotensin system (RAS) control of BP in women with AE-PCOS. We measured the sympathetic baroreflex (sBR) and cardiovagal baroreflex (cvBR) with the modified Oxford procedure, and integrated baroreflex (iBR) and the RAS response to lower body negative pressure (LBNP) in obese, insulin resistant (IR) women with AE-PCOS (n=9; age=23±4 y; BMI=36.3±6.4 kg/m2) and obese, IR controls (CTL) (n=7; age=29±7 y; BMI=34.9±6.8 kg/m2). Studies were conducted at baseline (BSL), after 4 days of reproductive hormone suppression with a gonadotropin-releasing hormone antagonist (ANT, 250 μg/day), and after 4 days of ANT+testosterone (ANT+T, 5 mg/day). At BSL, AE-PCOS and CTL had similar systolic BP (137±14 vs.133±14 mmHg, respectively) and diastolic BP (76±8 vs.63±12 mmHg, respectively). Resting MSNA burst incidence was lower (10.3±3.1 vs. 14.3±4.4 bursts-1×100 hb, P=0.04), but total MSNA activity was greater in AE-PCOS compared to CTL (249±112 vs. 156±44 bursts/min, respectively, P=0.04). Hormone intervention did not impact resting MSNA or BP in either group. In the AE-PCOS group, sBR gain increased during modified Oxford with ANT suppression of T, but sBR gain was restored to BSL when T was reintroduced (-0.48±0.15, -0.63±0.19, and -0.50±0.15 bursts -1 ·100 hb·mmHg -1 for BSL, ANT and ANT+T, respectively, P=0.01). Hormone interventions did not impact sBR gain in CTL (-0.48±0.06, -0.47±0.10, and -0.46±0.09 bursts -1 ·100 hb·mmHg -1 for BSL, ANT and ANT+T, respectively). iBR gain for AE-PCOS and CTL was similar at BSL (1.4±0.9 vs. 1.0±1.3 FVR unit/mmHg, respectively). In AE-PCOS, T suppression increased iBR gain, which was restored to BSL with ANT+T (4.3±6.5 vs.1.5±0.8 FVR unit/mmHg for ANT and ANT+T respectively, P&lt;0.04), with no effect in CTL (1.9 ± 3.0 vs. 0.7±0.9 FVR unit/mmHg for ANT and ANT+T, respectively). cvBR gain was unaffected by group or treatment. Serum aldosterone was greater in AE-PCOS vs CTL (136.5±60.2 vs. 75.7±41.4 pg/ml, respectively, P&lt;0.04), but unaffected by hormone intervention. Serum angiotensin converting enzyme (S [ACE] ) in AE-PCOS was greater compared to CTL at BSL (101.9±93.4 vs. 38.2 ±14.7 pg/ml, respectively, P&lt;0.04). In AE-PCOS, S [ACE] was reduced by ANT (77.7 ±76.5 and 40.6±10.6 μg/L for ANT vs. ANT+T, respectively, P&lt;0.04), but hormone intervention did not impact CTL (43.4±27.3 and 40.6±1 μg/L for ANT vs. ANT+T, respectively, P&lt;0.04). These data suggest the milieu of AE-PCOS increases susceptibility to T driven autonomic perturbations as T elevation had differential effects in AE-PCOS vs. CTL. Our data indicate a powerful relationship among elevated androgens, autonomic function, and the kidney.NIH HL135089/P20GM 121334 National Institutes of Health, NHLBI HL135089 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.