ALDOB/KAT2A interactions epigenetically modulate TGF-ß expression and T cell functions in hepatocellular carcinogenesis.

BACKGROUND AND AIMS: Cross talk between tumor cells and immune cells enables tumor cells to escape immune surveillance and dictate responses to immunotherapy. Previous studies have identified that downregulation of the glycolytic enzyme fructose-1,6-bisphosphate aldolase B (ALDOB) in tumor cells orchestrated metabolic programming to favor HCC. However, it remains elusive whether and how ALDOB expression in tumor cells affects the tumor microenvironment in HCC. APPROACH AND RESULTS: We found that ALDOB downregulation was negatively correlated with CD8 + T cell infiltration in human HCC tumor tissues but in a state of exhaustion. Similar observations were made in mice with liver-specific ALDOB knockout or in subcutaneous tumor models with ALDOB knockdown. Moreover, ALDOB deficiency in tumor cells upregulates TGF-ß expression, thereby increasing the number of Treg cells and impairing the activity of CD8 + T cells. Consistently, a combination of low ALDOB and high TGF-ß expression exhibited the worst overall survival for patients with HCC. More importantly, the simultaneous blocking of TGF-ß and programmed cell death (PD) 1 with antibodies additively inhibited tumorigenesis induced by ALDOB deficiency in mice. Further mechanistic experiments demonstrated that ALDOB enters the nucleus and interacts with lysine acetyltransferase 2A, leading to inhibition of H3K9 acetylation and thereby suppressing TGFB1 transcription. Consistently, inhibition of lysine acetyltransferase 2A activity by small molecule inhibitors suppressed TGF-ß and HCC. CONCLUSIONS: Our study has revealed a novel mechanism by which a metabolic enzyme in tumor cells epigenetically modulates TGF-ß signaling, thereby enabling cancer cells to evade immune surveillance and affect their response to immunotherapy.

Liver fat is superior to visceral and pancreatic fat as a risk biomarker of impaired glucose regulation in overweight/obese subjects.

AIM: To investigate the distribution of abdominal fat, particularly ectopic fat accumulation, in relation to glucose metabolism in overweight/obese patients. MATERIALS AND METHODS: This study included 257 overweight/obese subjects with body mass index ≥23 kg/m2 . All the subjects underwent an oral glucose tolerance test. Magnetic resonance imaging-proton density fat fraction was used to measure fat accumulation in the liver, pancreas and abdomen. Impaired glucose regulation (IGR) was defined as the presence of prediabetes or diabetes. RESULTS: Liver fat content (LFC) and visceral adipose tissue (VAT) were higher in overweight/obese subjects with diabetes than in those with normal glucose tolerance (NGT). No significant differences were observed in the pancreas fat content and subcutaneous fat area between subjects with NGT and IGR. LFC was an independent risk factor of IGR (odds ratio = 1.824 per standard deviation unit, 95% CI 1.242-2.679, p = .002). Compared with the lowest tertile of LFC, the multivariate-adjusted odds ratio for the prevalence of IGR in the highest tertile was 2.842 (95% CI 1.205-6.704). However, no association was observed between the VAT per standard deviation increment and tertiles after adjusting for multiple factors. For discordant visceral and liver fat phenotypes, the high LFC-low VAT and high LFC-high VAT groups had a higher prevalence of IGR than the low LFC-low VAT group. However, there was no difference in the prevalence of IGR between the low LFC-low VAT and low LFC-high VAT groups. CONCLUSION: Compared with visceral and pancreatic fat content, LFC is a superior risk biomarker for IGR in overweight/obese subjects.

Prediction model of gleason score upgrading after radical prostatectomy based on a bayesian network.

OBJECTIVE: To explore the clinical value of the Gleason score upgrading (GSU) prediction model after radical prostatectomy (RP) based on a Bayesian network. METHODS: The data of 356 patients who underwent prostate biopsy and RP in our hospital from January 2018 to May 2021 were retrospectively analysed. Fourteen risk factors, including age, body mass index (BMI), total prostate-specific antigen (tPSA), prostate volume, total prostate-specific antigen density (PSAD), the number and proportion of positive biopsy cores, PI-RADS score, clinical stage and postoperative pathological characteristics, were included in the analysis. Data were used to establish a prediction model for Gleason score elevation based on the tree augmented naive (TAN) Bayesian algorithm. Moreover, the Bayesia Lab validation function was used to calculate the importance of polymorphic Birnbaum according to the results of the posterior analysis and to obtain the importance of each risk factor. RESULTS: In the overall cohort, 110 patients (30.89%) had GSU. Based on all of the risk factors that were included in this study, the AUC of the model was 81.06%, and the accuracy was 76.64%. The importance ranking results showed that lymphatic metastasis, the number of positive biopsy cores, ISUP stage and PI-RADS score were the top four influencing factors for GSU after RP. CONCLUSIONS: The prediction model of GSU after RP based on a Bayesian network has high accuracy and can more accurately evaluate the Gleason score of prostate biopsy specimens and guide treatment decisions.

Overexpressed LAMC2 promotes trophoblast over-invasion through the PI3K/Akt/MMP2/9 pathway in placenta accreta spectrum.

BACKGROUND: Placenta accreta spectrum (PAS) is an ongoing major iatrogenic public health challenge with devastating obstetric complications, but its underlying molecular pathogenesis remains poorly illuminated. LAMC2 is reported to regulate tumor cells proliferation and invasion, yet has not been explored in placenta trophoblast cells. This study investigated LAMC2 expression and its contribution in the etiology of PAS. METHODS: Quantitative polymerase chain reaction, western blot, and immunohistochemistry were performed to detect the expression of LAMC2 in placentas. Cell proliferation, invasion, migration, and apoptosis were monitored by CCK8 assay, wound healing assay, transwell invasion assay, and flow cytometry assay. Western blot was conducted to confirm the pertinent proteins level of PI3K/Akt/MMP2/9 pathway in HTR8/SVneo cells. RESULTS: LAMC2 was predominantly expressed in placental villous syncytiotrophoblasts and cytotrophoblasts. LAMC2 mRNA and protein expression were substantially upregulated in placental tissues with PAS compared to those with pernicious placenta previa without PAS. LAMC2 overexpression eminently boosted HTR8/SVneo cells proliferation, invasion, and migration, but inhibited apoptosis, accompanied by elevated protein expression of MMP2, MMP9, and phosphorylated Akt (pAkt). Knockdown of LAMC2 yielded the converse results. Additionally, when treated with LY294002, the effects of LAMC2 overexpression on proliferation, migration, invasion, and apoptosis of HTR8/SVneo cells were abolished and concomitantly the elevated pAkt, MMP2, and MMP9 proteins induced by LAMC2 overexpression were eliminated. CONCLUSION: Our study highlighted the involvement of LAMC2 in the pathogenesis of PAS by activating the PI3K/Akt/MMP2/9 signaling pathway to stimulate trophoblast over-invasion. These findings provide a new target for the diagnosis and disease stratification of PAS.

Follicular free fatty acid metabolic signatures and their effects on oocyte competence in non-obese PCOS patients.

In Brief: Polycystic ovary syndrome (PCOS) is a common cause of anovulatory infertility in women. This study identified changes in free fatty acids profiles in the follicular fluid that may lead to better diagnosis and management of infertility in PCOS women. Abstract: Polycystic ovary syndrome (PCOS) is a heterogeneous disease characterized by various endocrine/metabolic disorders and impaired reproductive potential. Alterations in oocyte competence are considered potentially causative factors for infertility in PCOS women and analyzing the composition of follicular fluid in these patients may help to identify which changes have the potential to alter oocyte quality. In this study, free fatty acid metabolic signatures in follicular fluid were performed to identify changes that may impact oocyte competence in non-obese PCOS women. Sixty-four non-obese women (32 with PCOS and 32 age- and BMI-matched controls) undergoing in vitro fertilization were recruited. Embryo quality was morphologically assessed. Free fatty acid metabolic profiling in follicular fluid was performed using gas/liquid chromatography-mass spectrometry. Principal component analysis and orthogonal partial least squares-discriminant analysis models were further constructed. Nine free fatty acids and 24 eicosanoids were identified and several eicosanoids synthesized by the cyclooxygenase pathway were significantly elevated in PCOS patients compared to controls. The combination of PGE2, PGF2α, PGJ2, and TXB2 had an area under the curve of 0.867 (0.775-0.960) for PCOS discrimination. Furthermore, follicular fluid levels of PGE2 and PGJ2 were negatively correlated with high-quality embryo rate in PCOS patients (P < 0.05). Metabolomic analysis revealed that follicular fluid lipidomic profiles undergo changes in non-obese PCOS women, which suggests that identifying changes in important metabolic signatures may give us a better understanding of the pathogenesis of PCOS. Furthermore, elevated PGE2 and PGJ2 concentrations may contribute to impaired oocyte competence in non-obese PCOS patients.

Culture on a native bone marrow-derived extracellular matrix restores the pancreatic islet basement membrane, preserves islet function, and attenuates islet immunogenicity.

Islet transplantation in man is limited by multiple factors including islet availability, islet cell damage caused by collagenase during isolation, maintenance of islet function between isolation and transplantation, and allograft rejection. In this study, we describe a new approach for preparing islets that enhances islet function in vitro and reduces immunogenicity. The approach involves culture on native decellularized 3D bone marrow-derived extracellular matrix (3D-ECM), which contains many of the matrix components present in pancreas, prior to islet transplantation. Compared to islets cultured on tissue culture plastic (TCP), islets cultured on 3D-ECM exhibited greater attachment, higher survival rate, increased insulin content, and enhanced glucose-stimulated insulin secretion. In addition, culture of islets on 3D-ECM promoted recovery of vascular endothelial cells within the islets and restored basement membrane-related proteins (eg, fibronectin and collagen type VI). More interestingly, culture on 3D-ECM also selectively decontaminated islets of "passenger" cells (co-isolated with the islets) and restored basement membrane-associated type VI collagen, which were associated with an attenuation in islet immunogenicity. These results demonstrate that this novel approach has promise for overcoming two major issues in human islet transplantation: (a) poor yield of islets from donated pancreas tissue and (b) the need for life-long immunosuppression.

Correlation between glucose metabolism and serum steroid hormones in patients with polycystic ovary syndrome.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with an increased prevalence of dysglycaemia, which includes impaired glucose tolerance and type 2 diabetes mellitus (T2DM). Patients with PCOS demonstrate abnormal patterns of steroid hormones. Here, we analyse the correlation between glucose metabolism and serum steroid hormones in PCOS. DESIGN: Observational double-centre study. PATIENTS: 914 patients with PCOS. MEASUREMENTS: We assessed the glucose metabolism status of all patients according to the 1999 WHO criteria. Serum steroid hormones were measured by liquid chromatography-tandem mass spectrometry. RESULTS: The median age of the patients was 26 years (interquartile range: 21-30), and 40.6% (371/914) had abnormal glucose metabolism: 29.3% (268/914) had prediabetes, and 11.3% (103/914) had T2DM. Correlation analysis not adjusting for confounding factors revealed that serum aldosterone, androstenedione, oestrone, pregnenolone and the free androgen index were positively correlated, while progesterone was negatively correlated with the risk of abnormal glucose metabolism. After adjusting for age, body mass index and fasting insulin levels in the logistic regression model, only aldosterone (P = .013), androstenedione (P = .046) and oestrone (P = .014; in quartiles) were correlated with the risk of abnormal glucose metabolism. CONCLUSIONS: This study indicates a high prevalence of prediabetes and T2DM in patients with PCOS. Furthermore, there were positive correlations of serum aldosterone, androstenedione and oestrone with the risk of abnormal glucose metabolism after adjusting for confounding factors.

Elevated levels of arachidonic acid metabolites in follicular fluid of PCOS patients.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women usually accompanied by lipid metabolic disorders. However, it remains unknown whether arachidonic acid (AA) and its metabolites in follicular fluid (FF) were altered in PCOS patients. This study was intended to measure the levels of AA and its metabolites in the FF of non-obese PCOS patients that underwent in vitro fertilization (IVF) and to explore the possible causes of the alterations. Thirty-nine non-obese women with PCOS and 30 non-obese women without PCOS were enrolled. AA and its metabolites were measured by liquid chromatography-mass spectrometry. The levels of AA metabolites generated via cyclooxygenase-2 (COX-2) pathway and cytochrome P450 epoxygenase pathway but not lipoxygenase (LOX) pathway were significantly higher in the FF of PCOS patients. The metabolites generated via COX-2 pathway were significantly correlated with levels of testosterone and fasting insulin in serum. The in vitro study further demonstrated that insulin but not testosterone could promote the IL-1ß and hCG-induced COX-2 expression and prostaglandin E2 (PGE2) secretion in primary human granulosa cells. In conclusion, there was an elevation in AA metabolites in FF of PCOS patients. Insulin played a pivotal role in the increased AA metabolites generated via COX-2, which could be interpreted as another novel molecular pathophysiological mechanism of PCOS.

Role of Androgen in Liver Fat Content in Women: Metabolically Advantageous or Disadvantageous?

OBJECTIVE: Androgens have a controversial effect on liver fat content (LFC) in androgen-excess females and androgen-deficient males. Polycystic ovarian syndrome (PCOS) is often associated with hyperandrogenism and nonalcoholic fatty liver disease. The aim of this study was to explore the association between hyperandrogenemia and increased liver fat content in women with PCOS, independent of other metabolic parameters. METHODS: This case series study included 501 women with PCOS and 112 aged-matched controls in the outpatient department of a tertiary hospital. Anthropometric measurements, hepatic and renal function, glucose and lipid metabolism parameters, and sex hormones were examined in these women. LFC was measured by quantitative ultrasonography. RESULTS: Women with hyperandrogenism (P<.001), an oligomenorrhoea/anovulation phenotype (P = .0064), and a diagnosis of PCOS (P<.001) had higher LFC. Androgen level is an important factor among the 9 independent risk factors of LFC (P = .0239) and may have a dimorphic impact on LFC. In all women, when the free androgen index (FAI) was less than 41.94, LFC increased with the elevated FAI; when the FAI was greater than 41.94, LFC decreased with the elevated FAI (P<.001). In women with PCOS, receiver operating characteristic curve analysis demonstrated that LFC could at least partially predict impaired glucose regulation, impaired lipid metabolism, and insulin resistance (P<.0001 for all). CONCLUSION: Androgen level is associated with LFC in dimorphic directions. LFC may be a predictive factor of insulin resistance, impaired glucose regulation, and impaired lipid metabolism in women with PCOS.

Ceramide subclasses identified as novel lipid biomarker elevated in women with polycystic ovary syndrome: a pilot study employing shotgun lipidomics.

This study aimed to identify potential lipid biomarkers in women with polycystic ovary syndrome (PCOS) and determine their predictive value for PCOS. Eighteen women with PCOS and 17 healthy controls were enrolled. A multi-dimensional mass spectrometry-based shotgun lipidomics approach was employed to analyze serum lipid profiles. Shotgun lipidomics revealed that the concentrations of ceramide (Cer) and phosphatidylcholine (PC) were higher (PC: 831.6 ± 217.4 vs. 605.2 ± 164.2 µmol/l; Cer: 3,387.6 ± 829.9 vs. 2,552.2 ± 679.4 nmol/l, respectively), whereas that of lysophosphatidylcholine was lower, in PCOS women than in healthy controls (82.02 ± 39.49 vs. 133.62 ± 65.36 µmol/l, respectively). Receiver operating characteristic analysis showed that the combination of Cer (OH_N16:0/N18:0) and Cer (N22:0) had the greatest discriminatory power to differentiate between women with and without PCOS (area under the curve: 0.889, 95% confidence interval: 0.784-0.994). These results indicate that the combination of Cer (OH_N16:0/N18:0) and Cer (N22:0) may represent a novel lipid predictor of PCOS.

Label-Free and Multiplexed Quantification of microRNAs by Mass Spectrometry Based on Duplex-Specific-Nuclease-Assisted Recycling Amplification.

MicroRNAs (miRNAs) are important biomarker candidates for cancer screening and early detection research. Generally, miRNAs undergo synergistic adjustments in tumor cells. Herein, a mass-spectrometric method based on a duplex-specific-nuclease (DSN)-enzyme-assisted signal-amplification technique was proposed for label-free and multiplexed detection of multiple miRNAs, and applied to the quantification of three miRNAs (i.e., miRNA-141, miRNA-21, and let-7a) in samples of HeLa and MDA-MB231 cell extracts. Experimental results showed that the digestion modes of DSN against three different DNAs complementary to miRNA-141, miRNA-21, and let-7a in their DNA-miRNA heteroduplexes were quite different, verifying the multiplexed-detection capability of the proposed method. Moreover, an advanced calibration model was derived for the quantitative analysis of the complex mass-spectral data measured during the label-free and multiplexed detection of miRNA-141, miRNA-21, and let-7a by the proposed mass-spectrometric method. With the aid of the advanced calibration model, the proposed mass-spectrometric method achieved quite reliable quantitative results for miRNA-141, miRNA-21, and let-7a in samples of HeLa and MDA-MB231 cell extracts, with recovery rates within the range of 89.2 to 111.6%. The limits of detection (LODs) of the proposed mass-spectrometric method for miRNA-141, miRNA-21, and let-7a in standard samples were estimated to be 42, 41, and 95 pM, respectively. Therefore, it is reasonable to expect that the proposed mass-spectrometric method can be a competitive alternative for the label-free and multiplexed detection of multiple miRNAs in clinical diagnosis.

Oncologic outcomes comparison of partial ureterectomy and radical nephroureterectomy for urothelial carcinoma.

BACKGROUND: The appropriate application of various treatment for upper tract urothelial carcinomas (UTUCs) is the key to prolong the survival of UTUC patients. Herein, we used data in our database to assess the oncological outcomes between partial ureterectomy (PU) and radical nephroureterectomy (RNU). METHODS: From 2007 to 2014, 255 patients with UTUC undergoing PU or RNU in our hospital database were investigated. Perioperative, postoperative data, and pathologic outcomes were obtained from our database. Cancer-specific survival (CSS) was assessed through the Kaplan-Meier method with Cox regression models to test the effect of these two surgery types. RESULTS: The mean length of follow-up was 35.8 months (interquartile range 10-47 months). Patients with high pT stage (pT2-4) suffered shorter survival span (HR: 9.370, 95% CI: 2.956-29.697, P < 0.001). There were no significant differences in CSS between PU and RNU (P = 0.964). In the sub-analysis, CSS for RNU and PU showed no significant difference for pTa-1 or pT2-4 tumor patients (P = 0.516, P = 0.475, respectively). CONCLUSIONS: PU is not inferior to RNU in oncologic outcomes. Furthermore, PU is generally recognized with less invasive and better renal function preservation compared with RNU. Thus, PU would be rational for specific patients with UTUCs.

High concentration of chemerin caused by ovarian hyperandrogenism may lead to poor IVF outcome in polycystic ovary syndrome: a pilot study.

A chronic low-grade inflammation state accounts for an important part of the pathogenesis of polycystic ovary syndrome (PCOS). The adipose tissue derived cytokine chemerin has recently been proven to be a proinflammatory chemokine, but its mechanism involved in the pathogenesis of PCOS remains largely unresolved. From non-obese patients with and without PCOS, follicular fluid and granulosa cells were retrieved. The effect of testosterone on the expression of chemerin and its receptors was explored in granulosa cells. IVF outcomes in different groups based on FF-chemerin (chemerin in the follicular fluid) level were further compared. The concentration of FF-chemerin, and the mRNA expression of chemerin and its receptors in granulosa cells from PCOS were significantly higher than those from non-PCOS. FF-chemerin was positively correlative to total testosterone (TT) and luteinizing hormone (LH) in the follicular fluid. Furthermore, testosterone upregulated the expression of chemerin and its receptors in vitro. The oocyte utilization rate and high-quality embryo rate were significantly decreased in the high FF-chemerin group. The upregulated chemerin levels in the ovary of PCOS patients, which may be caused by ovarian hyperandrogenism, may be a risk factor for oocyte maturation and embryo development. These findings may provide a basis for novel interventions to improve IVF outcomes.

Alterations of polyunsaturated fatty acid metabolism in ovarian tissues of polycystic ovary syndrome rats.

The metabolism of polyunsaturated fatty acids (PUFAs) remains poorly characterized in ovarian tissues of patients with polycystic ovary syndrome (PCOS). This study aimed to explore alterations in the levels of PUFAs and their metabolites in serum and ovarian tissues in a PCOS rat model treated with a high-fat diet and andronate. Levels of PUFAs and their metabolites were measured using gas/liquid chromatography-mass spectrometry after the establishment of a PCOS rat model. Only 3 kinds of PUFAs [linoleic acid, arachidonic acid (AA) and docosahexaenoic acid] were detected in both the circulation and ovarian tissues of the rats, and their concentrations were lower in ovarian tissues than in serum. Moreover, significant differences in the ovarian levels of AA were observed between control, high-fat diet-fed and PCOS rats. The levels of prostaglandins, AA metabolites via the cyclooxygenase (COX) pathway, in ovarian tissues of the PCOS group were significantly increased compared to those in the controls. Further studies on the mechanism underlying this phenomenon showed a correlation between decreased expression of phosphorylated cytosolic phospholipase A2 (p-cPLA2) and increased mRNA and protein expression of COX2, potentially leading to a deeper understanding of altered AA and prostaglandin levels in ovarian tissues of PCOS rats.

Reversion of aging-related DHEAS decline in mouse plasma alleviates aging-related glucose tolerance impairment by potentiation of glucose-stimulated insulin secretion of acute phase.

AIMS/HYPOTHESIS: The latest research proposes mild age-related diabetes (MARD) as a subgroup of type 2 diabetes. While in human circulating dehydroepiandrosterone sulfate (DHEAS) decline with age is related to MARD, the role of circulating DHEAS in insulin secretion remains little known. METHODS: After intraperitoneal administration of glucose (2 g/kg) together with DHEAS (50 µg/kg) or equivalent DMSO to young (6-8 week old) or aging (12 month old) male C57BL/6 mice, plasma DHEAS and blood glucose were measured at indicated time point. Then in vitro, we investigated DHEAS effects on GSIS of acute phase in aging mice pancreatic islets as well as in MIN6 cells. Finally we conducted pharmacological studies in MIN6 cells to examine whether exert its effects on insulin secretion by itself. RESULTS: We found in vivo that aging mice had lower plasma DHEAS levels and impaired glucose tolerence compared to young mice and that the aged mice but not the young mice receiving DHEAS supplement had improved glucose tolerance as soon as 15 min after glucose injection compared to the ones with DMSO administration. These results indicate that in male mice, aging-related DHEAS decline in plasma contribute to aging-related impairment of glucose tolerence and that reversion of aging-related DHEAS deficiency in aging mice plasma could alleviate aging-related glucose tolerance impairment. Consistently, in vitro DHEAS glucose-and dose-dependently potentiated glucose-stimulated insulin secretion (GSIS) of acute phase in both aging male mice pancreatic islets and MIN6 cells. Moreover, none of steroid sulfatase (STS) inhibitor STX64 (10 nM), androgen receptor (AR) blocker flutamide (1 mM) or estrogen receptor (ER) antagonist ICI182780 (1 mM), affected DHEAS-potentiated high GSIS of acute phase indicating this potentiation exercised by DHEAS per se CONCLUSIONS: /interpretation These results lead us to tentatively conclude that aging-related DHEAS decline may imply MARD development and that adequate DHEAS supplement may be a precise medicine and preventive measure for MARD.

A dense mapping study of six European AITD susceptibility regions in a large Chinese Han Cohort of Graves' disease.

OBJECTIVE: We aimed to investigate the six susceptibility loci of GD identified from European population in Chinese Han population and further to estimate the genetic heterogeneity of them in stratification of our GD patients. DESIGN: Dense mapping studies based on GWAS. PATIENTS: A total of 1536 GD patients and 1516 controls in GWAS stage and 1994 GD patients and 2085 controls and 5033 GD patients and 5389 controls in two replication stages. MEASUREMENTS: Based on our previous GWAS data, independently GD-associated SNPs in each region were identified by TagSNP analysis and logistic regression analysis. The association of these SNPs was investigated in 1994 GD patients and 2085 controls, and then, the significantly associated SNPs (P < 0.05) were further genotyped in a second cohort including 5033 GD patients and 5389 controls. RESULTS: After the first replication stage, four SNPs from three regions with Pfirst  < 0.05 were further selected and genotyped in another independent cohort. The association of two SNPs with GD was confirmed in combined Chinese cohorts: rs12575636 at 11q21 (Pcombined  = 7.55 × 10-11 , OR = 1.27) and rs1881145 in TRIB2 at 2p25.1 (Pcombined  = 5.59 × 10-8 , OR = 1.14). Further study disclosed no significant difference for these SNPs between GD subsets. However, eQTL data revealed that SESN3 could be a potential susceptibility gene of GD in 11q21 region. CONCLUSIONS: Out of the six susceptibility loci of GD identified from European population, two risk loci were confirmed in a large Chinese Han population. There is variability in GD genetic susceptibility in different ethnic groups. SESN3 is a potential susceptible gene of GD in 11q21.

An inverse association between serum soluble receptor of advanced glycation end products and hyperandrogenism and potential implication in polycystic ovary syndrome patients.

BACKGROUND: Studies found that AGE-RAGE system is closely related to insulin resistance and hyperandrogenemia, which are two core pathophysiological processes in polycystic ovary syndrome (PCOS). This study is to investigate the relationship among advanced glycation end-products/soluble receptor of advanced glycation end-products (AGEs/sRAGE) and anthropometric evaluation, homeostatic model assessment-insulin resistance (HOMA-IR), free androgen index (FAI) in reproductive-aged PCOS patients. METHODS: One hundred and forty-eight Chinese women with PCOS were enrolled in this study. Subgroups were divided according to body mass index (BMI), waist circumference (WC), quartile intervals of HOMA-IR and androgen levels. The relationships between AGEs/sRAGE and above clinical markers were assessed by Pearson's correlation analyses. RESULTS: Serum AGEs showed a gradually increased tendency with BMI and WC. It reached statistical significant between the normal weight group (BMI < 24 kg/m2) and the obesity group (BMI ≥ 28 kg/m2) . The sRAGE levels gradually decreased with increasing BMI, WC, HOMA-IR and FAI respectively. Furthermore, the differences between each group were statistical significant. The correlation analysis showed a positive correlation between BMI and serum AGEs levels. On the contrary, the sRAGE levels showed significantly inverse correlations with BMI, WC, HOMA-IR and FAI. The optimal point of sRAGE for the presence of insulin resistance was 704.097 pg/ml by ROC curve analysis. CONCLUSIONS: Along with the body fat accumulation, the serum levels of AGEs were increased, whereas, the serum levels of sRAGE were reduced in obese PCOS patients. The serum levels of sRAGE, which is a decoy receptor, dramatically decreased in the patients with more severe insulin resistant states and higher FAI, which might be a potential biomarker and a promising therapeutic target in the treatment of PCOS, especially in obese subjects.

Expression of sweet taste receptor and gut hormone secretion in modelled type 2 diabetes.

Sweet taste receptors (STRs) are expressed in L cells which secret glucagon-like peptide-1 (GLP-1) in the gut. The STR blocker lactisole reduces GLP-1 secretion and increases blood glucose levels. Therefore, we investigated the expression of sweet taste molecules in the proximal and distal small intestine, and gut hormone secretion, in healthy control and type 2 diabetic rats. Two groups of rats (Sprague Dawley (SD), and Zucker diabetic fatty (ZDF)) were involved in the study. Each group (n=10) received an intragastric glucose infusion (50% glucose solution, 2g/kg body weight). Blood samples were taken for measurement of blood glucose, plasma insulin, and GLP-1 concentrations. One week later, we obtained small intestinal tissue and detected the expression of STRs and glucose transporters (GTs) by real time polymerase chain reaction (Real Time-PCR). Sweet taste molecules of T1R2, T1R3, α-gustducin and TRPM5 in ileum were dramatically higher than those in duodenum (P<0.01 for each). T1R3, α-gustducin and TRPM5 expression were less in the ileum of ZDF than those in SD (P<0.05 for each), while expression of glucose transporter 2 (GLUT-2) in ileum was significantly higher in ZDF rats. Plasma GLP-1 levels were higher in ZDF rats than SD rats at t=0, 15, 30, 60 and 120min (P<0.01). In conclusion, transcript levels of ileal T1R3 and GLUT-2 are disordered in ZDF rats suggesting that intestinal sweet taste receptor expression is associated with altered glucose metabolism. The mechanism needs further investigation, but might provide a potential therapy in the treatment of type 2 diabetes.

Gastrointestinal hormone secretion in women with polycystic ovary syndrome: an observational study.

STUDY QUESTION: Is the secretion of gastrointestinal hormones impaired in patients with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Gastrointestinal hormone levels were abnormal in patients with PCOS. WHAT IS KNOWN ALREADY: The hormones glucagon-like peptide-1 (GLP-1) and peptide tyrosine-tyrosine (PYY) are both involved in signaling satiety. Secretion of GLP-1 and PYY in response to nutrients in the small intestine plays an important role in energy metabolism. Most PCOS patients are overweight or obese, which suggests dysregulation of appetite. STUDY DESIGN, SIZE, DURATION: In order to evaluate levels of gastrointestinal hormones in PCOS, a cohort study was undertaken, involving 30 PCOS patients and 29 BMI-matched healthy women recruited from Shanghai Renji Hospital between 1 March 2013 and 30 May 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: After an overnight fast, all participants underwent an oral glucose tolerance test. Blood was sampled frequently for measurement of blood glucose and plasma insulin, total GLP-1 and PYY concentrations. MAIN RESULTS AND THE ROLE OF CHANCE: Fasting and postprandial insulin levels were significantly higher in patients with PCOS compared with the healthy controls (P < 0.05). Fasting and postprandial GLP-1 (t = 0 and 30 min; mean ± SEM) were also higher in PCOS group (17.5 ± 1.07 pM versus 14.1 ± 1.16 pM, P < 0.05; 29.7 ± 2.39 pM versus 22.8 ± 2.09 pM, P < 0.05). However, there were no differences in plasma PYY between patients with PCOS and healthy controls either fasting or postprandially. PYY levels were lower in obese PCOS patients than in lean PCOS patients (P < 0.05). LIMITATIONS, REASONS FOR CAUTION: The study involved a small number of subjects with PCOS, and examined hormone responses to oral glucose rather than a physiological meal. WIDER IMPLICATIONS OF THE FINDINGS: Deficient secretion of GLP-1 and PYY does not contribute to excessive food intake in the pathophysiology of PCOS.

Characteristics and contributions of hyperandrogenism to insulin resistance and other metabolic profiles in polycystic ovary syndrome.

OBJECTIVE: To investigate the different characteristics in Chinese Han women with polycystic ovary syndrome, and to analyze the significance of hyperandrogenism in insulin resistance and other metabolic profiles. DESIGN: A cross-sectional study. SETTING: Medical university hospital. POPULATION: A total of 229 women with polycystic ovary syndrome aged 18-45 years. METHODS: Women with polycystic ovary syndrome, diagnosed by Rotterdam criteria, were divided into four groups according to the quartile intervals of free androgen index levels. MAIN OUTCOME MEASURES: Comparisons between groups were performed using one-way analysis of variance. Stepwise logistic regression analysis was performed to investigate the association between homeostasis model assessment-insulin resistance and independent variables. RESULTS: Within the four phenotypes, women with phenotype 1 (hyperandrogenism, oligo/anovulation, and polycystic ovaries) exhibited higher total testosterone, free androgen index, androstenedione, low-density lipoprotein, and lower quantitative insulin sensitivity check index (p < 0.05); women with phenotype 4 (oligo/anovulation and polycystic ovaries) showed lower total cholesterol, low-density lipoprotein, and homeostasis model assessment-insulin resistance, but higher high-density lipoprotein (p < 0.05). The levels of triglycerides, total cholesterol, low-density lipoprotein, and homeostasis model assessment-insulin resistance significantly increased, but high-density lipoprotein and quantitative insulin sensitivity check index decreased with the elevation of free androgen index intervals. After adjustment for lipid profiles, free androgen index was significantly associated with homeostasis model assessment-insulin resistance in both lean and overweight/obese women (odds ratio 1.302, p = 0.039 in lean vs. odds ratio 1.132, p = 0.036 in overweight/obese). CONCLUSIONS: Phenotypes 1 and 4 represent groups with the most and least severe metabolic profiles, respectively. Hyperandrogenism, particularly with elevated free androgen index, is likely a key contributing factor for insulin resistance and for the aggravation of other metabolic profiles.