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Monney M, Mavromati M, Leboulleux S, Gariani K. Endocrine and metabolic effects of GLP-1 receptor agonists on women with PCOS, a narrative review. Endocr Connect 2025; 14:e240529. [PMID: 40066975 PMCID: PMC11949528 DOI: 10.1530/ec-24-0529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 03/01/2025] [Accepted: 03/11/2025] [Indexed: 03/14/2025]
Abstract
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. This condition is associated with various hormonal, reproductive and metabolic alterations, including androgen excess, ovulatory disorders and a hyperinsulinemic state. A personalized therapeutic approach is necessary to improve PCOS, focusing on patients' main concerns, with the goal of addressing ovarian dysfunction, reducing hyperandrogenism and improving metabolic alterations, particularly through weight reduction. The therapeutic class of glucagon-like peptide-1 receptor analogues (GLP-1 RAs) represents an attractive option for PCOS due to its various beneficial effects, such as weight loss. In this review, we discuss the clinical and pathological aspects of PCOS, as well as the data and potential roles of GLP-1 RAs in managing this condition.
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Affiliation(s)
- Marine Monney
- Division of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, Department of Medical Specialties, Geneva University Hospitals, Geneva, Switzerland
| | - Maria Mavromati
- Division of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, Department of Medical Specialties, Geneva University Hospitals, Geneva, Switzerland
- Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Sophie Leboulleux
- Division of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, Department of Medical Specialties, Geneva University Hospitals, Geneva, Switzerland
- Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Karim Gariani
- Division of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, Department of Medical Specialties, Geneva University Hospitals, Geneva, Switzerland
- Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Qian Y, Tong Y, Zeng Y, Huang J, Liu K, Xie Y, Chen J, Gao M, Liu L, Zhao J, Hong Y, Nie X. Integrated lipid metabolomics and proteomics analysis reveal the pathogenesis of polycystic ovary syndrome. J Transl Med 2024; 22:364. [PMID: 38632610 PMCID: PMC11022415 DOI: 10.1186/s12967-024-05167-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 04/05/2024] [Indexed: 04/19/2024] Open
Abstract
BACKGROUND Polycystic ovary syndrome (PCOS) is an endocrinological and metabolic disorder that can lead to female infertility. Lipid metabolomics and proteomics are the new disciplines in systems biology aimed to discover metabolic pathway changes in diseases and diagnosis of biomarkers. This study aims to reveal the features of PCOS to explore its pathogenesis at the protein and metabolic level. METHODS We collected follicular fluid samples and granulosa cells of women with PCOS and normal women who underwent in vitro fertilization(IVF) and embryo transfer were recruited. The samples were for the lipidomic study and the proteomic study based on the latest metabolomics and proteomics research platform. RESULTS Lipid metabolomic analysis revealed abnormal metabolism of glycerides, glycerophospholipids, and sphingomyelin in the FF of PCOS. Differential lipids were strongly linked with the rate of high-quality embryos. In total, 144 differentially expressed proteins were screened in ovarian granulosa cells in women with PCOS compared to controls. Go functional enrichment analysis showed that differential proteins were associated with blood coagulation and lead to follicular development disorders. CONCLUSION The results showed that the differential lipid metabolites and proteins in PCOS were closely related to follicle quality,which can be potential biomarkers for oocyte maturation and ART outcomes.
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Affiliation(s)
- Yu Qian
- Department of Reproductive Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Yun Tong
- Department of Reproductive Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Yaqiong Zeng
- Department of Reproductive Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Jingyu Huang
- Department of Reproductive Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Kailu Liu
- Department of Reproductive Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Ying Xie
- Department of Reproductive Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Juan Chen
- Department of Reproductive Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Mengya Gao
- Department of Reproductive Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Li Liu
- Department of Reproductive Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Juan Zhao
- Department of Reproductive Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Yanli Hong
- Department of Reproductive Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
| | - Xiaowei Nie
- Department of Reproductive Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
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Xu Y, Zhou Z, Zhang G, Yang Z, Shi Y, Jiang Z, Liu Y, Chen H, Huang H, Zhang Y, Pan J. Metabolome implies increased fatty acid utilization and histone methylation in the follicles from hyperandrogenic PCOS women. J Nutr Biochem 2024; 125:109548. [PMID: 38104867 DOI: 10.1016/j.jnutbio.2023.109548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 11/21/2023] [Accepted: 12/11/2023] [Indexed: 12/19/2023]
Abstract
Well-balanced metabolism is essential for the high-quality of oocytes, and metabolic fluctuations of follicular microenvironment potentially encourage functional changes in follicle cells, ultimately impacting the developmental potential of oocytes. Here, the global metabolomic profiles of follicular fluid from PCOS women with ovarian hyperandrogenism and nonhyperandrogenism were depicted by untargeted metabolome and transcriptome. In parallel, functional methods were employed to evaluate the possible impact of dysregulated metabolites on oocyte and embryo development. Our findings demonstrated that PCOS women exhibited distinct metabolic features in follicles, such as the increase in fatty acid utilization and the downregulation in amino acid metabolism. And intrafollicular androgen levels were positively correlated with contents of multiple fatty acids, suggesting androgen as one of the contributing factors to the metabolic abnormalities in PCOS follicles. Moreover, we further demonstrated that elevated levels of α-linolenic acid and H3K27me3 could hinder oocyte maturation, fertilization, and early embryo development. Hopefully, our data serve as a broad resource on the metabolic abnormalities of PCOS follicles, and advances in the relevant knowledge will allow the identification of biomarkers that predict the progression of PCOS and its poor pregnancy outcomes.
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Affiliation(s)
- Yue Xu
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China; Shanghai Key Laboratory of Reproduction and Development, Shanghai, China; Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China
| | - Zhiyang Zhou
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China; Shanghai Key Laboratory of Reproduction and Development, Shanghai, China; Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China
| | - Gaochen Zhang
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China; Shanghai Key Laboratory of Reproduction and Development, Shanghai, China; Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China
| | - Zuwei Yang
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China; Shanghai Key Laboratory of Reproduction and Development, Shanghai, China; Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China; The International Peace Maternal and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yan Shi
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China; Shanghai Key Laboratory of Reproduction and Development, Shanghai, China; Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China
| | - Zhaoying Jiang
- Key Laboratory of Reproductive Genetics (Ministry of Education), Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ye Liu
- The International Peace Maternal and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Huixi Chen
- Shanghai Key Laboratory of Reproduction and Development, Shanghai, China; Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China; The International Peace Maternal and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hefeng Huang
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China; Shanghai Key Laboratory of Reproduction and Development, Shanghai, China; Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China; The International Peace Maternal and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Key Laboratory of Reproductive Genetics (Ministry of Education), Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Yu Zhang
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China; Shanghai Key Laboratory of Reproduction and Development, Shanghai, China; Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China.
| | - Jiexue Pan
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China; Shanghai Key Laboratory of Reproduction and Development, Shanghai, China; Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China; The International Peace Maternal and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Key Laboratory of Reproductive Genetics (Ministry of Education), Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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Sahin RB, Kilic FA, Hizli P, Baykan O. Serum zinc-alpha-2 glycoprotein and insulin levels and their correlation with metabolic syndrome in patients with rosacea. J Cosmet Dermatol 2023; 22:645-650. [PMID: 36207990 DOI: 10.1111/jocd.15447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 10/03/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND Metabolic syndrome and insulin resistance may accompany rosacea. Zinc-alpha-2 glycoprotein (ZAG) is an adipokine involved in lipid, glucose, and insulin metabolism and might be associated with metabolic syndrome and insulin resistance. AIMS To investigate the serum ZAG levels, presence of metabolic syndrome, insulin resistance, and the correlation between ZAG levels, rosacea severity, and metabolic syndrome in patients with rosacea. PATIENTS/METHODS Seventy-nine patients with rosacea and 80 healthy volunteers were included. Anthropometric and demographic features, personal and family histories, clinical data, the subtype, severity, and duration of rosacea were recorded. Metabolic syndrome, insulin resistance, and dyslipidemia were evaluated in both groups. Fasting blood sugar, lipid panel, C-reactive protein, sedimentation rate, insulin, and serum ZAG levels were investigated. RESULTS Frequency of metabolic syndrome, systolic and diastolic blood pressures, and C-reactive protein levels were significantly higher in the rosacea group (p < 0.001 and p = 0.001, respectively). Frequency of dyslipidemia and insulin resistance did not significantly differ between the groups (p = 0.175 and 0.694, respectively). The mean serum ZAG levels were lower in the rosacea group, but no significant difference was evident. In rosacea patients with metabolic syndrome, serum ZAG levels were significantly lower (p = 0.043); however, serum ZAG levels, insulin, and the homeostasis model assessment-estimated insulin resistance values were significantly higher (p = 0.168, 0.013 and 0.001, respectively). CONCLUSION Metabolic syndrome, high blood pressure, and high C-reactive protein levels were associated with rosacea indicating chronic systemic inflammation. ZAG levels were associated with metabolic syndrome in patients with rosacea but not associated with rosacea subtype and disease severity.
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Affiliation(s)
| | - Fatma Arzu Kilic
- Department of Dermatology, Faculty of Medicine, Balikesir University, Balikesir, Turkey
| | - Pelin Hizli
- Department of Dermatology, Faculty of Medicine, Balikesir University, Balikesir, Turkey
| | - Ozgur Baykan
- Department of Biochemistry, Faculty of Medicine, Balikesir University, Balikesir, Turkey
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Jensterle M, Herman R, Janež A. Therapeutic Potential of Glucagon-like Peptide-1 Agonists in Polycystic Ovary Syndrome: From Current Clinical Evidence to Future Perspectives. Biomedicines 2022; 10:1989. [PMID: 36009535 PMCID: PMC9405922 DOI: 10.3390/biomedicines10081989] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/30/2022] [Accepted: 08/14/2022] [Indexed: 11/16/2022] Open
Abstract
Despite the continuous effort to understand the pathophysiology and determine potential therapeutic targets, PCOS treatment largely depends on lifestyle intervention and symptomatic management of individual signs and symptoms. International guidelines recognize the importance of weight reduction as a cornerstone for the achievement of better metabolic, reproductive, and cardiovascular outcomes in PCOS women who are overweight or obese. With its profound weight loss potential in patients with or without diabetes, the administration of GLP-1 receptor agonists has been investigated in overweight/obese women with PCOS in several single-center randomized control trials with considerable variation in the dosing regimen, follow-up duration, and outcome measurements over recent years. Most trials reported superior weight loss effects of GLP-1 receptor agonists compared to lifestyle changes or metformin, with additional metabolic, reproductive, and cardiovascular benefits in this population. However, their use is currently not widely accepted by the clinical community that treats this population. The major concern is how to balance the reproductive and metabolic treatment strategies since the use of GLP-1 receptor agonists requires effective contraception while on therapy and a washout period before pregnancy. Both approaches are not mutually exclusive, yet the best choice requires a careful assessment of the clinical context. Knowing a patient's individual circumstances, precise clinical sub-phenotyping, and regular monitoring are crucial components for the safe and effective use of these new tools. In the present narrative review, we explore the current clinical evidence and provide the future perspectives and challenges for their implementation in PCOS management.
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Affiliation(s)
- Mojca Jensterle
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, 1000 Ljubljana, Slovenia
- Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Rok Herman
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, 1000 Ljubljana, Slovenia
- Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Andrej Janež
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, 1000 Ljubljana, Slovenia
- Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
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Yu J, Xie X, Zhang Y, Jiang F, Wu C. Construction and Analysis of a Joint Diagnosis Model of Random Forest and Artificial Neural Network for Obesity. Front Med (Lausanne) 2022; 9:906001. [PMID: 35677823 PMCID: PMC9168076 DOI: 10.3389/fmed.2022.906001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 04/19/2022] [Indexed: 12/28/2022] Open
Abstract
Obesity is a significant global health concern since it is connected to a higher risk of several chronic diseases. As a consequence, obesity may be described as a condition that reduces human life expectancy and significantly impacts life quality. Because traditional obesity diagnosis procedures have several flaws, it is vital to design new diagnostic models to enhance current methods. More obesity-related markers have been discovered in recent years as a result of improvements and enhancements in gene sequencing technology. Using current gene expression profiles from the Gene Expression Omnibus (GEO) collection, we identified differentially expressed genes (DEGs) associated with obesity and found 12 important genes (CRLS1, ANG, ALPK3, ADSSL1, ABCC1, HLF, AZGP1, TSC22D3, F2R, FXN, PEMT, and SPTAN1) using a random forest classifier. ALPK3, HLF, FXN, and SPTAN1 are the only genes that have never been linked to obesity. We also used an artificial neural network to build a novel obesity diagnosis model and tested its diagnostic effectiveness using public datasets.
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Affiliation(s)
- Jian Yu
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaoyan Xie
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yun Zhang
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Feng Jiang
- Department of Neonatology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- *Correspondence: Feng Jiang
| | - Chuyan Wu
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Chuyan Wu
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Amisi CA. Markers of insulin resistance in Polycystic ovary syndrome women: An update. World J Diabetes 2022; 13:129-149. [PMID: 35432749 PMCID: PMC8984569 DOI: 10.4239/wjd.v13.i3.129] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 09/14/2021] [Accepted: 02/22/2022] [Indexed: 02/06/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders, affecting 5%-10% of women of reproductive age. The importance of this syndrome lies in the magnitude of associated comorbidities: infertility, metabolic dysfunction, cardiovascular disease (CVD), plus psychological and oncological complications. Insulin resistance (IR) is a prominent feature of PCOS with a prevalence of 35%-80%. Without adequate management, IR with compensatory hyperinsulinemia contributes directly to reproductive dysfunction in women with PCOS. Furthermore, epidemiological data shows compelling evidence that PCOS is associated with an increased risk of impaired glucose tolerance, gestational diabetes mellitus and type 2 diabetes. In addition, metabolic dysfunction leads to a risk for CVD that increases with aging in women with PCOS. Indeed, the severity of IR in women with PCOS is associated with the amount of abdominal obesity, even in lean women with PCOS. Given these drastic implications, it is important to diagnose and treat insulin resistance as early as possible. Many markers have been proposed. However, quantitative assessment of IR in clinical practice remains a major challenge. The gold standard method for assessing insulin sensitivity is the hyperinsulinemic euglycemic glucose clamp. However, it is not used routinely because of the complexity of its procedure. Consequently, there has been an urgent need for surrogate markers of IR that are more applicable in large population-based epidemiological investigations. Despite this, many of them are either difficult to apply in routine clinical practice or useless for women with PCOS. Considering this difficulty, there is still a need for an accurate marker for easy, early detection and assessment of IR in women with PCOS. This review highlights markers of IR already used in women with PCOS, including new markers recently reported in literature, and it establishes a new classification for these markers.
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Affiliation(s)
- Chantal Anifa Amisi
- Endocrinology and Diabetes Unit, Department of Medicine, Universita Campus Bio-medico di Rome, Rome 00128, Italy
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Namkhah Z, Naeini F, Ostadrahimi A, Tutunchi H, Hosseinzadeh-Attar MJ. The association of the adipokine zinc-alpha2-glycoprotein with non-alcoholic fatty liver disease and related risk factors: A comprehensive systematic review. Int J Clin Pract 2021; 75:e13985. [PMID: 33404166 DOI: 10.1111/ijcp.13985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 01/03/2021] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND AND AIM The adipokine zinc-alpha2-glycoprotein (ZAG), a multidisciplinary protein, is involved in lipid metabolism, glucose homeostasis and energy balance. Accumulating evidence demonstrates that the expression of ZAG is mainly downregulated in obesity and obesity-related conditions. In the present study, we assessed the association of ZAG with non-alcoholic fatty liver disease (NAFLD) and the related risk factors including obesity, metabolic factors and inflammatory parameters, with emphasis on potential mechanisms underlying these associations. METHODS PRISMA guidelines were followed in this review. Systematic searches were performed using the PubMed/Medline, ScienceDirect, Scopus, EMBASE, ProQuest and Google Scholar databases, up to August 2020 for all relevant published papers. RESULTS Out of 362 records screened, 34 articles were included in the final analysis. According to the studies reviewed here, ZAG appears to exert a protective effect against NAFLD by enhancing mRNA expression levels of peroxisome proliferator-activated receptor α (PPARα) and PPARγ, promoting mRNA expression levels of the lipolysis-related genes, reducing mRNA expression levels of the lipogenesis-related genes, increasing hepatic fatty acid oxidation, ameliorating hepatic steatosis, promoting the activity of brown adipose tissue and the expression of thermogenesis-related genes, modulating energy balance and glucose homeostasis, and elevating plasma levels of healthy adipokines such as adiponectin. ZAG can also be involved in the regulation of inflammatory responses by attenuation of the expression of pro-inflammatory and pro-fibrotic mediators. CONCLUSION According to the studies reviewed here, ZAG is suggested to be a promising therapeutic target for NAFLD. However, the favourable effects of ZAG need to be confirmed in prospective cohort studies.
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Affiliation(s)
- Zahra Namkhah
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Science, Tehran, Iran
| | - Fatemeh Naeini
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Science, Tehran, Iran
| | - Alireza Ostadrahimi
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Helda Tutunchi
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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Banaszak M, Górna I, Przysławski J. Zinc and the Innovative Zinc-α2-Glycoprotein Adipokine Play an Important Role in Lipid Metabolism: A Critical Review. Nutrients 2021; 13:nu13062023. [PMID: 34208404 PMCID: PMC8231141 DOI: 10.3390/nu13062023] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 06/10/2021] [Accepted: 06/10/2021] [Indexed: 12/14/2022] Open
Abstract
Numerous studies indicate that zinc and the new zinc-related adipokine, zinc-α2-glycoprotein (ZAG), are involved in lipid metabolism. Excess body fat lowers blood concentrations of Zn and ZAG, leading not only to the development of obesity but also to other components of the metabolic syndrome. Zinc homeostasis disorders in the body negatively affect the lipid profile and cytokine secretion. Zinc appears to be a very important ZAG homeostasis regulator. The physiological effects of ZAG are related to lipid metabolism, but studies show that ZAG also affects glucose metabolism and is linked to insulin resistance. ZAG has a zinc binding site in its structure, which may indicate that ZAG mediates the effect of zinc on lipid metabolism. The review aimed to verify the available studies on the effects of zinc and ZAG on lipid metabolism. A literature review within the scope of this research area was conducted using articles available in PubMed (including MEDLINE), Web of Science and Cochrane Library databases. An analysis of available studies has shown that zinc improves hepatic lipid metabolism and has an impact on the lipid profile. Numerous studies have found that zinc supplementation in overweight individuals significantly reduced blood levels of total cholesterol, LDL (Low-density lipoprotein)cholesterol and triglycerides, potentially reducing cardiovascular morbidity and mortality. Some results also indicate that it increases HDL-C (High-density lipoprotein) cholesterol levels. ZAG has been shown to play a significant role in reducing obesity and improving insulin sensitivity, both in experimental animal model studies and in human studies. Furthermore, ZAG at physiologically relevant concentrations increases the release of adiponectin from human adipocytes. In addition, ZAG has been shown to inhibit in vitro leptin production. Further studies are needed to provide more data on the role of zinc and zinc-α2-glycoprotein.
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Affiliation(s)
- Michalina Banaszak
- Faculty of Medical Sciences, Poznan University of Medical Sciences, 60-812 Poznan, Poland;
| | - Ilona Górna
- Department of Bromatology, Poznan University of Medical Sciences, 60-354 Poznan, Poland;
- Correspondence: ; Tel.: +48-61-854-7204
| | - Juliusz Przysławski
- Department of Bromatology, Poznan University of Medical Sciences, 60-354 Poznan, Poland;
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Pearsey HM, Henson J, Sargeant JA, Davies MJ, Khunti K, Suzuki T, Bowden-Davies KA, Cuthbertson DJ, Yates TE. Zinc-alpha2-glycoprotein, dysglycaemia and insulin resistance: a systematic review and meta-analysis. Rev Endocr Metab Disord 2020; 21:569-575. [PMID: 32377863 PMCID: PMC7557496 DOI: 10.1007/s11154-020-09553-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
To systematically review the current literature investigating associations between zinc-alpha2-glycoprotein (ZAG) and dysglycaemia (including type 2 diabetes (T2DM), poly-cystic-ovary syndrome (PCOS), pre-diabetes or insulin resistance). This included relationships between ZAG and continuous measures of insulin and glucose. Additionally, we performed a meta-analysis to estimate the extent that ZAG differs between individuals with or without dysglycaemia; whilst examining the potential influence of adiposity. A systematic search was performed on four databases for studies on circulating ZAG concentrations in adult human populations, comparing healthy controls to individuals with dysglycaemia. Key characteristics, including the mean ZAG concentrations (mg∙L-1), and any correlational statistics between ZAG and continuous measures of glucose, glycated haemoglobin (HbA1c) or insulin were extracted. Meta-analyses were performed to compare metabolically healthy controls to cases, and on studies that compared controls and cases considered overweight or obese (body mass index (BMI) ≥25 kg.m2). 1575 papers were identified and 14 studies (16 cohorts) were considered eligible for inclusion. Circulating ZAG was lower in individuals with dysglycaemia compared to metabolically healthy controls (-4.14 [-8.17, -0.11] mg.L-1; I2 = 98.5%; p < 0.001). When using data from only studies with overweight or obese groups with or without dysglycaemia (three studies (four cohorts); pooled n = 332), the difference in circulating ZAG was no longer significant (-0.30 [-3.67, 3.07] mg. L-1; I2 = 28.0%; p = 0.225). These data suggest that ZAG may be implicated in dysglycaemia, although there was significant heterogeneity across different studies and the mediating effect of adiposity cannot be excluded. Therefore, more research is needed before robust conclusions can be drawn.
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Affiliation(s)
- Harriet M Pearsey
- Diabetes Research Centre, Leicester General Hospital, Gwendolen Road, Leicester, LE5 4PW, UK.
- NIHR Leicester Biomedical Research Centre, Leicester, UK.
- Department of Health Science, University of Leicester, Leicester, UK.
| | - Joseph Henson
- Diabetes Research Centre, Leicester General Hospital, Gwendolen Road, Leicester, LE5 4PW, UK
- NIHR Leicester Biomedical Research Centre, Leicester, UK
| | - Jack A Sargeant
- Diabetes Research Centre, Leicester General Hospital, Gwendolen Road, Leicester, LE5 4PW, UK
- NIHR Leicester Biomedical Research Centre, Leicester, UK
| | - Melanie J Davies
- Diabetes Research Centre, Leicester General Hospital, Gwendolen Road, Leicester, LE5 4PW, UK
- NIHR Leicester Biomedical Research Centre, Leicester, UK
| | - Kamlesh Khunti
- Diabetes Research Centre, Leicester General Hospital, Gwendolen Road, Leicester, LE5 4PW, UK
- NIHR ARC East Midlands, Leicester, UK
| | - Toru Suzuki
- NIHR Leicester Biomedical Research Centre, Leicester, UK
- Cardiovascular Sciences Unit, Leicester Glenfeild Hospital, Leicester, UK
| | | | - Daniel J Cuthbertson
- Clinical Sciences Centre, Aintree University Hospitals NHS Foundation Trust, Liverpool, UK
- Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
| | - Thomas E Yates
- Diabetes Research Centre, Leicester General Hospital, Gwendolen Road, Leicester, LE5 4PW, UK
- NIHR Leicester Biomedical Research Centre, Leicester, UK
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11
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Berezin AE, Berezin AA, Lichtenauer M. Emerging Role of Adipocyte Dysfunction in Inducing Heart Failure Among Obese Patients With Prediabetes and Known Diabetes Mellitus. Front Cardiovasc Med 2020; 7:583175. [PMID: 33240938 PMCID: PMC7667132 DOI: 10.3389/fcvm.2020.583175] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 10/05/2020] [Indexed: 12/13/2022] Open
Abstract
Adipose tissue dysfunction is a predictor for cardiovascular (CV) events and heart failure (HF) in patient population with obesity, metabolic syndrome, and known type 2 diabetes mellitus. Previous preclinical and clinical studies have yielded controversial findings regarding the role of accumulation of adipose tissue various types in CV risk and HF-related clinical outcomes in obese patients. There is evidence for direct impact of infiltration of epicardial adipocytes into the underlying myocardium to induce adverse cardiac remodeling and mediate HF development and atrial fibrillation. Additionally, perivascular adipocytes accumulation is responsible for release of proinflammatory adipocytokines (adiponectin, leptin, resistin), stimulation of oxidative stress, macrophage phenotype switching, and worsening vascular reparation, which all lead to microvascular inflammation, endothelial dysfunction, atherosclerosis acceleration, and finally to increase in CV mortality. However, systemic effects of white and brown adipose tissue can be different, and adipogenesis including browning of adipose tissue and deficiency of anti-inflammatory adipocytokines (visfatin, omentin, zinc-α2-glycoprotein, glypican-4) was frequently associated with adipose triglyceride lipase augmentation, altered glucose homeostasis, resistance to insulin of skeletal muscles, increased cardiomyocyte apoptosis, lowered survival, and weak function of progenitor endothelial cells, which could significantly influence on HF development, as well as end-organ fibrosis and multiple comorbidities. The exact underlying mechanisms for these effects are not fully understood, while they are essential to help develop improved treatment strategies. The aim of the review is to summarize the evidence showing that adipocyte dysfunction may induce the onset of HF and support advance of HF through different biological mechanisms involving inflammation, pericardial, and perivascular adipose tissue accumulation, adverse and electrical cardiac remodeling, and skeletal muscle dysfunction. The unbalancing effects of natriuretic peptides, neprilysin, and components of renin-angiotensin system, as exacerbating cause of altered adipocytokine signaling on myocardium and vasculature, in obesity patients at high risk of HF are disputed. The profile of proinflammatory and anti-inflammatory adipocytokines as promising biomarker for HF risk stratification is discussed in the review.
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Affiliation(s)
- Alexander E. Berezin
- Internal Medicine Department, State Medical University, Ministry of Health of Ukraine, Zaporozhye, Ukraine
| | - Alexander A. Berezin
- Internal Medicine Department, Medical Academy of Post-Graduate Education, Ministry of Health of Ukraine, Zaporozhye, Ukraine
| | - Michael Lichtenauer
- Division of Cardiology, Department of Internal Medicine II, Paracelsus Medical University Salzburg, Salzburg, Austria
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12
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Liu S, Hu W, He Y, Li L, Liu H, Gao L, Yang G, Liao X. Serum Fetuin-A levels are increased and associated with insulin resistance in women with polycystic ovary syndrome. BMC Endocr Disord 2020; 20:67. [PMID: 32429902 PMCID: PMC7236448 DOI: 10.1186/s12902-020-0538-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 04/27/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Insulin resistance (IR) is a common characteristic of women with polycystic ovary syndrome (PCOS). It has been reported that circulating Fetuin-A levels were associated with IR and type 2 diabetes mellitus (T2DM). However, previous reports were inconsistent. METHODS Two hundred seven subjects were screened for PCOS according to the diagnostic guideline of the Rotterdam consensus criterion. Serum Fetuin-A levels were measured using an ELISA kit. An independent t-test or Nonparametric test was used to detect differences between PCOS and control groups. Spearman's correlation analysis was used to examine the association of the serum Fetuin-A with other parameters. RESULTS Our findings showed that circulating Fetuin-A concentration ranged from 196.6 to 418.2 μg/L for most women without PCOS (95%). Women with PCOS had higher circulating Fetuin-A levels than healthy women (437.9 ± 119.3 vs. 313.8 ± 60.5 μg/L; p < 0.01). Serum Fetuin-A was positively correlated with BMI, WHR, TG, TC, LDL-C, HOMA-IR, LH, T, and DHEA-S. Multivariate regression analysis showed that WHR, TG, HOMA-IR, and DHEA-S were independent predictors of the levels of circulating Fetuin-A. Binary logistic regression revealed that serum Fetuin-A was associated with the occurrence of PCOS. In addition, our ROC curve analysis found that the cutoff values for Fetuin-A to predict PCOS and IR were 366.3 and 412.6 μg/L. CONCLUSION Blood Fetuin-A may be a useful biomarker for screening women for PCOS and IR.
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Affiliation(s)
- Sha Liu
- Department of Endocrinology, the Affiliated Hospital, Zunyi Medical University, Zunyi, 563003 Guizhou China
| | - Wenjing Hu
- Chongqing Prevention and Treatment Hospital for Occupational Diseases, Chongqing, China
| | - Yirui He
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ling Li
- Key Laboratory of Diagnostic Medicine (Ministry of Education) and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016 China
| | - Hua Liu
- Department of Pediatrics, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS USA
| | - Lin Gao
- Department of Endocrinology, the Affiliated Hospital, Zunyi Medical University, Zunyi, 563003 Guizhou China
| | - Gangyi Yang
- Department of Endocrinology, the Affiliated Hospital, Zunyi Medical University, Zunyi, 563003 Guizhou China
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Xin Liao
- Department of Endocrinology, the Affiliated Hospital, Zunyi Medical University, Zunyi, 563003 Guizhou China
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13
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Tang C, Li X, Tang S, Wang Y, Tan X. Association between circulating zinc-α2-glycoprotein levels and the different phenotypes of polycystic ovary syndrome. Endocr J 2020; 67:249-255. [PMID: 31748429 DOI: 10.1507/endocrj.ej18-0506] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Polycystic ovary syndrome (PCOS) diagnosis combines various clinical phenotypes. The definition of PCOS is still controversial because insulin resistance (IR) and dysmetabolism do not constitute PCOS diagnostic criteria. We analyzed whether a circulating biomarker zinc-α2-glycoprotein (ZAG) related to IR and metabolic dysfunction can predict PCOS phenotypes. We then recruited 100 PCOS patients and 99 healthy women as the control group to assess the relationship between ZAG and metabolic characteristics. The euglycemic-hyperinsulinemic clamp helped assess insulin sensitivity, and the enzyme immunometric assay was deployed for ZAG levels. Our PCOS cohort presented sixty-nine patients with hyperandrogenism, eighty-six patients with chronic oligoanovulation, and eighty-one patients with polycystic ovaries by ultrasonographic evaluation. Additionally, the circulating ZAG levels were considerably reduced in all PCOS patients compared with healthy women (p < 0.05 or p < 0.01). Additionally, sixty-nine PCOS patients had IR, and circulating ZAG levels were also different among the phenotypes. Furthermore, the normoandrogenic type specifically exhibited the highest circulating ZAG levels among all PCOS phenotypes (p < 0.05 or p < 0.01). Additionally, normoandrogenic phenotype patients had reduced HOMA-IR scores and greater M-values than those in the classic phenotypes (p < 0.05). The circulating ZAG levels, however, were not associated with oligoanovulation but were correlated with hyperandrogenism and PCO morphology. In summary, circulating ZAG levels serve as suitable PCOS phenotype biomarkers, aiding physicians to identify women who merit screening.
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Affiliation(s)
- Chenchen Tang
- Department of Endocrinology, 9th People's Hospital of Chongqing, Beibei City, Chongqong, 400700, China
| | - Xiaoqiang Li
- Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, Yuzhong City, Chongqing 400014, China
| | - Shiguo Tang
- Department of Endocrinology, 9th People's Hospital of Chongqing, Beibei City, Chongqong, 400700, China
| | - Yi Wang
- Department of Endocrinology, 9th People's Hospital of Chongqing, Beibei City, Chongqong, 400700, China
| | - Xingrong Tan
- Department of Endocrinology, 9th People's Hospital of Chongqing, Beibei City, Chongqong, 400700, China
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14
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Adipose Insulin Resistance and Circulating Betatrophin Levels in Women with PCOS. BIOMED RESEARCH INTERNATIONAL 2020; 2020:1253164. [PMID: 32076603 PMCID: PMC6996693 DOI: 10.1155/2020/1253164] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 11/29/2019] [Accepted: 12/16/2019] [Indexed: 12/14/2022]
Abstract
The role of IR and metabolic disorders has become a crucial topic of study in the pathogenesis of PCOS. Adipose tissue is an important target organ of insulin, and adipose IR plays an important role in the occurrence and development of PCOS. This study seeks to investigate the role of adipose IR in the development of PCOS and to examine its relationship with circulating betatrophin levels in women with PCOS. A cross-sectional analysis of a cohort of women with PCOS and healthy women was performed in this study. Serum betatrophin concentrations were measured by ELISA. Adipose IR was calculated using the product of fasting insulin and FFA concentrations, and the relationship between adipose IR, circulating betatrophin, and other parameters was analyzed. Adipose IR in women with PCOS was significantly higher than that in controls. We found that women with PCOS who have adipose IR (adipose IR ≥ 55) have a higher BMI and higher blood glucose, insulin, PRL, FFA, TG, HOMA-IR, AUCglucose, AUCinsulin, VAIfemale, and BAI levels than PCOS-afflicted women without adipose IR, while M-values, and SHBG and LH levels were lower. In women with PCOS, serum betatrophin levels were significantly increased compared with controls. Adipose IR negatively correlated with M values and positively with circulating betatrophin levels in the study population. After metformin treatment, circulating betatrophin levels and adipose IR in women with PCOS were significantly decreased compared with pretreatment. Adipose IR is associated with betatrophin levels in women with PCOS. The combination of adipose IR and circulating betatrophin measurements may be significant for screening patients with PCOS.
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15
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Wang L, Liu M, Ning D, Zhu H, Shan G, Wang D, Ping B, Yu Y, Yang H, Yan K, Pan H, Gong F. Low Serum ZAG Levels Correlate With Determinants of the Metabolic Syndrome in Chinese Subjects. Front Endocrinol (Lausanne) 2020; 11:154. [PMID: 32265843 PMCID: PMC7105689 DOI: 10.3389/fendo.2020.00154] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 03/05/2020] [Indexed: 12/11/2022] Open
Abstract
Introduction: Zinc-α2-glycoprotein (ZAG) is a novel adipokine, which is involved in metabolic syndrome (MetS). This study aimed to investigate the relationship between serum ZAG and MetS in Chinese adults, who diagnosed according to the 2005 International Diabetes Federation (IDF) criteria. Methods: A group of 151 MetS patients, 84 patients with central obesity and 70 healthy controls were enrolled. General clinical information, serum samples were obtained from all subjects and serum ZAG levels were determined via the commercial ELISA kits. Results: Serum ZAG levels were the highest in the control group, then gradually decreased with the severity of the metabolic abnormalities increased (8.78 ± 1.66 μg/mL for control vs. 8.37 ± 1.52 μg/mL for central obesity vs. 7.98 ± 0.94 μg/mL for MetS, P < 0.05). It was also decreased progressively with an increasing number of the MetS components (P for trend = 0.002). Additionally, serum ZAG/fat mass ratio was calculated and the similar changes were observed in the three groups (0.85 ± 0.53 μg/mL/kg for control vs. 0.39 ± 0.10 μg/mL/kg for central obesity vs. 0.36 ± 0.08 μg/mL/kg for MetS, P < 0.05). In the multiple regression analysis, group was a strong independent factor contributing to serum ZAG levels (P < 0.001). Furthermore, compared with subjects with the highest tertile of ZAG, subjects in the lowest tertile of ZAG had 1.946-fold higher risk of MetS (95% CI 1.419-6.117, P = 0.004). This phenomenon still existed after controlling for age, gender (Model 1), ALP, AST, Cr, UA, Urea based on Model 1 (Model 2), grip strength, smoking, drinking, birth place, current address, education level, manual labor, and exercise frequency based on Model 2 (Model 3). Receiver operation characteristic (ROC) curve analysis revealed that serum ZAG might serve as a candidate biomarker for MetS (sensitivity 57.6%, specificity 70.0% and area under the curve 0.655), and serum ZAG/fat mass ratio showed improved diagnosis value accuracy, with ROC curve area of 0.951 (95% CI, 0.920-0.983, P < 0.001), and 90.7% sensitivity and 88.6% specificity. Conclusions: Serum ZAG levels were lowered in patients with MetS and central obesity. The decreased serum ZAG levels were associated with the increased risks of MetS. Serum ZAG, especially serum ZAG/fat mass ratio might be the candidate diagnostic biomarkers for MetS.
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Affiliation(s)
- Linjie Wang
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Meijuan Liu
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Dongping Ning
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Huijuan Zhu
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Guangliang Shan
- Department of Epidemiology and Health Statistics, Institute of Basic Medical Sciences, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Dingming Wang
- Guizhou Provincial Center for Disease Control and Prevention, Guiyang, China
| | - Bo Ping
- Longli Center for Disease Control and Prevention, Longli, China
| | - Yangwen Yu
- Guizhou Provincial Center for Disease Control and Prevention, Guiyang, China
| | - Hongbo Yang
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Kemin Yan
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Hui Pan
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- *Correspondence: Hui Pan
| | - Fengying Gong
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- Fengying Gong ;
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16
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Thromboinflammatory changes in plasma proteome of pregnant women with PCOS detected by quantitative label-free proteomics. Sci Rep 2019; 9:17578. [PMID: 31772271 PMCID: PMC6879536 DOI: 10.1038/s41598-019-54067-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 10/25/2019] [Indexed: 12/14/2022] Open
Abstract
Polycystic ovary syndrome (PCOS) is the most common endocrinological disorder of fertile-aged women. Several adverse pregnancy outcomes and abnormalities of the placenta have been associated with PCOS. By using quantitative label-free proteomics we investigated whether changes in the plasma proteome of pregnant women with PCOS could elucidate the mechanisms behind the pathologies observed in PCOS pregnancies. A total of 169 proteins with ≥2 unique peptides were detected to be differentially expressed between women with PCOS (n = 7) and matched controls (n = 20) at term of pregnancy, out of which 35 were significant (p-value < 0.05). A pathway analysis revealed that networks related to humoral immune responses, inflammatory responses, cardiovascular disease and cellular growth and proliferation were affected by PCOS. Classification of cases and controls was carried out using principal component analysis, orthogonal projections on latent structure-discriminant analysis (OPLS-DA), hierarchical clustering, self-organising maps and ROC-curve analysis. The most significantly enriched proteins in PCOS were properdin and insulin-like growth factor II. In the dataset, properdin had the best predictive accuracy for PCOS (AUC = 1). Additionally, properdin abundances correlated with AMH levels in pregnant women.
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17
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Luo P, Zhang C, He Y, Yang G, Liu H, Li L. Several Circulating Biomarkers for PCOS Diagnosis. Exp Clin Endocrinol Diabetes 2019; 129:705-712. [PMID: 31683329 DOI: 10.1055/a-1025-3711] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
AIMS Irisin, Betatrophin and Zinc-α2-glycoprotein (ZAG) have been shown to be associated with insulin resistance (IR) and polycystic ovary syndrome (PCOS), respectively. The purpose of this study is to explore the potential accuracy of this combination of three cytokines in screening PCOS. METHODS 186 individuals were recruited for this study. Circulating Irisin, Betatrophin and ZAG concentrations were measured by enzyme-linked immunosorbent assay. The association between these serum biomarkers and PCOS was assessed by logistic regression analysis. Receiver operating curve (ROC) analysis was performed to evaluate the diagnostic value of these biomarkers for PCOS women. RESULTS In women with PCOS, serum Irisin and Betatrophin levels were markedly elevated compared to those in healthy controls (p<0.01), while ZAG levels were lower (p<0.01). PCOS women with IR (M-value<6.28) had lower circulating ZAG concentrations, and higher circulating Irisin and Betatrophin levels relative to PCOS women without IR (M-value ≥ 6.28). ROC curve analyses showed that the AUC for Irisin, ZAG and Betatrophin for predicting PCOS were 0.77, 0.83 and 0.85, respectively. In a joint ROC curves analysis of these serum markers and other parameters, the results showed that the AUC was 0.93, and the sensitivity and specificity were 82.1 % and 92.3 %, respectively. CONCLUSIONS When compared to using single cytokine, the analysis of Irisin, ZAG and Betatrophin elevates the accuracy in diagnosing PCOS.
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Affiliation(s)
- Peiqi Luo
- Laboratory of Diagnostic Medicine (Ministry of Education) and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Cheng Zhang
- Laboratory of Diagnostic Medicine (Ministry of Education) and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.,The Center of Clinical Research of Endocrinology and Metabolic Diseases in Chongqing and Department of Endocrinology, Chongqing Three Gorges Central Hospital, Chongqing, China
| | - Yirui He
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Gangyi Yang
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Hua Liu
- Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Ling Li
- Laboratory of Diagnostic Medicine (Ministry of Education) and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
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18
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Zheng S, Liu E, Zhang Y, Long T, Liu X, Gong Y, Mai T, Shen H, Chen H, Lin R, Zheng Y, Xie Y, Wang F. Circulating zinc-α2-glycoprotein is reduced in women with polycystic ovary syndrome, but can be increased by exenatide or metformin treatment. Endocr J 2019; 66:555-562. [PMID: 30918134 DOI: 10.1507/endocrj.ej18-0153] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
The study was to investigate circulating zinc-α2-glycoprotein (ZAG) concentrations in women with PCOS, and changes in ZAG levels after exenatide or metformin treatment. One hundred eighty-two women with polycystic ovary syndrome (PCOS) who met the 2003 Rotterdam diagnostic criteria and 150 controls without PCOS were recruited. We partitioned women with PCOS into groups according to body mass index or blood glucose concentrations, determined serum ZAG, anthropometric parameters, metabolic and endocrine indicators, and inflammatory markers, and statistically analyzed the results. Eighty-two overweight/obese subjects of the recruited women with PCOS were then randomly assigned to groups administered either 12 weeks of exenatide injection (10 μg b.i.d.) or oral metformin (1,000 mg b.i.d.). Circulating ZAG levels were determined after 12 weeks of treatment. The results showed that circulating ZAG was significantly lower in PCOS women than in healthy women (p < 0.01). Overweight/obese women and those with higher blood glucose levels had lower circulating ZAG. After 12 weeks of exenatide or metformin treatment, there were significant increases (p < 0.01) in circulating ZAG in both treatment groups (the exenatide baseline level was 46.54 ± 2.38 ng/mL vs. 56.41 ± 2.02 ng/mL after treatment, p < 0.01; metformin baseline was 47.81 ± 2.14 ng/mL vs. 55.67 ± 2.01 ng/mL after treatment, p < 0.01), however there was no statistical difference between the 2 treatments (p > 0.05). Circulating ZAG is closely related to PCOS and could be an important adipokine involved in the occurrence and development of PCOS. ZAG might possibly be applicable as a new observational indicator in the treatment of PCOS.
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Affiliation(s)
- Siyuan Zheng
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - En Liu
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Ying Zhang
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Tao Long
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Xin Liu
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Yi Gong
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Tingting Mai
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Huanling Shen
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Hui Chen
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Rong Lin
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Yongxiong Zheng
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Yijuan Xie
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Fang Wang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
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19
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Hansen SL, Svendsen PF, Jeppesen JF, Hoeg LD, Andersen NR, Kristensen JM, Nilas L, Lundsgaard AM, Wojtaszewski JFP, Madsbad S, Kiens B. Molecular Mechanisms in Skeletal Muscle Underlying Insulin Resistance in Women Who Are Lean With Polycystic Ovary Syndrome. J Clin Endocrinol Metab 2019; 104:1841-1854. [PMID: 30544235 DOI: 10.1210/jc.2018-01771] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 12/10/2018] [Indexed: 12/12/2022]
Abstract
CONTEXT Skeletal muscle molecular mechanisms underlying insulin resistance in women with polycystic ovary syndrome (PCOS) are poorly understood. OBJECTIVE To provide insight into mechanisms regulating skeletal muscle insulin resistance in women who are lean with PCOS. PARTICIPANTS AND METHODS A hyperinsulinemic-euglycemic clamp with skeletal muscle biopsies was performed. Thirteen women who are lean who have hyperandrogenism and PCOS and seven age- and body mass index-matched healthy control subjects were enrolled. Skeletal muscle protein expression and phosphorylation were analyzed by Western blotting and intramuscular lipid content was measured by thin-layer chromatography. RESULTS Women with PCOS had 25% lower whole-body insulin sensitivity and 40% lower plasma adiponectin concentration than in control subjects. Intramuscular triacylglycerol, sn-1.3 diacylglycerol, and ceramide contents in skeletal muscle were higher (40%, 50%, and 300%, respectively) in women with PCOS than in control subjects. Activation of insulin signaling did not differ between groups. In women with PCOS, the insulin-stimulated glucose oxidation was reduced and insulin-stimulated dephosphorylation of pyruvate dehydrogenase (PDH) Ser293 was absent. AMP-activated protein kinase (AMPK) α2 protein expression and basal Thr172 phosphorylation were 45% and 50% lower in women with PCOS than in control subjects, respectively. CONCLUSIONS Whole-body insulin resistance in women who are lean who have hyperandrogenism and PCOS was not related to changes in the proximal part of the insulin signaling cascade in skeletal muscle despite lipid accumulation. Rather, reduced insulin sensitivity was potentially related to plasma adiponectin levels playing a modulating role in human skeletal muscle via AMPK. Furthermore, abnormal PDH regulation may contribute to reduced whole-body metabolic flexibility and thereby insulin resistance.
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Affiliation(s)
- Solvejg L Hansen
- Molecular Physiology Section, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Pernille F Svendsen
- Department of Obstetrics and Gynaecology, Copenhagen University Hospital at Hvidovre, Hvidovre, Denmark
| | - Jacob F Jeppesen
- Molecular Physiology Section, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Louise D Hoeg
- Molecular Physiology Section, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Nicoline R Andersen
- Molecular Physiology Section, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Jonas M Kristensen
- Molecular Physiology Section, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Lisbeth Nilas
- Department of Obstetrics and Gynaecology, Copenhagen University Hospital at Hvidovre, Hvidovre, Denmark
| | - Anne-Marie Lundsgaard
- Molecular Physiology Section, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Jørgen F P Wojtaszewski
- Molecular Physiology Section, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Copenhagen University Hospital at Hvidovre, Hvidovre, Denmark
| | - Bente Kiens
- Molecular Physiology Section, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
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20
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Xiao XH, Qi XY, Li JY, Wang YB, Wang YD, Liao ZZ, Yang J, Ran L, Wen GB, Liu JH. Serum zinc-α2-glycoprotein levels are elevated and correlated with thyroid hormone in newly diagnosed hyperthyroidism. BMC Endocr Disord 2019; 19:12. [PMID: 30670019 PMCID: PMC6343254 DOI: 10.1186/s12902-019-0336-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 01/09/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Zinc-α2-glycoprotein (ZAG) is a recently novel lipolytic adipokine implicated in regulation of glucose and lipid metabolism in many metabolic disorders. In vitro and animal studies suggest that thyroid hormones (TH) up-regulates ZAG production in hepatocytes. However, there is no data evaluating the possible relationship between ZAG and TH in a human model of hyperthyroidism. The objective of the present study is to assess the association of serum ZAG levels with TH and lipid profile in patients with hyperthyroidism before and after methimazole treatment. METHODS A total of 120 newly diagnosed overt hyperthyroidism and 122 healthy control subjects were recruited. Of them, 39 hyperthyroidism patients were assigned to receive methimazole treatment as follow-up study for 2 months. RESULTS The clinical consequence showed that serum ZAG levels were elevated in patients with hyperthyroidism (P < 0.01). Adjust for age, gender and BMI, serum ZAG levels were positively related with serum free T3 (FT3), free T4 (FT4) levels and negatively correlated with serum total cholesterol (TC), low density lipoprotein cholesterol (LDLC) levels in hyperthyroidism subjects (all P < 0.01). After methimazole treatment, serum ZAG levels were decreased and the decline was associated with decreased FT3, FT4 and increased TC levels (all P < 0.001). CONCLUSION We conclude that ZAG may be involved in the pathogenesis of lipid metabolism disorder in patients with hyperthyroidism. TRIAL REGISTRATION ChiCTR-ROC-17012943 . Registered 11 October 2017, retrospectively registered.
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Affiliation(s)
- Xin-Hua Xiao
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001 China
| | - Xiao-Yan Qi
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001 China
| | - Jiao-Yang Li
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001 China
| | - Yi-Bing Wang
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001 China
| | - Ya-Di Wang
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001 China
| | - Zhe-Zhen Liao
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001 China
| | - Jing Yang
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001 China
| | - Li Ran
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001 China
| | - Ge-Bo Wen
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001 China
| | - Jiang-Hua Liu
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001 China
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21
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Expression and Function of Zinc-α2-Glycoprotein. Neurosci Bull 2019; 35:540-550. [PMID: 30610461 DOI: 10.1007/s12264-018-00332-x] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Accepted: 09/26/2018] [Indexed: 12/13/2022] Open
Abstract
Zinc-α2-glycoprotein (ZAG), encoded by the AZGP1 gene, is a major histocompatibility complex I molecule and a lipid-mobilizing factor. ZAG has been demonstrated to promote lipid metabolism and glucose utilization, and to regulate insulin sensitivity. Apart from adipose tissue, skeletal muscle, liver, and kidney, ZAG also occurs in brain tissue, but its distribution in brain is debatable. Only a few studies have investigated ZAG in the brain. It has been found in the brains of patients with Krabbe disease and epilepsy, and in the cerebrospinal fluid of patients with Alzheimer disease, frontotemporal lobe dementia, and amyotrophic lateral sclerosis. Both ZAG protein and AZGP1 mRNA are decreased in epilepsy patients and animal models, while overexpression of ZAG suppresses seizure and epileptic discharges in animal models of epilepsy, but knowledge of the specific mechanism of ZAG in epilepsy is limited. In this review, we summarize the known roles and molecular mechanisms of ZAG in lipid metabolism and glucose metabolism, and in the regulation of insulin sensitivity, and discuss the possible mechanisms by which it suppresses epilepsy.
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22
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Liu M, Zhu H, Zhai T, Pan H, Wang L, Yang H, Yan K, Zeng Y, Gong F. Serum Zinc-α2-Glycoprotein Levels Were Decreased in Patients With Premature Coronary Artery Disease. Front Endocrinol (Lausanne) 2019; 10:197. [PMID: 30984114 PMCID: PMC6449697 DOI: 10.3389/fendo.2019.00197] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 03/08/2019] [Indexed: 12/12/2022] Open
Abstract
Objectives: To explore serum zinc-α2-glycoprotein (ZAG) changes in patients with or without premature coronary artery disease (PCAD) and its association with several cardiovascular risk factors. Methods: A total of 3,364 patients who were undergone coronary angiography in Peking Union Medical College Hospital were screened. According to the degree of coronary artery stenosis, the number of 364 patients with PCAD (age <55 years in males and <65 years in females) and 126 age and gender matched patients without premature coronary artery disease (NPCAD) were recruited in our present study. In addition, 182 age and gender matched healthy controls were also enrolled. Serum ZAG levels were determined by enzyme-linked immunosorbent assay (ELISA) method. Results: Serum ZAG were significantly lower in the PCAD (8.03 ± 1.01 vs. 8.78 ± 1.89 μg/mL, p < 0.05) and NPCAD groups (8.28 ± 1.61 vs. 8.78 ± 1.89 μg/mL, p < 0.05), respectively, when compared with the controls. Multiple regression analysis showed that PCAD was independently associated with serum ZAG levels (B = -0.289, p = 0.002). The probability of PCAD in subjects with low tertile ZAG levels was 2.48-fold higher than those with high tertile levels after adjusting for other confounders [OR = 3.476, 95% CI 1.387-8.711, p = 0.008]. This phenomenon was more likely to be observed in male subjects with BMI <24 kg/m2. The receiver operating curve (ROC) analysis showed a weak diagnostic performance of serum ZAG for PCAD (AUC = 0.659, 95% CI 0.612-0.705, p < 0.05). At the cutoff value of 7.955 μg/mL serum ZAG, the sensitivity and specificity for differentiating patients with PCAD from controls were 50.5 and 78.0%, respectively. The combination of ZAG with other clinical variables including age, gender, BMI, SBP, FBG, TC, HDL-C, Cr, and Urea had significantly improved the diagnosis accuracy with a sensitivity of 82.6%, a specificity of 95.0%, and AUC of 0.957 (95% CI, 0.940-0.975, p < 0.05). Conclusion: Serum ZAG levels were firstly found to be decreased in Chinese PCAD patients. Subjects with lower ZAG levels were more likely to have PCAD, especially for male subjects with BMI <24 kg/m2. ZAG might be the potential diagnostic biomarkers for PCAD patients, and the combination of ZAG and clinical variables had higher discriminative performance.
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Affiliation(s)
- Meijuan Liu
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Huijuan Zhu
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Tianshu Zhai
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Hui Pan
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Linjie Wang
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Hongbo Yang
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Kemin Yan
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Yong Zeng
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Fengying Gong
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- *Correspondence: Fengying Gong ;
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Xiao XH, Wang YD, Qi XY, Wang YY, Li JY, Li H, Zhang PY, Liao HL, Li MH, Liao ZZ, Yang J, Xu CX, Wen GB, Liu JH. Zinc alpha2 glycoprotein protects against obesity-induced hepatic steatosis. Int J Obes (Lond) 2018; 42:1418-1430. [PMID: 30006580 DOI: 10.1038/s41366-018-0151-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 05/14/2018] [Accepted: 06/03/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIM Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity, and chronic low-grade inflammation. Our previous studies indicated that zinc alpha2 glycoprotein (ZAG) alleviates palmitate (PA)-induced intracellular lipid accumulation in hepatocytes. This study is to further characterize the roles of ZAG on the development of hepatic steatosis, insulin resistance (IR), and inflammation. METHODS ZAG protein levels in the livers of NAFLD patients, high-fat diet (HFD)-induced or genetically (ob/ob) induced obese mice, and in PA-treated hepatocytes were determined by western blotting. C57BL/6J mice injected with an adenovirus expressing ZAG were fed HFD for indicated time to induce hepatic steatosis, IR, and inflammation, and then biomedical, histological, and metabolic analyses were conducted to identify pathologic alterations in these mice. The molecular mechanisms underlying ZAG-regulated hepatic steatosis were further explored and verified in mice and hepatocytes. RESULTS ZAG expression was decreased in NAFLD patient liver biopsy samples, obese mice livers, and PA-treated hepatocytes. Simultaneously, ZAG overexpression alleviated intracellular lipid accumulation via upregulating adiponectin and lipolytic genes (FXR, PPARα, etc.) while downregulating lipogenic genes (SREBP-1c, LXR, etc.) in obese mice as well as in cultured hepatocytes. ZAG improved insulin sensitivity and glucose tolerance via activation of IRS/AKT signaling. Moreover, ZAG significantly inhibited NF-ĸB/JNK signaling and thus resulting in suppression of obesity-associated inflammatory response in hepatocytes. CONCLUSIONS Our results revealed that ZAG could protect against NAFLD by ameliorating hepatic steatosis, IR, and inflammation.
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Affiliation(s)
- Xin-Hua Xiao
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001, China
| | - Ya-Di Wang
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001, China
| | - Xiao-Yan Qi
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001, China
| | - Yuan-Yuan Wang
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001, China
| | - Jiao-Yang Li
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001, China
| | - Han Li
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001, China
| | - Pei-Ying Zhang
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001, China
| | - Hai-Lin Liao
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001, China
| | - Mei-Hua Li
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001, China
| | - Zhe-Zhen Liao
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001, China
| | - Jing Yang
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001, China
| | - Can-Xin Xu
- Department of Pathology & Immunology, Washington University in, St. Louis, MO, 63110, USA
| | - Ge-Bo Wen
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001, China
| | - Jiang-Hua Liu
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001, China.
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24
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Circulating bone morphogenetic protein-9 levels are associated with hypertension and insulin resistance in humans. ACTA ACUST UNITED AC 2018; 12:372-380. [PMID: 29550458 DOI: 10.1016/j.jash.2018.02.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Revised: 02/02/2018] [Accepted: 02/15/2018] [Indexed: 12/12/2022]
Abstract
It has been demonstrated that bone morphogenetic protein-9 (BMP-9) may have an important role in vascular development and stability. However, the association of circulating BMP-9 with essential hypertension (HTN) has not been established in humans. The objective of this study is to observe the changes of circulating BMP-9 levels in patients with HTN and to investigate the association of circulation BMP-9 and insulin resistance (IR) in a cross-sectional study. Two hundred twenty-five individuals, including 132 patients with hypertension, and 93 healthy controls, were included in the present study. Circulating BMP-9 concentrations were measured with an ELISA kit. The association of circulating BMP-9 with other parameters was analyzed. When compared with healthy subjects, circulating BMP-9 concentrations were markedly lower in HTN patients (46.20 [31.85-62.80] vs. 77.21 [39.33-189.15], P < .01) and correlated negatively with blood pressure and the homeostasis model assessment of insulin resistance (P < .05 or P < .01). Decreasing levels of BMP-9 were independently and markedly related to HTN. In a multiple linear regression analysis, only systolic blood pressure and free fatty acid concentrations were independently associated with circulating BMP-9. Our findings suggest that BMP-9 may be a serum biomarker for HTN and IR.
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Lei L, Li K, Li L, Fang X, Zhou T, Zhang C, Luo Y, Liu H, Li X, Zheng H, Zhang L, Yang G, Gao L. Circulating zinc-α2-glycoprotein levels are low in newly diagnosed patients with metabolic syndrome and correlate with adiponectin. Nutr Metab (Lond) 2017; 14:53. [PMID: 28814962 PMCID: PMC5556976 DOI: 10.1186/s12986-017-0210-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 08/03/2017] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Zinc-α2-glycoprotein (ZAG) is a novel adipokine that reduces insulin resistance, protecting against type 2 diabetes. However, past studies have been contradictory. This cross-sectional study aims to investigate the association of circulating ZAG with metabolic syndrome (MetS) in middle-aged and older Chinese adults. METHODS Four hundred eighty nine individuals (234 healthy controls and 255 MetS patients) were examined. All individuals were screened for MetS according to the diagnostic guidelines of the United States National Cholesterol Education Program (NCEP) Expert Panel Adult Treatment Panel (ATP) III criteria. Circulating ZAG and ADI levels were measured by ELISA. Blood fat, glucose and insulin were measured with a commercial kit. Circulating ZAG levels were compared with various parameters in study subjects. RESULTS Plasma ZAG levels were lower in MetS patients compared to those of the healthy controls (35.0 ± 11.7 vs. 46.1 ± 18.6 mg/L, P < 0.01). ZAG showed a positive correlation with age, HDL-C, HOMA-β and ADI, but a negative correlation with Fat%, BMI, WHR, blood pressure, triglycerides, FFA, FBG, 2 h-BG, fasting insulin, 2 h-Ins, HbA1c and HOMA-IR (P < 0.01). When the population was divided according to tertiles of ADI, subjects in the highest tertile had the highest ZAG levels. The analysis of ROC curves revealed that the best cutoff value for plasma ZAG to predict MetS was 45.2 mg/L (sensitivity 92%, specificity 59%, and AUC 0.80). CONCLUSIONS We found that circulating ZAG levels were decreased in patients with MetS. In fact, circulating ZAG decreased progressively with an increasing number of MetS components and associated with ADI levels, suggesting that ZAG is related to IR and MetS and may be a sensitizer. TRIAL REGISTRATION ChiCTR-OCC-11001422. Registered 23 June 2011.
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Affiliation(s)
- Lu Lei
- Department of Endocrinology, the Affiliated Hospital, Zunyi Medical College, Guizhou, China
| | - Kejia Li
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ling Li
- Key Laboratory of Diagnostic Medicine (Ministry of Education) and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Xia Fang
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Tingting Zhou
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Cheng Zhang
- The Center of Clinical Research of Endocrinology and Metabolic Diseases in Chongqing and Department of Endocrinology, Chongqing three Gorges Central Hospital, Chongqing, China
| | - Yong Luo
- The Center of Clinical Research of Endocrinology and Metabolic Diseases in Chongqing and Department of Endocrinology, Chongqing three Gorges Central Hospital, Chongqing, China
| | - Hua Liu
- Department of Pediatrics, University of Mississippi Medical Center, 2500 North State Street, Jackson, Mississippi MS 39216-4505 USA
| | - Xiaoqiang Li
- Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Hongting Zheng
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Lin Zhang
- Department of Endocrinology, the Ba Yan NaoEr Hospital, Inner Mongolia, 015000 China
| | - Gangyi Yang
- Department of Endocrinology, the Affiliated Hospital, Zunyi Medical College, Guizhou, China.,Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Lin Gao
- Department of Endocrinology, the Affiliated Hospital, Zunyi Medical College, Guizhou, China
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