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Cevik EC, Erel CT, Ozcivit Erkan IB, Sarafidis P, Armeni E, Fistonić I, Hillard T, Hirschberg AL, Meczekalski B, Mendoza N, Mueck AO, Simoncini T, Stute P, van Dijken D, Rees M, Lambrinoudaki I. Chronic kidney disease and menopausal health: An EMAS clinical guide. Maturitas 2025; 192:108145. [PMID: 39609235 DOI: 10.1016/j.maturitas.2024.108145] [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] [Indexed: 11/30/2024]
Abstract
UNLABELLED Kidney diseases are related to the aging process. Ovarian senescence and the loss of estrogen's renoprotective effects are directly associated with a decline in renal function and indirectly with an accumulation of cardiometabolic risk factors. The latter can predispose to the development of chronic kidney disease (CKD). Conversely, CKD diagnosed during reproductive life adversely affects ovarian function. AIM To set out an individualized approach to menopause management in women with CKD. MATERIALS AND METHODS Literature review and consensus of expert opinion. SUMMARY RECOMMENDATIONS Menopause hormone therapy can be given to women with CKD. The regimen should be selected on the basis of patient preference and the individual's cardiovascular risk. The dose of hormonal and non-hormonal preparations should be adjusted in accordance with the patient's creatinine clearance. The management of a postmenopausal woman with CKD should focus on lifestyle advice as well as regular monitoring of the main cardiovascular risk factors and evaluation of bone mineral density. Tailored multidisciplinary advice should be given to women with comorbidities such as diabetes, dyslipidemia, and hypertension. Management of osteoporosis should be based on the severity of the CKD.
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Affiliation(s)
- E Cansu Cevik
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT 06520, USA
| | - C Tamer Erel
- Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Department of Obstetrics and Gynecology, İstanbul, Turkey.
| | - Ipek Betul Ozcivit Erkan
- Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Department of Obstetrics and Gynecology, İstanbul, Turkey
| | - Pantelis Sarafidis
- First Department of Nephrology, Aristotle University, Hippokration Hospital, Thessaloniki, Greece
| | - Eleni Armeni
- Second Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Greece and Royal Free Hospital, London, United Kingdom
| | - Ivan Fistonić
- Faculty for Health Studies, University of Rijeka, Rijeka, Croatia
| | - Timothy Hillard
- Department of Obstetrics & Gynaecology, University Hospitals Dorset, Poole, United Kingdom
| | - Angelica Lindén Hirschberg
- Department of Women's and Children's Health, Karolinska Institutet and Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Blazej Meczekalski
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, Poznan, Poland
| | - Nicolás Mendoza
- Department of Obstetrics and Gynecology, University of Granada, Spain
| | - Alfred O Mueck
- Department of Women's Health, University Hospital Tübingen, Germany and Beijing OB/GYN Hospital, Capital Medical University, China
| | - Tommaso Simoncini
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 67, 56100, Pisa, Italy
| | - Petra Stute
- Department of Obstetrics and Gynecology, University Clinic Inselspital, Bern, Switzerland
| | - Dorenda van Dijken
- Department of Obstetrics and Gynecology, OLVG Hospital, Amsterdam, the Netherlands
| | - Margaret Rees
- Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
| | - Irene Lambrinoudaki
- Second Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Greece
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Ahmad Hairi H, Ibrahim NI, Sadikan MZ, Jayusman PA, Shuid AN. Deciphering the role of classical oestrogen receptor in insulin resistance and type 2 diabetes mellitus: From molecular mechanism to clinical evidence. BIOIMPACTS : BI 2024; 15:30378. [PMID: 40256228 PMCID: PMC12008500 DOI: 10.34172/bi.30378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 04/19/2024] [Accepted: 05/28/2024] [Indexed: 04/22/2025]
Abstract
The biological actions of oestrogen are mediated by the oestrogen receptor α or β (ERα or ERβ), which are members of a broad nuclear receptor superfamily. Numerous in vivo and in vitro studies have demonstrated that loss of circulating oestrogen modulated by classical ERα and ERβ led to rapid changes in pancreatic β-cell and islet function, GLUT4 expression, insulin sensitivity and glucose tolerance, dysfunctional lipid homeostasis, oxidative stress, and inflammatory cascades. Remarkably, 17β-oestradiol (E2) can completely reverse these effects. This review evaluates the current understanding of the protective role of classical ER in critical pathways and molecular mechanisms associated with insulin resistance and type 2 diabetes mellitus (T2DM). It also examines the effectiveness of menopausal hormone therapy (MHT) in reducing the risk of developing T2DM in menopausal women. Clinical trials have shown the protective effects of MHT on glucose metabolism, which may be useful to treat T2DM in perimenopausal women. However, there are concerns about E2's potential side effects of obesity and hyperlipidaemia in menopausal women. Further studies are warranted to gain understanding and find other oestrogen alternatives for treatment of insulin resistance and T2DM in postmenopausal women.
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Affiliation(s)
- Haryati Ahmad Hairi
- Department of Biochemistry, Faculty of Medicine, Manipal University College Malaysia, Jalan Batu Hampar, Bukit Baru, 75150 Melaka, Malaysia
| | - Nurul Izzah Ibrahim
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, 56000 Kuala Lumpur, Malaysia
| | - Muhammad Zulfiqah Sadikan
- Department of Pharmacology, Faculty of Medicine, Manipal University College Malaysia, Jalan Batu Hampar, Bukit Baru, 75150 Melaka, Malaysia
| | - Putri Ayu Jayusman
- Department of Craniofacial Diagnostics and Biosciences, Faculty of Dentistry, Universiti Kebangsaan Malaysia, 50300 Kuala Lumpur, Malaysia
| | - Ahmad Nazrun Shuid
- Department of Pharmacology, Faculty of Medicine, Universiti Teknologi Mara (UITM), Jalan Hospital, 47000 Sungai Buloh, Selangor, Malaysia
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Xiang X, Palasuberniam P, Pare R. The Role of Estrogen across Multiple Disease Mechanisms. Curr Issues Mol Biol 2024; 46:8170-8196. [PMID: 39194700 DOI: 10.3390/cimb46080483] [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: 06/13/2024] [Revised: 07/18/2024] [Accepted: 07/24/2024] [Indexed: 08/29/2024] Open
Abstract
Estrogen is a significant hormone that is involved in a multitude of physiological and pathological processes. In addition to its pivotal role in the reproductive system, estrogen is also implicated in the pathogenesis of a multitude of diseases. Nevertheless, previous research on the role of estrogen in a multitude of diseases, including Alzheimer's disease, depression, cardiovascular disease, diabetes, osteoporosis, gastrointestinal diseases, and estrogen-dependent cancers, has concentrated on a single disease area, resulting in a lack of comprehensive understanding of cross-disease mechanisms. This has brought some challenges to the current treatment methods for these diseases, because estrogen as a potential therapeutic tool has not yet fully developed its potential. Therefore, this review aims to comprehensively explore the mechanism of estrogen in these seven types of diseases. The objective of this study is to describe the relationship between each disease and estrogen, including the ways in which estrogen participates in regulating disease mechanisms, and to outline the efficacy of estrogen in treating these diseases in clinical practice. By studying the role of estrogen in a variety of disease mechanisms, it is hoped that a more accurate theoretical basis and clinical guidance for future treatment strategies will be provided, thus promoting the effective management and treatment of these diseases.
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Affiliation(s)
- Xiuting Xiang
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu 88400, Malaysia
| | - Praneetha Palasuberniam
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu 88400, Malaysia
| | - Rahmawati Pare
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu 88400, Malaysia
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4
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Tian N, Chen S, Han H, Jin J, Li Z. Association between triglyceride glucose index and total bone mineral density: a cross-sectional study from NHANES 2011-2018. Sci Rep 2024; 14:4208. [PMID: 38378872 PMCID: PMC10879154 DOI: 10.1038/s41598-024-54192-9] [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: 09/25/2023] [Accepted: 02/09/2024] [Indexed: 02/22/2024] Open
Abstract
The Homeostatic Model Assessment for Triglyceride Glucose Index (TyG) and its related indices, including triglyceride glucose-waist circumference (TyG-WC), triglyceride glucose-waist-to-height ratio (TyG-WHtR) and triglyceride glucose-body mass index (TyG-BMI), has emerged as a practical tool for assessing insulin resistance in metabolic disorders. However, limited studies have explored the connection between TyG, TyG-related indices and osteoporosis. This population-based study, utilizing data from the National Health and Nutrition Examination Survey 2011-2018, involved 5456 participants. Through weighted multivariate linear regression and smoothed curve fitting, a significant positive correlation was found between TyG, TyG-related indices and total bone mineral density (BMD) after adjusting for covariates [β = 0.0124, 95% CI (0.0006, 0.0242), P = 0.0390; β = 0.0004, 95% CI (0.0003, 0.0004), P < 0.0001; β = 0.0116, 95% CI (0.0076, 0.0156), P < 0.0001; β = 0.0001, 95% CI (0.0001, 0.0001), P < 0.0001]. In subgroup analysis, race stratification significantly affected the relationship between TyG and total BMD. Additionally, gender and race were both significant for TyG-related indices. Non-linear relationships and threshold effects with inflection points at 9.106, 193.9265, 4.065, and 667.5304 (TyG, TyG-BMI, TyG-WHtR, TyG-WC) were identified. Saturation phenomena were observed between TyG-BMI, TyG-WC and total BMD with saturation thresholds at 314.177 and 1022.0428. These findings contributed to understanding the association between TyG, TyG-related indices and total BMD, offering insights for osteoporosis prevention and treatment.
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Affiliation(s)
- Ningsheng Tian
- Department of Orthopaedics, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, No.23, Nanhu Road, Jianye District, Nanjing, 210017, Jiangsu Province, People's Republic of China
| | - Shuai Chen
- Department of Orthopaedics, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, No.23, Nanhu Road, Jianye District, Nanjing, 210017, Jiangsu Province, People's Republic of China
| | - Huawei Han
- Department of Orthopaedics, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, No.23, Nanhu Road, Jianye District, Nanjing, 210017, Jiangsu Province, People's Republic of China
| | - Jie Jin
- Department of Orthopaedics, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, No.23, Nanhu Road, Jianye District, Nanjing, 210017, Jiangsu Province, People's Republic of China
| | - Zhiwei Li
- Department of Orthopaedics, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, No.23, Nanhu Road, Jianye District, Nanjing, 210017, Jiangsu Province, People's Republic of China.
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5
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Deng X, Liu D, Li M, He J, Fu Y. Association between systemic immune-inflammation index and insulin resistance and mortality. Sci Rep 2024; 14:2013. [PMID: 38263234 PMCID: PMC10806274 DOI: 10.1038/s41598-024-51878-y] [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: 10/19/2023] [Accepted: 01/10/2024] [Indexed: 01/25/2024] Open
Abstract
The role of inflammation in disease promotion is significant, yet the precise association between a newly identified inflammatory biomarker and insulin resistance (IR) and mortality remains uncertain. We aim to explore the potential correlation between systemic immune-inflammation index (SII) and these factors. We used data from 2011 to 2016 of National Health and Nutrition Examination Survey, and multivariate logistic regression and restricted cubic spline were employed. Subgroup and interaction analysis were conducted to recognize the consistency of the results. The association between SII and mortality was described by survival analysis. 6734 participants were enrolled, of whom 49.3% (3318) exhibited IR and 7.02% experienced mortality. Multivariate logistic regression revealed that individuals in the highest quartile (Q4) of SII had a significantly increased risk of IR compared to those in the lowest quartile (Q1). We then identified a linear association between SII and IR with an inflection point of 407, but may be influenced by gender. Similarly, compared to Q1, people whose SII at Q4 showed a higher all-cause and cardiovascular mortality. It showed a significant association between SII and both all-cause and cardiovascular mortality, but the results need to be interpreted with caution.
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Affiliation(s)
- Xiaoqi Deng
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Dichuan Liu
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
| | - Miao Li
- Nursing Department, Beijing Tiantan Hospital, Beijing, 100070, China
| | - Jie He
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Yufan Fu
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
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Speksnijder EM, Ten Noever de Brauw GV, Malekzadeh A, Bisschop PH, Stenvers DJ, Siegelaar SE. Effect of Postmenopausal Hormone Therapy on Glucose Regulation in Women With Type 1 or Type 2 Diabetes: A Systematic Review and Meta-analysis. Diabetes Care 2023; 46:1866-1875. [PMID: 37729504 DOI: 10.2337/dc23-0451] [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: 03/14/2023] [Accepted: 07/27/2023] [Indexed: 09/22/2023]
Abstract
BACKGROUND Blood glucose regulation in women with diabetes may change during and after menopause, which could be attributed, in part, to decreased estrogen levels. PURPOSE To determine the effect of postmenopausal hormone therapy (HT) on HbA1c, fasting glucose, postprandial glucose, and use of glucose-lowering drugs in women with type 1 and women with type 2 diabetes. DATA SOURCES We conducted a systematic search of MEDLINE, Embase, Scopus, the Cochrane Library, and the ClinicalTrials.gov registry to identify randomized controlled trials (RCTs). STUDY SELECTION We selected RCTs on the effect of HT containing estrogen therapy in postmenopausal women (≥12 months since final menstrual period) with type 1 or type 2 diabetes. DATA EXTRACTION Data were extracted for the following outcomes: HbA1c, fasting glucose, postprandial glucose, and use of glucose-lowering medication. DATA SYNTHESIS Nineteen RCTs were included (12 parallel-group trials and 7 crossover trials), with a total of 1,412 participants, of whom 4.0% had type 1 diabetes. HT reduced HbA1c (mean difference -0.56% [95% CI -0.80, -0.31], -6.08 mmol/mol [95% CI -8.80, -3.36]) and fasting glucose (mean difference -1.15 mmol/L [95% CI -1.78, -0.51]). LIMITATIONS Of included studies, 50% were at high risk of bias. CONCLUSIONS When postmenopausal HT is considered for menopausal symptoms in women with type 2 diabetes, HT is expected to have a neutral-to-beneficial impact on glucose regulation. Evidence for the effect of postmenopausal HT in women with type 1 diabetes was limited.
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Affiliation(s)
- Esther M Speksnijder
- Department of Endocrinology and Metabolism, Amsterdam UMC, location University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Gaby V Ten Noever de Brauw
- Department of Endocrinology and Metabolism, Amsterdam UMC, location University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands
| | - Arjan Malekzadeh
- Medical Library, Amsterdam UMC, location University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands
| | - Peter H Bisschop
- Department of Endocrinology and Metabolism, Amsterdam UMC, location University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Dirk Jan Stenvers
- Department of Endocrinology and Metabolism, Amsterdam UMC, location University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
- Department of Endocrinology and Metabolism, Amsterdam UMC, location VU University, Meibergdreef 9, Amsterdam, the Netherlands
| | - Sarah E Siegelaar
- Department of Endocrinology and Metabolism, Amsterdam UMC, location University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
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Inada A, Yasunami Y, Yoshiki A, Nabeshima YI, Inada O. Greb1 Transiently Accelerates Pancreatic β-Cell Proliferation in Diabetic Mice Exposed to Estradiol. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1081-1100. [PMID: 37516458 DOI: 10.1016/j.ajpath.2023.04.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 03/14/2023] [Accepted: 04/04/2023] [Indexed: 07/31/2023]
Abstract
Decrease of pancreatic β cells leads to diabetes. In an inducible cAMP early suppressor (ICER-Iγ) transgenic mouse model of severe type 2 diabetes with reduced insulin production and depleted β cells, supplementation with high concentrations of 17β-estradiol (E2) markedly enhances β-cell proliferation and normalizes glucose levels. The current study explored the underlying mechanisms leading to a dynamic increase of β cells and pathologic changes in diabetic mice exposed to E2. Gene expression profiling of pancreatic islets of 6-month-old ICER-transgenic mice recovering from diabetes due to elevated E2 levels identified growth regulation by estrogen in breast cancer 1 (Greb1) as a gene significantly up-regulated during the recovery phase. To substantiate this, β-cell-specific Greb1-deficient mice were generated, and Greb1 was shown to be essential for recovery of depleted β cells in diabetic mice. Graft growth and glucose lowering were observed in 50 islets with increased Greb1 expression transplanted adjacent to E2 pellets beneath the kidney capsule of streptozotocin-induced diabetic mice. Greb1 expression due to a drastic increase in exogenous or endogenous E2 was transient and closely correlated with changes in E2-related and some cell cycle-related genes. These findings provide new insights into in vivo proliferation of deficient β cells and suggest the possibility of new therapeutic approaches targeting pancreatic β cells that could revolutionize the concept of diabetes treatment, which has been considered difficult to cure completely.
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Affiliation(s)
- Akari Inada
- Clinical Research Department, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan; Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan; Diabetes and Genes, Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | | | - Atsushi Yoshiki
- Experimental Animal Division, RIKEN BioResource Research Center, Tsukuba, Japan
| | - Yo-Ichi Nabeshima
- Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan
| | - Oogi Inada
- Diabetes and Genes, Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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8
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Conte C, Antonelli G, Melica ME, Tarocchi M, Romagnani P, Peired AJ. Role of Sex Hormones in Prevalent Kidney Diseases. Int J Mol Sci 2023; 24:ijms24098244. [PMID: 37175947 PMCID: PMC10179191 DOI: 10.3390/ijms24098244] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/29/2023] [Accepted: 05/03/2023] [Indexed: 05/15/2023] Open
Abstract
Chronic kidney disease (CKD) is a constantly growing global health burden, with more than 840 million people affected worldwide. CKD presents sex disparities in the pathophysiology of the disease, as well as in the epidemiology, clinical manifestations, and disease progression. Overall, while CKD is more frequent in females, males have a higher risk to progress to end-stage kidney disease. In recent years, numerous studies have highlighted the role of sex hormones in the health and diseases of several organs, including the kidney. In this review, we present a clinical overview of the sex-differences in CKD and a selection of prominent kidney diseases causing CKD: lupus nephritis, diabetic kidney disease, IgA nephropathy, and autosomal dominant polycystic kidney disease. We report clinical and experimental findings on the role of sex hormones in the development of the disease and its progression to end-stage kidney disease.
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Affiliation(s)
- Carolina Conte
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
- Nephrology and Dialysis Unit, Meyer Children's Hospital IRCCS, 50139 Florence, Italy
| | - Giulia Antonelli
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
- Nephrology and Dialysis Unit, Meyer Children's Hospital IRCCS, 50139 Florence, Italy
| | - Maria Elena Melica
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
| | - Mirko Tarocchi
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
| | - Paola Romagnani
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
- Nephrology and Dialysis Unit, Meyer Children's Hospital IRCCS, 50139 Florence, Italy
| | - Anna Julie Peired
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
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9
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Mendoza N, Ramírez I, de la Viuda E, Coronado P, Baquedano L, Llaneza P, Nieto V, Otero B, Sánchez-Méndez S, de Frutos VÁ, Andraca L, Barriga P, Benítez Z, Bombas T, Cancelo MJ, Cano A, Branco CC, Correa M, Doval JL, Fasero M, Fiol G, Garello NC, Genazzani AR, Gómez AI, Gómez MÁ, González S, Goulis DG, Guinot M, Hernández LR, Herrero S, Iglesias E, Jurado AR, Lete I, Lubián D, Martínez M, Nieto A, Nieto L, Palacios S, Pedreira M, Pérez-Campos E, Plá MJ, Presa J, Quereda F, Ribes M, Romero P, Roca B, Sánchez-Capilla A, Sánchez-Borrego R, Santaballa A, Santamaría A, Simoncini T, Tinahones F, Calaf J. Eligibility criteria for Menopausal Hormone Therapy (MHT): a position statement from a consortium of scientific societies for the use of MHT in women with medical conditions. MHT Eligibility Criteria Group. Maturitas 2022; 166:65-85. [PMID: 36081216 DOI: 10.1016/j.maturitas.2022.08.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 06/21/2022] [Accepted: 08/17/2022] [Indexed: 11/26/2022]
Abstract
This project aims to develop eligibility criteria for menopausal hormone therapy (MHT). The tool should be similar to those already established for contraception A consortium of scientific societies coordinated by the Spanish Menopause Society met to formulate recommendations for the use of MHT by women with medical conditions based on the best available evidence. The project was developed in two phases. As a first step, we conducted 14 systematic reviews and 32 metanalyses on the safety of MHT (in nine areas: age, time of menopause onset, treatment duration, women with thrombotic risk, women with a personal history of cardiovascular disease, women with metabolic syndrome, women with gastrointestinal diseases, survivors of breast cancer or of other cancers, and women who smoke) and on the most relevant pharmacological interactions with MHT. These systematic reviews and metanalyses helped inform a structured process in which a panel of experts defined the eligibility criteria according to a specific framework, which facilitated the discussion and development process. To unify the proposal, the following eligibility criteria have been defined in accordance with the WHO international nomenclature for the different alternatives for MHT (category 1, no restriction on the use of MHT; category 2, the benefits outweigh the risks; category 3, the risks generally outweigh the benefits; category 4, MHT should not be used). Quality was classified as high, moderate, low or very low, based on several factors (including risk of bias, inaccuracy, inconsistency, lack of directionality and publication bias). When no direct evidence was identified, but plausibility, clinical experience or indirect evidence were available, "Expert opinion" was categorized. For the first time, a set of eligibility criteria, based on clinical evidence and developed according to the most rigorous methodological tools, has been defined. This will provide health professionals with a powerful decision-making tool that can be used to manage menopausal symptoms.
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Affiliation(s)
- Nicolás Mendoza
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain.
| | - Isabel Ramírez
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | | | - Pluvio Coronado
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Laura Baquedano
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Plácido Llaneza
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Verónica Nieto
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Borja Otero
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | | | | | - Leire Andraca
- Sociedad Española de Farmacia Comunitaria (SEFAC), Spain
| | | | - Zully Benítez
- Federación Latino Americana de Sociedades de Climaterio y Menopausia (FLASCYM)
| | - Teresa Bombas
- Red Iberoamericana de Salud Sexual y Reproductiva (REDISSER)
| | | | - Antonio Cano
- European Menopause and Andropause Society (EMAS)
| | | | | | - José Luis Doval
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - María Fasero
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Gabriel Fiol
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Nestor C Garello
- Federación Latino-Americana de Sociedades de Obstetricia y Ginecología (FLASOG)
| | | | - Ana Isabel Gómez
- Sociedad Española de Senología y Patología Mamaria (SESPM), Spain
| | - Mª Ángeles Gómez
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Silvia González
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | | | | | | | - Sonia Herrero
- Sociedad Española de Trombosis y Hemostasia (SETH), Spain
| | - Eva Iglesias
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Ana Rosa Jurado
- Sociedad Española de Médicos de Atención Primaria (SEMERGEN), Spain
| | - Iñaki Lete
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Daniel Lubián
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | | | - Aníbal Nieto
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Laura Nieto
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | | | | | | | | | - Jesús Presa
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | | | - Miriam Ribes
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Pablo Romero
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Beatriz Roca
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | | | | | | | | | | | | | - Joaquín Calaf
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
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10
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Lambrinoudaki I, Paschou SA, Armeni E, Goulis DG. The interplay between diabetes mellitus and menopause: clinical implications. Nat Rev Endocrinol 2022; 18:608-622. [PMID: 35798847 DOI: 10.1038/s41574-022-00708-0] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/27/2022] [Indexed: 12/27/2022]
Abstract
The menopausal transition is an impactful period in women's lives, when the risk of cardiovascular disease is accelerated. Similarly, diabetes mellitus profoundly impacts cardiovascular risk. However, the interplay between menopause and diabetes mellitus has not been adequately studied. The menopausal transition is accompanied by metabolic changes that predispose to diabetes mellitus, particularly type 2 diabetes mellitus (T2DM), as menopause results in increased risk of upper body adipose tissue accumulation and increased incidence of insulin resistance. Equally, diabetes mellitus can affect ovarian ageing, potentially causing women with type 1 diabetes mellitus and early-onset T2DM to experience menopause earlier than women without diabetes mellitus. Earlier age at menopause has been associated with a higher risk of T2DM later in life. Menopausal hormone therapy can reduce the risk of T2DM and improve glycaemic control in women with pre-existing diabetes mellitus; however, there is not enough evidence to support the administration of menopausal hormone therapy for diabetes mellitus prevention or control. This Review critically appraises studies published within the past few years on the interaction between diabetes mellitus and menopause and addresses all clinically relevant issues, such as the effect of menopause on the development of T2DM, and the management of both menopause and diabetes mellitus.
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Affiliation(s)
- Irene Lambrinoudaki
- Menopause Unit, 2nd Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Athens, Greece.
| | - Stavroula A Paschou
- Menopause Unit, 2nd Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Athens, Greece
- Endocrine Unit and Diabetes Centre, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece
| | - Eleni Armeni
- Menopause Unit, 2nd Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios G Goulis
- Unit of Reproductive Endocrinology, 1st Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki, Thessaloniki, Greece
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11
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Rodríguez-Castelán J, Zepeda-Pérez D, Rojas-Juárez R, Aceves C, Castelán F, Cuevas-Romero E. Effects of hypothyroidism on the female pancreas involve the regulation of estrogen receptors. Steroids 2022; 181:108996. [PMID: 35245530 DOI: 10.1016/j.steroids.2022.108996] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 02/22/2022] [Indexed: 11/25/2022]
Abstract
This study aimed to investigate the impact of short-time hypothyroidism on the expression of aromatase, estrogen receptors (ERα, β), and GPR30 in the pancreas of female rabbits. The formation of new islets and the expression of insulin, GLUT4, and lactate dehydrogenase (LDH) were also analyzed. This purpose is based on actions that thyroid hormones and estrogens have on β-cells differentiation, acinar cell function, and insulin secretion. Twelve Chinchilla-breed adult virgin female rabbits were divided into control (n = 6) and hypothyroid (n = 6; methimazole 10 mg/kg for 30 days) groups. In the complete pancreas, expressions of aromatase and estrogen receptors, as well as proinsulin, GLUT4, and LDH were determined by western blot. Characteristics of islets were measured in slices of the pancreas with immunohistochemistry for insulin. Islet and acinar cells express aromatase, ERα, ERβ, and GPR30. Hypothyroidism increased the expression of ERα and diminished that for aromatase, ERβ, and GPR30 in the pancreas. It also promoted a high number of extra small islets (new islets) and increased the expression of proinsulin and GLUT4 in the pancreas. Our results show that actions of thyroid hormones and estrogens on β-cells neogenesis, acinar cell function, and synthesis and secretion of insulin are linked. Thus, the effects of hypothyroidism on the pancreas could include summatory actions of thyroid hormones plus estrogens. Our findings indicate the importance of monitoring estrogen levels and actions on the pancreas of hypothyroid women, particularly when serum estrogen concentrations are affected such as menopausal, pregnant, and those with contraceptive use.
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Affiliation(s)
- Julia Rodríguez-Castelán
- Autonomous University of Tlaxcala, Tlaxcala, Tlaxcala, Mexico; Department of Cellular and Molecular Neurobiology, Institute of Neurobiology, Autonomous Nacional University of Mexico, Juriquilla, Querétaro, Mexico
| | | | | | - Carmen Aceves
- Department of Cellular and Molecular Neurobiology, Institute of Neurobiology, Autonomous Nacional University of Mexico, Juriquilla, Querétaro, Mexico
| | - Francisco Castelán
- Department of Cellular and Physiology, Institute of Biomedical Research, Autonomous Nacional University of Mexico, Mexico City, Mexico; Center Tlaxcala of Behavior Biology, Autonomous University of Tlaxcala, Tlaxcala, Tlaxcala, Mexico
| | - Estela Cuevas-Romero
- Center Tlaxcala of Behavior Biology, Autonomous University of Tlaxcala, Tlaxcala, Tlaxcala, Mexico.
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12
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Burch KE, McCracken K, Buck DJ, Davis RL, Sloan DK, Curtis KS. Relationship Between Circulating Metabolic Hormones and Their Central Receptors During Ovariectomy-Induced Weight Gain in Rats. Front Physiol 2022; 12:800266. [PMID: 35069259 PMCID: PMC8766843 DOI: 10.3389/fphys.2021.800266] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 12/08/2021] [Indexed: 11/13/2022] Open
Abstract
Although increasing research focuses on the phenomenon of body weight gain in women after menopause, the complexity of body weight regulation and the array of models used to investigate it has proven to be challenging. Here, we used ovariectomized (OVX) rats, which rapidly gain weight, to determine if receptors for ghrelin, insulin, or leptin in the dorsal vagal complex (DVC), arcuate nucleus (ARC), or paraventricular nucleus (PVN) change during post-ovariectomy weight gain. Female Sprague-Dawley rats with ad libitum access to standard laboratory chow were bilaterally OVX or sham OVX. Subgroups were weighed and then terminated on day 5, 33, or 54 post-operatively; blood and brains were collected. ELISA kits were used to measure receptors for ghrelin, insulin, and leptin in the DVC, ARC, and PVN, as well as plasma ghrelin, insulin, and leptin. As expected, body weight increased rapidly after ovariectomy. However, ghrelin receptors did not change in any of the areas for either group, nor did circulating ghrelin. Thus, the receptor:hormone ratio indicated comparable ghrelin signaling in these CNS areas for both groups. Insulin receptors in the DVC and PVN decreased in the OVX group over time, increased in the PVN of the Sham group, and were unchanged in the ARC. These changes were accompanied by elevated circulating insulin in the OVX group. Thus, the receptor:hormone ratio indicated reduced insulin signaling in the DVC and PVN of OVX rats. Leptin receptors were unchanged in the DVC and ARC, but increased over time in the PVN of the Sham group. These changes were accompanied by elevated circulating leptin in both groups that was more pronounced in the OVX group. Thus, the receptor:hormone ratio indicated reduced leptin signaling in the DVC and PVN of both groups, but only in the OVX group for the ARC. Together, these data suggest that weight gain that occurs after removal of ovarian hormones by ovariectomy is associated with selective changes in metabolic hormone signaling in the CNS. While these changes may reflect behavioral or physiological alterations, it remains to be determined whether they cause post-ovariectomy weight gain or result from it.
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Affiliation(s)
- Kaitlin E Burch
- Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, Tulsa, OK, United States
| | - Kelly McCracken
- Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, Tulsa, OK, United States
| | - Daniel J Buck
- Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, Tulsa, OK, United States
| | - Randall L Davis
- Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, Tulsa, OK, United States
| | - Dusti K Sloan
- Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, Tulsa, OK, United States
| | - Kathleen S Curtis
- Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, Tulsa, OK, United States
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13
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Parental insulin resistance is associated with unhealthy lifestyle behaviours independently of body mass index in children: The Feel4Diabetes study. Eur J Pediatr 2022; 181:2513-2522. [PMID: 35347419 PMCID: PMC9110461 DOI: 10.1007/s00431-022-04449-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 03/12/2022] [Accepted: 03/16/2022] [Indexed: 02/02/2023]
Abstract
UNLABELLED Parental health is associated with children's health and lifestyles. Thus, the aim of the present study was to assess lifestyle behaviours of children of parents with insulin resistance (IR) and at risk of type 2 diabetes. 2117 European families from the Feel4Diabetes-study were identified as being at risk for diabetes with the FINDRISC questionnaire and included in the present study. One parent and one child per family were included. Parental IR was considered when homeostasis model assessment (HOMA) was equal or higher than 2.5. Children's screen-time, physical activity and diet were assessed and clustered by K-means. Weight and height were measured and children's body mass index (BMI) was calculated. For children, a Healthy Diet Score (HDS) was calculated. Linear regression and multilevel logistic regression analyses were performed to assess the associations between parental IR and children's lifestyle behaviours in 2021. Children of parents with IR had higher BMI (p < 0.001) and spent more screen time (p = 0.014) than those of non-IR parents. Children of parents with IR had a lower value in the breakfast and vegetable components of the HDS (p = 0.008 and p = 0.05). Four lifestyle clusters were found. Children of IR parents had higher odds of being in a non-healthy cluster (OR: 1.19; 95%CI: 1.001-1.437). CONCLUSION Having an IR parent was associated with a high screen time and an increased probability of having an unhealthy lifestyle pattern in children. These data point out that children's lifestyles should be assessed in families with IR parents to provide tailored interventions. WHAT IS KNOWN • Children with diabetic or insulin-resistant parents could also develop this condition. • Unhealthy lifestyles are directly related with insulin resistance even in children. WHAT IS NEW • Children from parents with insulin resistance have higher chances of unhealthy lifestyles. • A higher BMI was found for those children with an insulin-resistant parent.
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Roa-Díaz ZM, Raguindin PF, Bano A, Laine JE, Muka T, Glisic M. Menopause and cardiometabolic diseases: What we (don't) know and why it matters. Maturitas 2021; 152:48-56. [PMID: 34674807 DOI: 10.1016/j.maturitas.2021.06.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/20/2021] [Accepted: 06/26/2021] [Indexed: 01/11/2023]
Abstract
This narrative review discusses the current understanding, knowledge gaps and challenges in expanding our knowledge of the association between menopause and the reproductive aging process and cardiometabolic disease (CMD) in women, with a focus on type 2 diabetes and cardiovascular disease. The physiological changes that occur at different stages of the reproductive life span, as well as type of menopause and timing, are factors widely associated with CMD risk; however, the underlying mechanisms remain either unclear or insufficiently studied. Decreased ovarian estrogen production and relative androgen excess around menopause onset are the most studied factors linking menopause and cardiometabolic health; nevertheless, the evidence is not persuasive and other hypotheses might explain the changes in CMD risk during menopausal transition. In this context, hormone therapy has been widely adopted in the treatment and prevention of CMD, although uncertainty regarding its cardiometabolic effects has raised the need to optimize therapeutic modalities. Mechanisms such as the "iron overload theory" and new "omics" platforms could provide new insights into potential pathways underlying the association between menopause and cardiometabolic health, such as the DNA damage response. Although it has been widely reported that environmental and lifestyle factors affect both menopause and cardiometabolic health, there is little evidence on the role of these exposures in menopause-associated CMD risk.
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Affiliation(s)
- Zayne M Roa-Díaz
- Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland; Graduate School for Health Sciences, University of Bern, Bern, Switzerland
| | - Peter Francis Raguindin
- Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland; Graduate School for Health Sciences, University of Bern, Bern, Switzerland; Swiss Paraplegic Research, Nottwil, Switzerland
| | - Arjola Bano
- Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland; Department of Cardiology, Inselspital, Bern University Hospital, Bern, Switzerland
| | - Jessica E Laine
- Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland
| | - Taulant Muka
- Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland
| | - Marija Glisic
- Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland; Swiss Paraplegic Research, Nottwil, Switzerland.
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15
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Tanaka K, Higuchi R, Mizusawa K, Nakamura T, Nakajima K. Fasting biochemical hypoglycemia and related-factors in non-diabetic population: Kanagawa Investigation of Total Check-up Data from National Database-8. World J Diabetes 2021; 12:1131-1140. [PMID: 34326960 PMCID: PMC8311474 DOI: 10.4239/wjd.v12.i7.1131] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/28/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In healthy people, the lowest daily blood glucose concentration is usually observed in the early morning, after overnight fasting. However, the clinical relevance and the prevalence of fasting biochemical hypoglycemia (FBH) are poorly understood in people who do not have diabetes, although the clinical implications of such hypoglycemia have been extensively studied in patients with diabetes. FBH can be influenced by many factors, including age, sex, body mass, smoking, alcohol drinking, exercise levels, medications, and eating behaviors, such as breakfast skipping and late-night eating. AIM To determine the prevalence of FBH and investigated its association with potential risk factors in a population without diabetes. METHODS Clinical parameters and lifestyle-related factors were assessed in a cross-sectional study of 695613 people aged 40-74 years who had undergone a health check-up (390282 men and 305331 women). FBH was defined as fasting plasma glucose < 70 mg/dL (3.9 mmol/L) after overnight fasting, regardless of any symptoms. The absence of diabetes was defined as HbA1c < 6.5%, fasting plasma glucose < 126 mg/dL (7.0 mmol/L), and no pharmacotherapy for diabetes. Multivariate logistic regression analysis, with adjustment for confounding factors, was used to identify associations. RESULTS FBH was present in 1842 participants (0.26%). There were significantly more women in the FBH group (59.1%) than in the non-FBH group (43.9%). Values of most of the clinical parameters, but not age, were significantly lower in the FBH group than in the non-FBH group. Logistic regression analysis showed that a body mass index of ≤ 20.9 kg/m2 (reference: 21-22.9 kg/m2) and current smoking were significantly associated with FBH, and this was not altered by adjustment for age, sex, and pharmacotherapy for hypertension or dyslipidemia. Female sex was associated with FBH. When the data were analyzed according to sex, men in their 60s or 70s appeared more likely to experience FBH compared with their 40s, whereas men in their 50s and women aged ≥ 50 years appeared less likely to experience FBH. The relationships of FBH with other factors including alcohol drinking and pharmacotherapies for hypertension and dyslipidemia also differed between men and women. CONCLUSION FBH occurs even in non-diabetic people, albeit at a very low frequency. FBH is robustly associated with low body mass and smoking, and its relationship with lifestyle factors varies according to sex.
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Affiliation(s)
- Kotone Tanaka
- Graduate School of Health Innovation, Kanagawa University of Human Services, Kawasaki 210-0821, Japan
| | - Ryoko Higuchi
- School of Nutrition and Dietetics, Faculty of Health and Social Services, Kanagawa University of Human Services, Yokosuka 238-8522, Japan
| | - Kaori Mizusawa
- School of Nutrition and Dietetics, Faculty of Health and Social Services, Kanagawa University of Human Services, Yokosuka 238-8522, Japan
| | - Teiji Nakamura
- School of Nutrition and Dietetics, Faculty of Health and Social Services, Kanagawa University of Human Services, Yokosuka 238-8522, Japan
| | - Kei Nakajima
- School of Nutrition and Dietetics, Faculty of Health and Social Services, Kanagawa University of Human Services, Yokosuka 238-8522, Japan
- Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University, Kawagoe 350-8550, Japan
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Giandalia A, Giuffrida AE, Gembillo G, Cucinotta D, Squadrito G, Santoro D, Russo GT. Gender Differences in Diabetic Kidney Disease: Focus on Hormonal, Genetic and Clinical Factors. Int J Mol Sci 2021; 22:5808. [PMID: 34071671 PMCID: PMC8198374 DOI: 10.3390/ijms22115808] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 05/21/2021] [Accepted: 05/25/2021] [Indexed: 02/07/2023] Open
Abstract
Diabetic kidney disease (DKD) is one of the most serious complications of both type 1 (T1DM) and type 2 diabetes mellitus (T2DM). Current guidelines recommend a personalized approach in order to reduce the burden of DM and its complications. Recognizing sex and gender- differences in medicine is considered one of the first steps toward personalized medicine, but the gender issue in DM has been scarcely explored so far. Gender differences have been reported in the incidence and the prevalence of DKD, in its phenotypes and clinical manifestations, as well as in several risk factors, with a different impact in the two genders. Hormonal factors, especially estrogen loss, play a significant role in explaining these differences. Additionally, the impact of sex chromosomes as well as the influence of gene-sex interactions with several susceptibility genes for DKD have been investigated. In spite of the increasing evidence that sex and gender should be included in the evaluation of DKD, several open issues remain uncovered, including the potentially different effects of newly recommended drugs, such as SGLT2i and GLP1Ras. This narrative review explored current evidence on sex/gender differences in DKD, taking into account hormonal, genetic and clinical factors.
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Affiliation(s)
- Annalisa Giandalia
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (A.G.); (D.C.); (G.S.)
| | - Alfio Edoardo Giuffrida
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (A.E.G.); (G.G.); (D.S.)
| | - Guido Gembillo
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (A.E.G.); (G.G.); (D.S.)
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, 98125 Messina, Italy
| | - Domenico Cucinotta
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (A.G.); (D.C.); (G.S.)
| | - Giovanni Squadrito
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (A.G.); (D.C.); (G.S.)
| | - Domenico Santoro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (A.E.G.); (G.G.); (D.S.)
| | - Giuseppina T. Russo
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (A.G.); (D.C.); (G.S.)
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Lau LHY, Nano J, Cecil A, Schederecker F, Rathmann W, Prehn C, Zeller T, Lechner A, Adamski J, Peters A, Thorand B. Cross-sectional and prospective relationships of endogenous progestogens and estrogens with glucose metabolism in men and women: a KORA F4/FF4 Study. BMJ Open Diabetes Res Care 2021; 9:9/1/e001951. [PMID: 33574134 PMCID: PMC7880095 DOI: 10.1136/bmjdrc-2020-001951] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 01/03/2021] [Accepted: 01/09/2021] [Indexed: 01/02/2023] Open
Abstract
INTRODUCTION Relationships between endogenous female sex hormones and glycemic traits remain understudied, especially in men. We examined whether endogenous 17α-hydroxyprogesterone (17-OHP), progesterone, estradiol (E2), and free estradiol (fE2) were associated with glycemic traits and glycemic deterioration. RESEARCH DESIGN AND METHODS 921 mainly middle-aged and elderly men and 390 perimenopausal/postmenopausal women from the German population-based Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort study were followed up for a median of 6.4 years. Sex hormones were measured at baseline using mass spectrometry. We calculated regression coefficients (β) and ORs with 95% CIs using multivariable-adjusted linear and logistic regression models for Z-standardized hormones and glycemic traits or glycemic deterioration (ie, worsening of categorized glucose tolerance status), respectively. RESULTS In the cross-sectional analysis (n=1222 men and n=594 women), in men, 17-OHP was inversely associated with 2h-glucose (2hG) (β=-0.067, 95% CI -0.120 to -0.013) and fasting insulin (β=-0.074, 95% CI -0.118 to -0.030), and positively associated with Quantitative Insulin Sensitivity Check Index (QUICKI) (β=0.061, 95% CI 0.018 to 0.105). Progesterone was inversely associated with fasting insulin (β=-0.047, 95% CI -0.088 to -0.006) and positively associated with QUICKI (β=0.041, 95% CI 0.001 to 0.082). E2 was inversely associated with fasting insulin (β=-0.068, 95% CI -0.116 to -0.020) and positively associated with QUICKI (β=0.059, 95% CI 0.012 to 0.107). fE2 was positively associated with glycated hemoglobin (HbA1c) (β=0.079, 95% CI 0.027 to 0.132). In women, 17-OHP was positively associated with fasting glucose (FG) (β=0.068, 95% CI 0.014 to 0.123). fE2 was positively associated with FG (β=0.080, 95% CI 0.020 to 0.141) and HbA1c (β=0.121, 95% CI 0.062 to 0.180). In the sensitivity analyses restricted to postmenopausal women, we observed a positive association between 17-OHP and glycemic deterioration (OR=1.518, 95% CI 1.033 to 2.264). CONCLUSIONS Inter-relations exist between female sex hormones and glucose-related traits among perimenopausal/postmenopausal women and insulin-related traits among men. Endogenous progestogens and estrogens appear to be involved in glucose homeostasis not only in women but in men as well. Further well-powered studies assessing causal associations between endogenous female sex hormones and glycemic traits are warranted.
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Affiliation(s)
- Lina Hui Ying Lau
- Institute of of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, München-Neuherberg, Germany
- Institute for Medical Information Processing, Biometry, and Epidemiology (IBE), Ludwig-Maximilians-Universität (LMU), München, Germany
- International Helmholtz Research School for Diabetes, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Jana Nano
- Institute of of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, München-Neuherberg, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Alexander Cecil
- Research Unit, Molecular Endocrinology and Metabolism, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Florian Schederecker
- Institute of of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, München-Neuherberg, Germany
| | - Wolfgang Rathmann
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Institute for Biometrics and Epidemiology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine Universität, Düsseldorf, Germany
| | - Cornelia Prehn
- Research Unit, Molecular Endocrinology and Metabolism, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Tanja Zeller
- Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Lübeck, Germany
| | - Andreas Lechner
- Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität (LMU), München, Germany
| | - Jerzy Adamski
- Research Unit, Molecular Endocrinology and Metabolism, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- Lehrstuhl für Experimentelle Genetik, Technische Universität München, München, Germany
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Annette Peters
- Institute of of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, München-Neuherberg, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, München, Germany
| | - Barbara Thorand
- Institute of of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, München-Neuherberg, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
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18
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Mann SN, Hadad N, Nelson Holte M, Rothman AR, Sathiaseelan R, Ali Mondal S, Agbaga MP, Unnikrishnan A, Subramaniam M, Hawse J, Huffman DM, Freeman WM, Stout MB. Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α. eLife 2020; 9:59616. [PMID: 33289482 PMCID: PMC7744101 DOI: 10.7554/elife.59616] [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: 06/03/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023] Open
Abstract
Metabolic dysfunction underlies several chronic diseases, many of which are exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging, although compliance issues remain paramount. 17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanisms by which 17α-estradiol elicits these benefits remain unresolved. Herein, we show that 17α-estradiol elicits similar genomic binding and transcriptional activation through estrogen receptor α (ERα) to that of 17β-estradiol. In addition, we show that the ablation of ERα completely attenuates the beneficial metabolic effects of 17α-E2 in male mice. Our findings suggest that 17α-E2 may act through the liver and hypothalamus to improve metabolic parameters in male mice. Lastly, we also determined that 17α-E2 improves metabolic parameters in male rats, thereby proving that the beneficial effects of 17α-E2 are not limited to mice. Collectively, these studies suggest ERα may be a drug target for mitigating chronic diseases in male mammals.
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Affiliation(s)
- Shivani N Mann
- Department of Nutritional Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, United States.,Oklahoma Center for Geroscience, University of Oklahoma Health Sciences Center, Oklahoma City, United States.,Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, United States
| | - Niran Hadad
- The Jackson Laboratory, Bar Harbor, United States
| | - Molly Nelson Holte
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
| | - Alicia R Rothman
- Department of Nutritional Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, United States
| | - Roshini Sathiaseelan
- Department of Nutritional Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, United States
| | - Samim Ali Mondal
- Department of Nutritional Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, United States
| | - Martin-Paul Agbaga
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, United States.,Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, United States.,Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, United States
| | - Archana Unnikrishnan
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, United States.,Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, United States
| | | | - John Hawse
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
| | - Derek M Huffman
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York, United States
| | - Willard M Freeman
- Oklahoma Center for Geroscience, University of Oklahoma Health Sciences Center, Oklahoma City, United States.,Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, United States.,Oklahoma City Veterans Affairs Medical Center, Oklahoma City, United States
| | - Michael B Stout
- Department of Nutritional Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, United States.,Oklahoma Center for Geroscience, University of Oklahoma Health Sciences Center, Oklahoma City, United States.,Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, United States
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Venetsanaki V, Polyzos SA. Menopause and Non-Alcoholic Fatty Liver Disease: A Review Focusing on Therapeutic Perspectives. Curr Vasc Pharmacol 2020; 17:546-555. [PMID: 29992886 DOI: 10.2174/1570161116666180711121949] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Revised: 06/05/2018] [Accepted: 06/14/2018] [Indexed: 02/06/2023]
Abstract
There is increasing evidence that menopause is associated with the progression and severity of non-alcoholic fatty liver disease (NAFLD). Estrogen deficiency worsens non-alcoholic steatohepatitis (NASH) in mice models with fatty liver. The prevalence of NAFLD seems to be higher in postmenopausal compared with premenopausal women. Although more data are needed, lower serum estradiol levels are associated with NASH in postmenopausal women. Apart from estrogen deficiency, relative androgen excess and decrease in sex hormone-binding protein are observed in postmenopausal women. These hormonal changes seem to interplay with an increase in abdominal adipose mass, also observed in postmenopausal women, and aging, which are both closely related to the severity and progressive forms of NAFLD. NAFLD adds extra morbidity to postmenopausal women, possibly increasing the risk of type 2 diabetes mellitus and cardiovascular disease. Improving parameters of the metabolic syndrome via modifications in diet and physical exercise may reduce the risk of NAFLD and its related morbidity. Limited studies have shown a beneficial effect of hormone replacement therapy (HRT) on NAFLD, although adverse hepatic effects have been attributed to progesterone in one study. Phytoestrogens may be alternatives to HRT, but their long-term efficacy and safety remain to be shown. The aim of this review was to summarize evidence linking menopause with NAFLD with a special focus on potential therapeutic perspectives.
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Affiliation(s)
- Vasiliki Venetsanaki
- Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynaecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Stergios A Polyzos
- First Department of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
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20
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Pietrobon CB, Miranda RA, Bertasso IM, Mathias PCDF, Bonfleur ML, Balbo SL, Reis MADB, Latorraca MQ, Arantes VC, de Oliveira E, Lisboa PC, de Moura EG. Early weaning induces short- and long-term effects on pancreatic islets in Wistar rats of both sexes. J Physiol 2020; 598:489-502. [PMID: 31828802 DOI: 10.1113/jp278833] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Accepted: 11/01/2019] [Indexed: 11/08/2022] Open
Abstract
KEY POINTS The World Health Organization recommends exclusive breastfeeding until 6 months of age as an important strategy to reduce child morbidity and mortality. Studies have associated early weaning with the development of obesity and type 2 diabetes in adulthood. In our model, we demonstrated that early weaning leads to increased insulin secretion in adolescent males and reduced insulin secretion in adult offspring. Early weaned males exhibit insulin resistance in skeletal muscle. Early weaning did not change insulin signalling in the muscle of female offspring. Taking into account that insulin resistance is one of the primary factors for the development of type 2 diabetes mellitus, this work demonstrates the importance of breastfeeding in the fight against this disease. ABSTRACT Early weaning (EW) leads to short- and long-term obesity and diabetes. This phenotype is also observed in experimental models, in which early-weaned males exhibit abnormal insulinaemia in adulthood. However, studies regarding the effect of EW on pancreatic islets are rare. We investigated the mechanisms by which glycaemic homeostasis is altered in EW models through evaluations of insulin secretion and its signalling pathway in offspring. Lactating Wistar rats and their pups were divided into the following groups: non-pharmacological EW (NPEW): mothers were wrapped with an adhesive bandage on the last 3 days of lactation; pharmacological EW (PEW): mothers received bromocriptine to inhibit prolactin (1 mg/kg body mass/day) on the last 3 days of lactation; and control (C): pups underwent standard weaning at PN21. Offspring of both sexes were euthanized at PN45 and PN180. At PN45, EW males showed higher insulin secretion (vs. C). At PN170, PEW males exhibited hyperglycaemia in an oral glucose tolerance test (vs. C and NPEW). At PN180, EW male offspring were heavier; however, both sexes showed higher visceral fat. Insulin secretion was lower in EW offspring of both sexes. Males from both EW groups had lower glucokinase in islets, but unexpectedly, PEW males showed higher GLUT2, than did C. EW males exhibited lower insulin signalling in muscle. EW females exhibited no changes in these parameters compared with C. We demonstrated distinct alterations in the insulin secretion of EW rats at different ages. Despite the sex dimorphism in insulin secretion in adolescence, both sexes showed impaired insulin secretion in adulthood due to EW.
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Affiliation(s)
- Carla Bruna Pietrobon
- Laboratory of Endocrine Physiology, Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Rosiane Aparecida Miranda
- Laboratory of Endocrine Physiology, Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Iala Milene Bertasso
- Laboratory of Endocrine Physiology, Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Paulo Cezar de Freitas Mathias
- Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringa, Maringá, PR, Brazil
| | - Maria Lúcia Bonfleur
- Laboratory of Endocrine Physiology and Metabolism, Center of Biological and Health Sciences, Western Paraná State University, Cascavel, PR, Brazil
| | - Sandra Lucinei Balbo
- Laboratory of Endocrine Physiology and Metabolism, Center of Biological and Health Sciences, Western Paraná State University, Cascavel, PR, Brazil
| | | | - Márcia Queiroz Latorraca
- Department of Food and Nutrition, Faculty of Nutrition, Federal University of Mato Grosso, Cuiabá, MT, Brazil
| | - Vanessa Cristina Arantes
- Department of Food and Nutrition, Faculty of Nutrition, Federal University of Mato Grosso, Cuiabá, MT, Brazil
| | - Elaine de Oliveira
- Laboratory of Endocrine Physiology, Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Patrícia Cristina Lisboa
- Laboratory of Endocrine Physiology, Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Egberto Gaspar de Moura
- Laboratory of Endocrine Physiology, Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
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Braxas H, Rafraf M, Karimi Hasanabad S, Asghari Jafarabadi M. Effectiveness of Genistein Supplementation on Metabolic Factors and Antioxidant Status in Postmenopausal Women With Type 2 Diabetes Mellitus. Can J Diabetes 2019; 43:490-497. [PMID: 31307913 DOI: 10.1016/j.jcjd.2019.04.007] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2018] [Revised: 03/14/2019] [Accepted: 04/12/2019] [Indexed: 01/22/2023]
Abstract
OBJECTIVES The risk of type 2 diabetes mellitus (T2DM) increases in women after menopause. Genistein is known to modulate metabolic pathways. The aim of this study was to investigate the effects of genistein supplementation on metabolic parameters, oxidative stress and obesity values in postmenopausal women with T2DM. METHODS This randomized, double-blind, placebo-controlled clinical trial was conducted on 54 postmenopausal women 47 to 69 years of age with T2DM. The genistein group (n=28) was given 2 genistein capsules daily for 12 weeks. Each capsule contained 54 mg genistein. The placebo group (n=26) received 2 placebo capsules daily for the same period. Fasting blood samples, anthropometric measurements, dietary intakes and physical activity levels of subjects were collected at baseline and at the end of the trial. Data were analyzed by independent t test, paired t test and analysis of covariance. RESULTS Genistein supplementation significantly reduced serum levels of fasting blood glucose (FBS), glycated hemoglobin (A1C), serum triglyceride (TG) and malondialdehyde (MDA) and increased total antioxidant capacity (TAC) compared with the placebo group at the end of the study (p<0.05 for all). Serum high-density lipoprotein cholesterol and quantitative insulin sensitivity check index significantly increased within the genistein group. Changes in anthropometric indexes and other variables were not significant in any of the groups. CONCLUSIONS Genistein administration improved FBS, A1C, serum TG, TAC and MDA in postmenopausal women with T2DM and may be useful in the control of metabolic status and oxidative stress in these subjects.
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Affiliation(s)
- Hassan Braxas
- Department of Community Nutrition, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Rafraf
- Nutrition Research Center, Department of Community Nutrition, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Saadat Karimi Hasanabad
- Department of Community Nutrition, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Asghari Jafarabadi
- Road Traffic Injury Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Statistics and Epidemiology, Faculty of Health, Tabriz University of Medical Sciences, Tabriz, Iran
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22
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23
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Grossmann M, Wierman ME, Angus P, Handelsman DJ. Reproductive Endocrinology of Nonalcoholic Fatty Liver Disease. Endocr Rev 2019; 40:417-446. [PMID: 30500887 DOI: 10.1210/er.2018-00158] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 11/19/2018] [Indexed: 02/07/2023]
Abstract
The liver and the reproductive system interact in a multifaceted bidirectional fashion. Sex steroid signaling influences hepatic endobiotic and xenobiotic metabolism and contributes to the pathogenesis of functional and structural disorders of the liver. In turn, liver function affects the reproductive axis via modulating sex steroid metabolism and transport to tissues via sex hormone-binding globulin (SHBG). The liver senses the body's metabolic status and adapts its energy homeostasis in a sex-dependent fashion, a dimorphism signaled by the sex steroid milieu and possibly related to the metabolic costs of reproduction. Sex steroids impact the pathogenesis of nonalcoholic fatty liver disease, including development of hepatic steatosis, fibrosis, and carcinogenesis. Preclinical studies in male rodents demonstrate that androgens protect against hepatic steatosis and insulin resistance both via androgen receptor signaling and, following aromatization to estradiol, estrogen receptor signaling, through regulating genes involved in hepatic lipogenesis and glucose metabolism. In female rodents in contrast to males, androgens promote hepatic steatosis and dysglycemia, whereas estradiol is similarly protective against liver disease. In men, hepatic steatosis is associated with modest reductions in circulating testosterone, in part consequent to a reduction in circulating SHBG. Testosterone treatment has not been demonstrated to improve hepatic steatosis in randomized controlled clinical trials. Consistent with sex-dimorphic preclinical findings, androgens promote hepatic steatosis and dysglycemia in women, whereas endogenous estradiol appears protective in both men and women. In both sexes, androgens promote hepatic fibrosis and the development of hepatocellular carcinoma, whereas estradiol is protective.
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Affiliation(s)
- Mathis Grossmann
- Department of Medicine Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.,Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia
| | - Margaret E Wierman
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.,Research Service, Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado
| | - Peter Angus
- Department of Medicine Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.,Departments of Gastroenterology and Hepatology, Heidelberg, Victoria, Australia
| | - David J Handelsman
- ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, New South Wales, Australia
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24
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Glavas MM, Hui Q, Tudurí E, Erener S, Kasteel NL, Johnson JD, Kieffer TJ. Early overnutrition reduces Pdx1 expression and induces β cell failure in Swiss Webster mice. Sci Rep 2019; 9:3619. [PMID: 30842440 PMCID: PMC6403421 DOI: 10.1038/s41598-019-39177-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 01/07/2019] [Indexed: 12/25/2022] Open
Abstract
Childhood obesity and early rapid growth increase the risk for type 2 diabetes. Such early overnutrition can be modeled in mice by reducing litter size. We investigated the effects of early overnutrition and increased dietary fat intake on β cell function in Swiss Webster mice. On a moderate-fat diet, early overnutrition accelerated weight gain and induced hyperinsulinemia in pups. Early overnutrition males exhibited higher β cell mass but reduced islet insulin content and Pdx1 expression. Males had a high diabetes incidence that was increased by early overnutrition, characterized by a progressive increase in insulin secretion as well as β cell death, indicated by histological analysis and increased circulating miR-375 levels. Females maintained normoglycemia throughout life. High-fat diet (HFD) increased diabetes incidence in males, whereas low-fat diet was completely protective. This protective effect was abolished in early overnutrition males transiently exposed to HFD in early life. Although Swiss Webster mice are not known to be diabetes-prone, the high diabetes incidence suggests an underlying genetic susceptibility that can be induced by overnutrition and increased dietary fat intake in early life. Thus, the nutritional environment in early life may impact long-term β cell function and increase diabetes risk, particularly in genetically susceptible individuals.
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Affiliation(s)
- Maria M Glavas
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Queenie Hui
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Eva Tudurí
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.,Centro de Investigación Biomédica en Red de Diabetes y , Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Suheda Erener
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Naomi L Kasteel
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - James D Johnson
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Timothy J Kieffer
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada. .,Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
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25
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Fitzgerald SJ, Janorkar AV, Barnes A, Maranon RO. A new approach to study the sex differences in adipose tissue. J Biomed Sci 2018; 25:89. [PMID: 30509250 PMCID: PMC6278144 DOI: 10.1186/s12929-018-0488-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 11/15/2018] [Indexed: 11/10/2022] Open
Abstract
Obesity is one of the most invaliding and preventable diseases in the United States. Growing evidence suggests that there are sex differences in obesity in human and experimental animals. However, the specific mechanisms of this disease are unknown. Consequently, there is any particular treatment according to the sex/gender at this time. During the last decade, we observe a rise in the study of adipocyte and the possible mechanisms involved in the different roles of the fat. Furthermore, the effect of sex steroids on the adipocyte is one of the fields that need elucidation. Supporting evidence suggests that sex steroids play an essential role not only in the fat distribution, but also, in its metabolism, proliferation, and function. Thus, using in vitro and in vivo studies will contribute to our fight against this critical health public problem encompassing both sexes. In the present review, we discuss some of the recent advances in the adipocytes and the effect of the sex steroids on the adipose tissue. Also, we propose a new alternative to study the role of sex steroids on adipocyte biology through human adipose-derived stem cells.
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Affiliation(s)
- Sarah Jayne Fitzgerald
- Department of Biomedical Materials Science, School of Dentistry, University of Mississippi Medical Center, Jackson, USA
| | - Amol Vijay Janorkar
- Department of Biomedical Materials Science, School of Dentistry, University of Mississippi Medical Center, Jackson, USA
| | - Allison Barnes
- Department of Cell and Molecular Biology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA
| | - Rodrigo Oscar Maranon
- Department of Cell and Molecular Biology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA. .,Department of Medicine/Nephrology, School of Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA. .,Mississippi Center for Excellence in Perinatal Research, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA. .,Cardio Renal Research Center, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA. .,The Women's Health Research Center, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA.
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26
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Wang X, Xian T, Jia X, Zhang L, Liu L, Man F, Zhang X, Zhang J, Pan Q, Guo L. A cross-sectional study on the associations of insulin resistance with sex hormone, abnormal lipid metabolism in T2DM and IGT patients. Medicine (Baltimore) 2017; 96:e7378. [PMID: 28658166 PMCID: PMC5500088 DOI: 10.1097/md.0000000000007378] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a long-term metabolic disorder. It is characterized by hyperglycemia, insulin resistance (IR), and relative impairment in insulin secretion. IR plays a major role in the pathogenesis of T2DM. Many previous studies have investigated the relationship between estrogen, androgen, and obesity, but few focused on the relationship between sex hormones, abnormal lipid metabolism, and IR. The goal for the present study was to identify the association of IR with sex hormone, abnormal lipid metabolism in type 2 diabetes, and impaired glucose tolerance (IGT) patients.In total 13,400 participants were analyzed based on the results of the glucose tolerance test. Using a cross-sectional study, we showed the relationship between IR and the level of sex hormones among 3 different glucose tolerance states: normal control people, IGT, and T2DM patients. We also analyzed the relationship between IR and abnormal lipid metabolism.Significantly, luteinizing, progesterone, estradiol, prolactin, and follicle-stimulating hormone levels decreased in T2DM and IGT patients compared with those in normal control people. The association between IR and lipid metabolism disorders in T2DM and IGT patients was also observed.Our clinical findings may offer new insights into understanding the mechanism of metabolic disorders and in new therapeutic methods for the treatment of the prevalence of type 2 diabetes.
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27
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Mauvais-Jarvis F, Manson JE, Stevenson JC, Fonseca VA. Menopausal Hormone Therapy and Type 2 Diabetes Prevention: Evidence, Mechanisms, and Clinical Implications. Endocr Rev 2017; 38:173-188. [PMID: 28323934 PMCID: PMC5460681 DOI: 10.1210/er.2016-1146] [Citation(s) in RCA: 200] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2016] [Accepted: 03/02/2017] [Indexed: 12/14/2022]
Abstract
Type 2 diabetes has reached epidemic proportions in the United States. Large, randomized controlled trials suggest that menopausal hormone therapy (MHT) delays the onset of type 2 diabetes in women. However, the mechanisms and clinical implications of this association are still a matter of controversy. This review provides an up-to-date analysis and integration of epidemiological, clinical, and basic studies, and proposes a mechanistic explanation for the effect of menopause and MHT on type 2 diabetes development and prevention. We discuss the beneficial effects of endogenous estradiol with respect to insulin secretion, insulin sensitivity, and glucose effectiveness; we also discuss energy expenditure and adipose distribution, both of which are affected by menopause and improved by MHT, which thereby decreases the incidence of type 2 diabetes. We reconcile differences among studies that investigated the effect of menopause and MHT formulations on type 2 diabetes. We argue that discrepancies arise from physiological differences in methods used to assess glucose homeostasis, ranging from clinical indices of insulin sensitivity to steady-state methods to assess insulin action. We also discuss the influence of the route of estrogen administration and the addition of progestogens. We conclude that, although MHT is neither approved nor appropriate for the prevention of type 2 diabetes due to its complex balance of risks and benefits, it should not be withheld from women with increased risk of type 2 diabetes who seek treatment for menopausal symptoms.
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Affiliation(s)
- Franck Mauvais-Jarvis
- Department of Medicine, Division of Endocrinology and Metabolism, School of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana 70112
| | - JoAnn E Manson
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.,Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115
| | - John C Stevenson
- National Heart and Lung Institute, Imperial College London, Royal Brompton Hospital, London SW3 6NP, United Kingdom
| | - Vivian A Fonseca
- Department of Medicine, Division of Endocrinology and Metabolism, School of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana 70112
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Abstract
Over the past three decades, the prevalence of diabetes has increased four-fold. Coupled with the global obesity epidemic and aging of the world's population, a perfect metabolic storm is brewing. The influence of menopause and exogenous estrogen and progestogens must be included in this equation. In this review, criteria for diagnosing diabetes and recommendations for screening are described. The reported effects of menopause on diabetes risk in healthy women are reviewed as well as the relationship between established diabetes and the timing of menopause. The effects of menopausal hormone therapies (MHT) on glucose control in women with diabetes and the effect of MHT on diabetes risk in menopausal women without diabetes are described. Evidence-based strategies to prevent diabetes in midlife women are highlighted. The augmenting effect of diabetes on chronic health concerns of aging women, such as cardiovascular disease, osteoporosis, and cancer, along with current recommendations for screening and prevention are presented. Given the current demographics of today's world, the content of this review may apply to as many as one-third of the average practitioner's postmenopausal patient population.
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Affiliation(s)
- C A Stuenkel
- a School of Medicine, Department of Medicine, Division of Endocrinology and Metabolism , University of California , San Diego , USA
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29
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Mauvais-Jarvis F. Menopause, Estrogens, and Glucose Homeostasis in Women. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1043:217-225. [DOI: 10.1007/978-3-319-70178-3_11] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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30
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Inada A, Fujii NL, Inada O, Higaki Y, Furuichi Y, Nabeshima YI. Effects of 17β-Estradiol and Androgen on Glucose Metabolism in Skeletal Muscle. Endocrinology 2016; 157:4691-4705. [PMID: 27653033 DOI: 10.1210/en.2016-1261] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Diabetes develops predominantly in males in experimental models, and extensive evidence suggests that 17β-estradiol (E2) modulates progression of diabetes in humans. We previously developed a severely diabetic transgenic (Tg) mouse model by β-cell-specific overexpression of inducible cAMP early repressor (ICER) and found that male ICER-Tg mice exhibit sustained severe hyperglycemia, but female ICER-Tg mice gradually became normoglycemic with aging. This implies that differences in circulating androgen and E2 levels might influence skeletal muscle glucose uptake and glycemic status. Here we examined whether a decrease of androgen or E2 excess can improve muscle glucose uptake in hyperglycemic male ICER-Tg mice and, conversely, whether a decrease of E2 or androgen excess can elevate blood glucose levels and impair muscle glucose uptake in normoglycemic female ICER-Tg mice. We treated hyperglycemic male ICER-Tg mice with orchiectomy (ORX) or ORX+E2 pellet implantation and normoglycemic female ICER-Tg mice with ovariectomy (OVX) or OVX+5α-DHT pellet implantation to alter the androgen to E2 ratio. ORX+E2 treatment of male ICER-Tg mice caused a rapid drop in blood glucose via both a dramatic increase of β-cells and significantly improved muscle glucose uptake due to the induction of glucose transporter type 4 (GLUT4) expression and translocation of GLUT4 to the cell membrane. In contrast, OVX+5α-DHT-treated female ICER-Tg mice showed an elevation of blood glucose without any decrease of β-cells; instead, they showed decreased muscle glucose uptake due to decreased activation of serine/threonine-specific protein kinase AKT and GLUT4 expression. These findings suggest that androgen (5α-DHT) promotes insulin resistance in females, whereas E2 improves insulin sensitivity in severely diabetic male mice.
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Affiliation(s)
- Akari Inada
- Laboratory of Molecular Life Science (A.I., Y.N.), Institute of Biomedical Research and Innovation, Kobe 650-0047, Japan; Department of Diabetes and Genes (A.I., O.I.), Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Health Promotion Sciences (N.L.F.), Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo 192-0397, Japan; and Faculty of Sports and Health Science (Y.H.) and Institute for Physical Activity (Y.H.), Fukuoka University, Fukuoka 814-0180, Japan
| | - Nobuharu L Fujii
- Laboratory of Molecular Life Science (A.I., Y.N.), Institute of Biomedical Research and Innovation, Kobe 650-0047, Japan; Department of Diabetes and Genes (A.I., O.I.), Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Health Promotion Sciences (N.L.F.), Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo 192-0397, Japan; and Faculty of Sports and Health Science (Y.H.) and Institute for Physical Activity (Y.H.), Fukuoka University, Fukuoka 814-0180, Japan
| | - Oogi Inada
- Laboratory of Molecular Life Science (A.I., Y.N.), Institute of Biomedical Research and Innovation, Kobe 650-0047, Japan; Department of Diabetes and Genes (A.I., O.I.), Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Health Promotion Sciences (N.L.F.), Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo 192-0397, Japan; and Faculty of Sports and Health Science (Y.H.) and Institute for Physical Activity (Y.H.), Fukuoka University, Fukuoka 814-0180, Japan
| | - Yasuki Higaki
- Laboratory of Molecular Life Science (A.I., Y.N.), Institute of Biomedical Research and Innovation, Kobe 650-0047, Japan; Department of Diabetes and Genes (A.I., O.I.), Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Health Promotion Sciences (N.L.F.), Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo 192-0397, Japan; and Faculty of Sports and Health Science (Y.H.) and Institute for Physical Activity (Y.H.), Fukuoka University, Fukuoka 814-0180, Japan
| | - Yasuro Furuichi
- Laboratory of Molecular Life Science (A.I., Y.N.), Institute of Biomedical Research and Innovation, Kobe 650-0047, Japan; Department of Diabetes and Genes (A.I., O.I.), Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Health Promotion Sciences (N.L.F.), Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo 192-0397, Japan; and Faculty of Sports and Health Science (Y.H.) and Institute for Physical Activity (Y.H.), Fukuoka University, Fukuoka 814-0180, Japan
| | - Yo-Ichi Nabeshima
- Laboratory of Molecular Life Science (A.I., Y.N.), Institute of Biomedical Research and Innovation, Kobe 650-0047, Japan; Department of Diabetes and Genes (A.I., O.I.), Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Health Promotion Sciences (N.L.F.), Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo 192-0397, Japan; and Faculty of Sports and Health Science (Y.H.) and Institute for Physical Activity (Y.H.), Fukuoka University, Fukuoka 814-0180, Japan
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Inada A, Inada O, Fujii NL, Nagafuchi S, Katsuta H, Yasunami Y, Matsubara T, Arai H, Fukatsu A, Nabeshima YI. Adjusting the 17β-Estradiol-to-Androgen Ratio Ameliorates Diabetic Nephropathy. J Am Soc Nephrol 2016; 27:3035-3050. [PMID: 26940099 PMCID: PMC5042662 DOI: 10.1681/asn.2015070741] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 01/14/2016] [Indexed: 12/28/2022] Open
Abstract
Diabetes is manifested predominantly in males in experimental models, and compelling evidence suggests that 17β-estradiol (E2) supplementation improves hyperglycemia in humans. We previously generated a severely diabetic transgenic (Tg) mouse model by β-cell–specific overexpression of inducible cAMP early repressor (ICER) and found that male but not female ICER-Tg mice exhibit sustained hyperglycemia and develop major clinical and pathologic features of human diabetic nephropathy (DN). Thus, we hypothesized that differences in circulating hormone levels have a key role in determining susceptibility to diabetes. Here, we examined whether DN in male ICER-Tg mice is rescued by adjusting the androgen-to-E2 ratio to approximate that in normoglycemic female ICER-Tg mice. We treated hyperglycemic male ICER-Tg mice with orchiectomy (ORX), E2 pellet implantation, or both. E2 pellet implantation at an early stage of DN with or without ORX caused a rapid drop in blood glucose and a dramatic increase in β-cell number, and it markedly inhibited DN progression [namely, E2 reduced glomerulosclerosis, collagen 4 deposition and albuminuria, and prevented hyperfiltration]. Furthermore, E2 pellet implantation was more effective than ORX alone and induced a remarkable improvement, even when initiated at advanced-stage DN. In contrast, induction of normoglycemia by islet transplant in ICER-Tg mice eliminated albuminuria but was less effective than E2 + ORX in reducing glomerulosclerosis, collagen 4 deposition, and hyperfiltration. These findings indicate that E2 treatment is effective, even after establishment of DN, whereas glucose normalization alone does not improve sclerotic lesions. We propose that E2 intervention is a potential therapeutic option for DN.
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Affiliation(s)
- Akari Inada
- Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation, Kobe, Japan;
| | - Oogi Inada
- Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation, Kobe, Japan; Diabetes and Genes, Advanced Medical Initiatives and
| | - Nobuharu L Fujii
- Health Promotion Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo, Japan
| | - Seiho Nagafuchi
- Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hitoshi Katsuta
- Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | | | - Takeshi Matsubara
- Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hidenori Arai
- Center for Gerontology and Social Science, National Center for Geriatrics and Gerontology, Obu, Japan; and
| | | | - Yo-Ichi Nabeshima
- Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation, Kobe, Japan
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Santos RS, Batista TM, Camargo RL, Morato PN, Borck PC, Leite NC, Kurauti MA, Wanschel ACBA, Nadal Á, Clegg DJ, Carneiro EM. Lacking of estradiol reduces insulin exocytosis from pancreatic β-cells and increases hepatic insulin degradation. Steroids 2016; 114:16-24. [PMID: 27192429 DOI: 10.1016/j.steroids.2016.05.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 04/18/2016] [Accepted: 05/11/2016] [Indexed: 01/08/2023]
Abstract
Low levels of plasma estrogens are associated with weight-gain, android fat distribution, and a high prevalence of obesity-related comorbidities such as glucose intolerance and type II diabetes. The mechanisms underlying the association between low levels of estrogens and impaired glucose homeostasis are not completely understood. To begin to test this, we used three-month-old female C57BL/6J mice that either underwent ovariectomy (OVX) or received a sham surgery (Sham), and we characterized glucose homeostasis. In a subsequent series of experiments, OVX mice received estradiol treatment (OVX+E2) or vehicle (OVX) for 6 consecutive days. As has been previously reported, lack of ovarian hormones resulted in dysregulated glucose homeostasis. To begin to explore the mechanisms by which this occurs, we characterized the impact of estrogens on insulin secretion and degradation in these mice. Insulin secretion and plasma insulin levels were lower in OVX mice. OVX mice had lower levels of pancreatic Syntaxin 1-A (Synt-1A) protein, which is involved in insulin extrusion from the pancreas. In the liver, OVX mice had higher levels of insulin-degrading enzyme (IDE) and this was associated with higher insulin clearance. Estradiol treatment improved glucose intolerance in OVX mice and restored insulin secretion, as well as normalized the protein content of pancreatic Synt-1A. The addition of estrogens to OVX mice reduced IDE protein to that of Sham mice. Our data suggest loss of ovarian estradiol following OVX led to impaired glucose homeostasis due to pancreatic β-cell dysfunction in the exocytosis of insulin, and upregulation of hepatic IDE protein content resulting in lower insulinemia, which was normalized by estradiol replacement.
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Affiliation(s)
- Roberta S Santos
- Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, e Centro de Pesquisa em Obesidade e Comorbidades, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil; Biomedical Research Department, Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Beverly Hills, CA, United States.
| | - Thiago M Batista
- Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, e Centro de Pesquisa em Obesidade e Comorbidades, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil
| | - Rafael L Camargo
- Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, e Centro de Pesquisa em Obesidade e Comorbidades, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil
| | - Priscila N Morato
- Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, e Centro de Pesquisa em Obesidade e Comorbidades, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil
| | - Patrícia C Borck
- Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, e Centro de Pesquisa em Obesidade e Comorbidades, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil
| | - Nayara C Leite
- Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, e Centro de Pesquisa em Obesidade e Comorbidades, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil
| | - Mirian A Kurauti
- Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, e Centro de Pesquisa em Obesidade e Comorbidades, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil
| | - Amarylis C B A Wanschel
- Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, e Centro de Pesquisa em Obesidade e Comorbidades, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil
| | - Ángel Nadal
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Universidad Miguel Hernández de Elche, Elche, Alicante, Spain
| | - Deborah J Clegg
- Biomedical Research Department, Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Beverly Hills, CA, United States
| | - Everardo M Carneiro
- Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, e Centro de Pesquisa em Obesidade e Comorbidades, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil
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Kim SW, Jeon JH, Lee WK, Lee S, Kim JG, Lee IK, Park KG. Long-term effects of oral contraceptives on the prevalence of diabetes in post-menopausal women: 2007-2012 KNHANES. Endocrine 2016; 53:816-22. [PMID: 27160817 DOI: 10.1007/s12020-016-0972-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2016] [Accepted: 04/25/2016] [Indexed: 11/29/2022]
Abstract
There is little information on whether past use of oral contraceptives (OCs) at child-bearing age influences the incidences of diabetes and insulin resistance (IR) after menopause. This study aimed to evaluate the association of past use of OCs with the development of diabetes and IR in post-menopausal women. This cross-sectional study was based on data from the Korea National Health and Nutrition Examination Survey carried out from 2007 to 2012. Of the 50405 participants, 6554 post-menopausal women were included in the analysis. The associations of OC use with the prevalence of diabetes in post-menopausal women were examined using multivariate logistic analysis. In addition, fasting glucose and insulin levels were measured in 3338 nondiabetic post-menopausal women, and the association between IR and OCs was examined by the analysis of covariance. The prevalence of diabetes was significantly higher in post-menopausal participants who had taken OCs for more than 6 months than in those who had never taken OCs. The association remained significant after adjusting for multiple confounding factors (odd ratio 1.379; 95 % CI 1.115-1.707; P = 0.003). The duration of OC use was also positively associated with the prevalence of diabetes. Furthermore, taking OCs for more than 6 months led to a significant increase in fasting insulin levels and HOMA-IR in nondiabetic participants. Past use of OCs for more than 6 months led to a significant increase in the prevalence of diabetes in post-menopausal women, and increased IR in nondiabetic participants. These results suggested that the prolonged use of OCs at reproductive age may be an important risk factor for developing diabetes in post-menopausal women.
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Affiliation(s)
- Sung-Woo Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Cha Gumi Medical Center, Cha University School of Medicine, Gumi, South Korea
| | - Jae-Han Jeon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea
| | - Won-Kee Lee
- Department of Preventive Medicine, Kyungpook National University School of Medicine, Daegu, South Korea
| | - Sungwoo Lee
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, South Korea
| | - Jung-Guk Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea
| | - In-Kyu Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea
| | - Keun-Gyu Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea.
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Riedel BC, Thompson PM, Brinton RD. Age, APOE and sex: Triad of risk of Alzheimer's disease. J Steroid Biochem Mol Biol 2016; 160:134-47. [PMID: 26969397 PMCID: PMC4905558 DOI: 10.1016/j.jsbmb.2016.03.012] [Citation(s) in RCA: 419] [Impact Index Per Article: 46.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2015] [Revised: 03/02/2016] [Accepted: 03/06/2016] [Indexed: 02/06/2023]
Abstract
Age, apolipoprotein E ε4 (APOE) and chromosomal sex are well-established risk factors for late-onset Alzheimer's disease (LOAD; AD). Over 60% of persons with AD harbor at least one APOE-ε4 allele. The sex-based prevalence of AD is well documented with over 60% of persons with AD being female. Evidence indicates that the APOE-ε4 risk for AD is greater in women than men, which is particularly evident in heterozygous women carrying one APOE-ε4 allele. Paradoxically, men homozygous for APOE-ε4 are reported to be at greater risk for mild cognitive impairment and AD. Herein, we discuss the complex interplay between the three greatest risk factors for Alzheimer's disease, age, APOE-ε4 genotype and chromosomal sex. We propose that the convergence of these three risk factors, and specifically the bioenergetic aging perimenopause to menopause transition unique to the female, creates a risk profile for AD unique to the female. Further, we discuss the specific risk of the APOE-ε4 positive male which appears to emerge early in the aging process. Evidence for impact of the triad of AD risk factors is most evident in the temporal trajectory of AD progression and burden of pathology in relation to APOE genotype, age and sex. Collectively, the data indicate complex interactions between age, APOE genotype and gender that belies a one size fits all approach and argues for a precision medicine approach that integrates across the three main risk factors for Alzheimer's disease.
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Affiliation(s)
- Brandalyn C Riedel
- Neuroscience Graduate Program, University of Southern California, Los Angeles, CA 90089, USA
| | - Paul M Thompson
- USC Institute for Neuroimaging and Informatics, University of Southern California, Marina del Rey, CA 90292, USA
| | - Roberta Diaz Brinton
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
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Bitoska I, Krstevska B, Milenkovic T, Subeska-Stratrova S, Petrovski G, Mishevska SJ, Ahmeti I, Todorova B. Effects of Hormone Replacement Therapy on Insulin Resistance in Postmenopausal Diabetic Women. Open Access Maced J Med Sci 2016; 4:83-8. [PMID: 27275336 PMCID: PMC4884259 DOI: 10.3889/oamjms.2016.024] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 01/24/2016] [Accepted: 01/25/2016] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Insulin resistance (IR) is closely associated with diabetes mellitus. On the other hand, increased visceral fat in menopause is also associated with IR, which makes postmenopausal diabetic women in a big risk for cardiovascular diseases. There are conflicting reports about the effects on hormone replacement therapy (HRT) on IR. AIM The aim of the study was to investigate the effects of HRT on IR. METHODS A total of 40 postmenopausal women with type 2 diabetes were enrolled and followed for 12 months. Half of them were assigned to take HRT, while the other half made the control group. Fasting plasma glucose (FPG) and insulinemia were measured in both groups at baseline and after 12 months. IR was represented by Homeostatic model assessment for IR (HOMA-IR). RESULTS HRT was associated with significant decrease in HOMA-IR, FPG and insulinemia in the examined group. There was no significant reduction in FPG and no significant increase in insulinemia levels and HOMA-IR values in control group after 12 months. CONCLUSION HRT was associated with statistically signifficant increase of insulin sensitivity. Larger clinical trials will be necessary to understand whether HRT may improve insulin resistance and glucose homeostasis in women with diabetes, especially when given shortly after entering menopause.
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Affiliation(s)
- Iskra Bitoska
- University Clinic of Endocrinology, Diabetology and Metabolic Disorders, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Branka Krstevska
- University Clinic of Endocrinology, Diabetology and Metabolic Disorders, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Tatjana Milenkovic
- University Clinic of Endocrinology, Diabetology and Metabolic Disorders, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Slavica Subeska-Stratrova
- University Clinic of Endocrinology, Diabetology and Metabolic Disorders, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Goran Petrovski
- University Clinic of Endocrinology, Diabetology and Metabolic Disorders, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Sasha Jovanovska Mishevska
- University Clinic of Endocrinology, Diabetology and Metabolic Disorders, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Irfan Ahmeti
- University Clinic of Endocrinology, Diabetology and Metabolic Disorders, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Biljana Todorova
- University Clinic of Endocrinology, Diabetology and Metabolic Disorders, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
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Chevalier N, Fénichel P. Endocrine disruptors: new players in the pathophysiology of type 2 diabetes? DIABETES & METABOLISM 2014; 41:107-15. [PMID: 25454091 DOI: 10.1016/j.diabet.2014.09.005] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2014] [Revised: 09/15/2014] [Accepted: 09/21/2014] [Indexed: 12/16/2022]
Abstract
The prevalence of type 2 diabetes (T2D) has dramatically increased worldwide during the last few decades. While lifestyle factors, such as decreased physical activity and energy-dense diets, together with genetic predisposition, are well-known actors in the pathophysiology of T2D, there is accumulating evidence suggesting that the increased presence of endocrine-disrupting chemicals (EDCs) in the environment, such as bisphenol A, phthalates and persistent organic pollutants, may also explain an important part in the incidence of metabolic diseases (the metabolic syndrome, obesity and T2D). EDCs are found in everyday products (including plastic bottles, metal cans, toys, cosmetics and pesticides) and used in the manufacture of food. They interfere with the synthesis, secretion, transport, activity and elimination of natural hormones. Such interferences can block or mimic hormone actions and thus induce a wide range of adverse effects (developmental, reproductive, neurological, cardiovascular, metabolic and immune). In this review, both in vivo and in vitro experimental data and epidemiological evidence to support an association between EDC exposure and the induction of insulin resistance and/or disruption of pancreatic β-cell function are summarized, while the epidemiological links with disorders of glucose homoeostasis are also discussed.
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Affiliation(s)
- N Chevalier
- CHU de Nice, Hôpital de l'Archet 2, Service d'Endocrinologie, Diabétologie et Médecine de la Reproduction, 06202 Nice, France; Institut National de la Santé et de la Recherche Médicale (INSERM) UMR U1065/UNS, Centre Méditerranéen de Médecine Moléculaire (C3M), Équipe 5 "Environnement, Reproduction et Cancers Hormono-Dépendants", 06204 Nice, France; Université de Nice-Sophia Antipolis, Faculté de Médecine, Institut Signalisation et Pathologie (IFR 50), 06107 Nice, France.
| | - P Fénichel
- CHU de Nice, Hôpital de l'Archet 2, Service d'Endocrinologie, Diabétologie et Médecine de la Reproduction, 06202 Nice, France; Institut National de la Santé et de la Recherche Médicale (INSERM) UMR U1065/UNS, Centre Méditerranéen de Médecine Moléculaire (C3M), Équipe 5 "Environnement, Reproduction et Cancers Hormono-Dépendants", 06204 Nice, France; Université de Nice-Sophia Antipolis, Faculté de Médecine, Institut Signalisation et Pathologie (IFR 50), 06107 Nice, France
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Inada A, Inada O, Fujii NL, Fujishima K, Inai T, Fujii H, Sueishi K, Kurachi K. β-cell induction in vivo in severely diabetic male mice by changing the circulating levels and pattern of the ratios of estradiol to androgens. Endocrinology 2014; 155:3829-42. [PMID: 25057794 DOI: 10.1210/en.2014-1254] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Previously we have generated transgenic (Tg) mice developing severe diabetes early in life with a profound depletion of β-cells with β-cell-directed expression of inducible cAMP early repressor-Iγ. Only male mice continue to demonstrate hyperglycemia throughout life. To investigate this sexual dimorphism, we treated severely diabetic male Tg mice with orchiectomy (ORX) or 17β-estradiol (E2) pellet implantation alone or in combination with ORX and E2-implantation to change the circulating levels and patterns of the ratio of estradiol to androgens. In the Tg-ORX group, the blood-glucose levels decreased to a certain level within several weeks but never reached the female Tg-control level. In contrast, the Tg-ORX+E2 or Tg-E2 group showed a more rapid drop in blood glucose to the basal level with a substantial increase in β-cells, thus preventing the occurrence of severe diabetes in the male mice. The β-cells, not only within islet but also in and adjacent to ducts and scattered β-cell clusters, were strongly induced by 1 week after treatment, and the islet morphology dramatically changed. Enhanced β-cell induction in the ducts occurred concomitantly with markedly increased levels of pancreatic duodenal homeobox-1 and related transcription factors. The glucose-lowering and β-cell-increasing effects were independent of the age at which the treatment is started. These data provide evidence that the circulating level of E2 and the ratio of E2 to T greatly affect the blood glucose levels, the β-cell induction, and the islet morphology in diabetic male Tg mice. This novel mechanism offers great potential for developing strategies to increase the number of β-cells in vivo.
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Affiliation(s)
- Akari Inada
- Departments of Diabetes and Genes and Advanced Medical Initiatives (A.I., O.I., K.F.), Developmental Molecular Anatomy (T.I.), and Pathophysiological and Experimental Pathology (HY.F., K.S.), and Medical Institute of Bioregulation (K.K.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and Department of Health Promotion Sciences (N.L.F.), Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo 192-0397, Japan
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Kuo FC, Hung YJ, Shieh YS, Hsieh CH, Hsiao FC, Lee CH. The levels of plasma growth arrest-specific protein 6 is associated with insulin sensitivity and inflammation in women. Diabetes Res Clin Pract 2014; 103:304-9. [PMID: 24468100 DOI: 10.1016/j.diabres.2013.12.057] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Revised: 08/28/2013] [Accepted: 12/28/2013] [Indexed: 02/07/2023]
Abstract
AIMS Vitamin K-dependent growth arrest-specific protein 6 (Gas6) and its receptors of the TAM (TYRO-3/Axl/Mer) family are ubiquitously expressed in immune, cardiovascular, and reproductive systems. They play pivotal roles of regulating tissue homeostasis via anti-inflammatory effects. Recent studies show that the Gas6/TAM system is involved in glucose tolerance-related metabolic disorders. Our aim was to investigate the link between Gas6 protein, insulin sensitivity and inflammatory cytokines in men and women. METHODS A total of 278 adults (126 men and 152 women) were recruited in this study. Plasma Gas6 concentration and various biochemical, proinflammatory and endothelial markers were measured. Insulin sensitivity was estimated by homeostasis model assessment. RESULTS Waist, fasting and 2h post-load glucose, and glycated hemoglobin (HbA1C) were significantly lower in women than in men. Age, high-density lipoprotein cholesterol, and highly-sensitive C-reactive protein levels were significantly higher in women than in men. Plasma Gas6 levels were negatively correlated with waist (r = -0.187, P = 0.022), HOMA-IR (r = -0.171, P=0.035), interleukin 6 (r = -0.362, P < 0.001), and E-selectin (r = -0.216, P = 0.008), while they were positively correlated with insulin sensitivity (QUICKI) (r = 0.168, P = 0.039) in women, but not in men. Stepwise multiple regression analysis showed that TNF-α was independently correlated with plasma Gas6 levels in both the sexes (P < 0.001). CONCLUSION Plasma Gas6 is associated with obesity, insulin sensitivity, inflammation, and endothelial dysfunction in women and may be a general marker of inflammatory conditions in women.
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Affiliation(s)
- Feng-Chih Kuo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yi-Jen Hung
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yi-Shing Shieh
- School of Dentistry, National Defense Medical Center, Taipei, Taiwan; Department of Oral Diagnosis and Pathology, Tri-Service General Hospital, Taipei, Taiwan
| | - Chang-Hsun Hsieh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Fone-Ching Hsiao
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chien-Hsing Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
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Fuente-Martín E, Argente-Arizón P, Ros P, Argente J, Chowen JA. Sex differences in adipose tissue: It is not only a question of quantity and distribution. Adipocyte 2013; 2:128-34. [PMID: 23991358 PMCID: PMC3756100 DOI: 10.4161/adip.24075] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Revised: 02/21/2013] [Accepted: 02/21/2013] [Indexed: 12/12/2022] Open
Abstract
Obesity and its associated secondary complications are active areas of investigation in search of effective treatments. As a result of this intensified research numerous differences between males and females at all levels of metabolic control have come to the forefront. These differences include not only the amount and distribution of adipose tissue, but also differences in its metabolic capacity and functions between the sexes. Here, we review some of the recent advances in our understanding of these dimorphisms and emphasize the fact that these differences between males and females must be taken into consideration in hopes of obtaining successful treatments for both sexes.
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40
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The combined effects of menopause and dietary glucosamine on the development of insulin resistance. Menopause 2012; 19:487-8. [DOI: 10.1097/gme.0b013e3182504111] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Podzolkov VI, Bragina AE. Essential arterial hypertension in women, or female arterial hypertension? КАРДИОВАСКУЛЯРНАЯ ТЕРАПИЯ И ПРОФИЛАКТИКА 2012. [DOI: 10.15829/1728-8800-2012-1-79-84] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
The paper discusses specific features of arterial hypertension (AH) in women: age-related aspects of AH incidence, pathogenetic and clinical AH variants, and optimal pharmacotherapy approaches.
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Abstract
Protecting the functional mass of insulin-producing β cells of the pancreas is a major therapeutic challenge in patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM). The gonadal hormone 17β-oestradiol (E2) is involved in reproductive, bone, cardiovascular and neuronal physiology. In rodent models of T1DM and T2DM, treatment with E2 protects pancreatic β cells against oxidative stress, amyloid polypeptide toxicity, lipotoxicity and apoptosis. Three oestrogen receptors (ERs)--ERα, ERβ and the G protein-coupled ER (GPER)--have been identified in rodent and human β cells. Whereas activation of ERα enhances glucose-stimulated insulin biosynthesis, reduces islet toxic lipid accumulation and promotes β-cell survival from proapoptotic stimuli, activation of ERβ increases glucose-stimulated insulin secretion. However, activation of GPER protects β cells from apoptosis, raises glucose-stimulated insulin secretion and lipid homeostasis without affecting insulin biosynthesis. Oestrogens are also improving islet engraftment in rodent models of pancreatic islet transplantation. This Review describes developments in the role of ERs in islet insulin biosynthesis and secretion, lipid homeostasis and survival. Moreover, we discuss why and how enhancing ER action in β cells without the undesirable effect of general oestrogen therapy is a therapeutic avenue to preserve functional β-cell mass in patients with diabetes mellitus.
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Affiliation(s)
- Joseph P Tiano
- Feinberg School of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine and Comprehensive Center on Obesity, Northwestern University, Chicago, IL 60611, USA
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Ganasyam SR, Rao TB, Murthy YSR, Jyothy A, Sujatha M. Association of Estrogen Receptor-α Gene & Metallothionein-1 Gene Polymorphisms in Type 2 Diabetic Women of Andhra Pradesh. Indian J Clin Biochem 2012; 27:69-73. [PMID: 23277715 DOI: 10.1007/s12291-011-0179-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2011] [Accepted: 11/10/2011] [Indexed: 11/26/2022]
Abstract
Type 2 diabetes mellitus (DM) is a multifactorial disease where both genetic and environmental factors contribute to its pathogenesis. Estrogen plays an important role in type 2 DM pathogenesis. A number of polymorphisms have been reported in the estrogen receptor (ESR1), including the XbaI and PvuII restriction enzyme polymorphisms of ESR1,which may be involved in disease pathogenesis. Metallothioneins (MT) act as potent antioxidants against various oxidative damages. Very few studies have indicated the association between Estrogen Receptor-α, MT1 gene polymorphisms with type2 DM. A total of 100 type 2 diabetic women and 100 age, sex matched controls were recruited. Using the PCR based RFLP method, the PvuII and XbaI polymorphisms of ESR1 and in MT1A (rs8052394 and rs11076161) gene polymorphisms were analysed. The genotype distribution and frequency of mutated allele showed no significant differences between diabetic and non-diabetic groups in PvuII (χ2 = 2.443; P = 0.1181) or XbaI (χ2 = 1.789; P = 0.1812) and rs8052394 (χ2 = 1.154; P = 0.2840) or rs11076161 (χ2 = 0.4141; P = 0.5199), polymorphisms. This is the first Indian study to conclude that ESR1 and MT1 gene polymorphisms are not associated with increased susceptibility to type 2 diabetes in Indian women.
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Affiliation(s)
- Shilpa Reddy Ganasyam
- Department of Biochemistry, Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Begumpet, Hyderabad, 500016 Andhra Pradesh India
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Ågren UM, Anttila M, Mäenpää-Liukko K, Rantala ML, Rautiainen H, Sommer WF, Mommers E. Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol compared with one containing levonorgestrel and ethinylestradiol on haemostasis, lipids and carbohydrate metabolism. EUR J CONTRACEP REPR 2011; 16:444-57. [PMID: 22066891 PMCID: PMC3233272 DOI: 10.3109/13625187.2011.604450] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
OBJECTIVES To compare the effects of a combined oral contraceptive (COC) containing nomegestrol acetate and 17β-oestradiol (NOMAC/E2) on haemostasis, lipids, carbohydrate metabolism, C-reactive protein (CRP) and sex hormone-binding globulin (SHBG) with those of a COC containing levonorgestrel and ethinylestradiol (LNG/EE). METHODS In a randomised, open-label study, 121 healthy women, 18-50 years of age, were randomly assigned to receive NOMAC/E2 (2.5 mg/1.5 mg) in a 24/4-day regimen (n=60) or LNG/EE (150 μg/30 μg) in a 21/7-day regimen (n=61) for six cycles. The primary outcome was the change from baseline to cycle 6 for all indices. RESULTS All parameters were similar at baseline between the two groups. Over six cycles, NOMAC/E2 had less effect on most haemostatic indices than LNG/EE. Lipids were essentially unchanged with NOMAC/E2, whereas with LNG/EE high-density lipoprotein cholesterol decreased and low-density lipoprotein cholesterol and triglycerides slightly increased. NOMAC/E2 induced negligible changes in glucose and insulin parameters, in contrast to LNG/EE. A much smaller increase in CRP was observed with NOMAC/E2 than with LNG/EE. NOMAC/E2 was associated with a greater increase in SHBG. CONCLUSIONS The monophasic COC NOMAC/E2 had less influence on haemostasis, lipids and carbohydrate metabolism than the COC LNG/EE.
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Nilsson BO, Olde B, Leeb-Lundberg LMF. G protein-coupled oestrogen receptor 1 (GPER1)/GPR30: a new player in cardiovascular and metabolic oestrogenic signalling. Br J Pharmacol 2011; 163:1131-9. [PMID: 21250980 DOI: 10.1111/j.1476-5381.2011.01235.x] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Oestrogens are important sex hormones central to health and disease in both genders that have protective effects on the cardiovascular and metabolic systems. These hormones act in complex ways via both genomic and non-genomic mechanisms. The genomic mechanisms are relatively well characterized, whereas the non-genomic ones are only beginning to be explored. Two oestrogen receptors (ER), ERα and ERβ, have been described that act as nuclear transcription factors but can also associate with the plasma membrane and influence cytosolic signalling. ERα has been shown to mediate both anti-atherogenic effects and pro-survival effects in pancreatic β-cells. In recent years, a third membrane-bound ER has emerged, G protein-coupled receptor 30 or G protein-coupled oestrogen receptor 1 (GPER1), which mediates oestrogenic responses in cardiovascular and metabolic regulation. Both GPER1 knock-out models and pharmacological agents are now available to study GPER1 function. These tools have revealed that GPER1 activation may have several beneficial effects in the cardiovascular system including vasorelaxation, inhibition of smooth muscle cell proliferation, and protection of the myocardium against ischaemia/reperfusion injury, and in the metabolic system including stimulation of insulin release and protection against pancreatic β-cell apoptosis. Thus, GPER1 is emerging as a candidate therapeutic target in both cardiovascular and metabolic disease.
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Affiliation(s)
- Bengt-Olof Nilsson
- Department of Experimental Medical Science, Lund University, Lund, Sweden
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Jackson KC, Wohlers LM, Valencia AP, Cilenti M, Borengasser SJ, Thyfault JP, Spangenburg EE. Wheel running prevents the accumulation of monounsaturated fatty acids in the liver of ovariectomized mice by attenuating changes in SCD-1 content. Appl Physiol Nutr Metab 2011; 36:798-810. [PMID: 22026420 DOI: 10.1139/h11-099] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Decreases in female sex steroids enhance the accumulation of visceral fat mass, leading to a predisposition to developing metabolic diseases. The purpose of this study was to determine whether loss of ovarian function alters the amount and (or) the fatty acid (FA) composition of triacylglycerol (TAG) levels in the liver of ovary-intact (SHAM) or ovariectomized (OVX) mice. We also sought to determine whether voluntary wheel running could attenuate the associated changes in the liver. Twenty-two C57/BL6 female mice were divided into 2 groups (SHAM, OVX) and were then subdivided into sedentary and exercising groups (SHAM-Sed, SHAM-Ex, OVX-Sed, OVX-Ex). Visceral fat mass significantly increased in the OVX-Sed animals; however, the effect was attenuated in the OVX-Ex animals. Total hepatic TAG content did not significantly increase in the OVX-Sed animals; however, SHAM-Ex and OVX-Ex animals demonstrated significant decreases in TAG levels. A significant increase in the FA desaturase index (18:1/18:0 and 16:1/16:0) was detected in the OVX-Sed animals compared with all other groups, which corresponded to increases in stearoyl-CoA desaturase (SCD-1) content. These results indicate that loss of ovarian function alters FA composition of hepatic TAG mediated by increases in SCD-1. These data indicate that female sex steroids influence lipid metabolism in the liver and provide important insight concerning the influence of exercise on hepatic function.
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Affiliation(s)
- Kathryn C Jackson
- Department of Kinesiology, School of Public Health, University of Maryland, College Park, MD 21045, USA
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Meyer MR, Clegg DJ, Prossnitz ER, Barton M. Obesity, insulin resistance and diabetes: sex differences and role of oestrogen receptors. Acta Physiol (Oxf) 2011; 203:259-69. [PMID: 21281456 DOI: 10.1111/j.1748-1716.2010.02237.x] [Citation(s) in RCA: 245] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Obesity increases the risk of coronary artery disease through insulin resistance, diabetes, arterial hypertension and dyslipidemia. The prevalence of obesity has increased worldwide and is particularly high among middle-aged women and men. After menopause, women are at an increased risk to develop visceral obesity due to the loss of endogenous ovarian hormone production. Effects of oestrogens are classically mediated by the two nuclear oestrogen receptors (ERs) α and β. In addition, more recent research has shown that the intracellular transmembrane G-protein-coupled oestrogen receptor (GPER) originally designated as GPR30 also mediates some of the actions attributed to oestrogens. Oestrogen and its receptors are important regulators of body weight and insulin sensitivity not only in women but also in men as demonstrated by ER mutations in rodents and humans. This article reviews the role of sex hormones and ERs in the context of obesity, insulin sensitivity and diabetes as well as the related clinical issues in women and men.
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Affiliation(s)
- M R Meyer
- Molecular Internal Medicine, University of Zurich, Switzerland
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Abbas AM, Elsamanoudy AZ. Effects of 17β-estradiol and antioxidant administration on oxidative stress and insulin resistance in ovariectomized rats. Can J Physiol Pharmacol 2011; 89:497-504. [DOI: 10.1139/y11-053] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The prevalence of insulin resistance syndrome increases during menopause with the overproduction of reactive oxygen species and impairment of the free radical scavenger function. Therefore, we investigated the effects of 17β-estradiol (E2) and vitamin E, as an antioxidant, on lipid peroxidation and antioxidant levels in the brain cortex and liver of ovariectomized rats as well as on insulin resistance in those rats. Forty female Sprague–Dawley rats, 3 months of age and weighing 231.5 ± 9.4 g, were divided into 4 groups: sham, ovariectomized (OVX), OVX treated with E2 (40 µg/kg subcutaneously), and OVX treated with E2 and vitamin E (100 mg/kg intraperitoneally). The 4 groups received the appropriate treatment every day for 8 weeks. Levels of glutathione, glutathione peroxidase, superoxide dismutase , catalase, and malondialdehyde in the brain cortex and liver of ovariectomized rats were measured. Also, fasting plasma insulin, glucose, and homeostatis model assessment of insulin resistance (HOMA-IR) were determined. Malondialdehyde increased and antioxidants (glutathione, glutathione peroxidase, catalase, superoxide dismutase) decreased in the brain cortex and liver of OVX rats. Also, fasting glucose, insulin, and HOMA-IR increased in OVX rats. E2 and E2 plus vitamin E decreased malondialdehyde and increased antioxidants in the brain cortex and liver of OVX rats. Moreover, they decreased fasting glucose, insulin, and HOMA-IR in ovariectomized rats. This study demonstrates that E2 and E2 plus vitamin E supplementation to OVX rats may improve insulin resistance, strengthen the antioxidant system, and reduce lipid peroxidation.
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Affiliation(s)
- Amr M. Abbas
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, P.O. Box 35516, Mansoura, Egypt
| | - Ayman Z. Elsamanoudy
- Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Egypt
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Giordano R, Forno D, Lanfranco F, Manieri C, Ghizzoni L, Ghigo E. Metabolic and cardiovascular outcomes in a group of adult patients with Turner's syndrome under hormonal replacement therapy. Eur J Endocrinol 2011; 164:819-26. [PMID: 21378088 DOI: 10.1530/eje-11-0002] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
OBJECTIVE Turner's syndrome (TS) is a rare genetic disorder caused by complete or partial X chromosome monosomy in a phenotypic female, and it is associated with increased morbidity and mortality for cardiovascular diseases, impaired glucose tolerance, and dyslipidemia. SUBJECTS AND METHODS In 30 adult TS patients under chronic hormonal replacement therapy (HRT), 17β-estradiol (E(2)), body mass index (BMI), waist circumference, fasting glucose and insulin, homeostatic model assessment (HOMA) index, serum lipids, oral glucose tolerance test (OGTT), 24 h ambulatory blood pressure monitoring (ABPM), and intima-media thickness (IMT) were evaluated and compared with those in 30 age- and sex-matched controls (CS). RESULTS No difference was found between TS and CS in E(2) and BMI, whereas waist circumference was higher (P<0.05) in TS (77.7±2.5 cm) than in CS (69.8±1.0 cm). Fasting glucose in TS and in CS was similar, whereas fasting insulin, HOMA index, and 2 h glucose after OGTT were higher (P<0.0005) in TS (13.2±0.8 mUI/l, 2.5±0.2, and 108.9±5.5 mg/dl respectively) than in CS (9.1±0.5 mUI/l, 1.8±0.1, and 94.5 ± 3.8 mg/dl respectively). Total cholesterol was higher (P<0.05) in TS (199.4 ± 6.6 mg/dl) than in CS (173.9±4.6 mg/dl), whereas no significant differences in high-density lipoprotein, low-density lipoprotein, and triglycerides were found between the two groups. In 13% of TS, ABPM showed arterial hypertension, whereas IMT was <0.9 mm in all TS and CS. A negative correlation between insulin levels, HOMA index, or 2 h glucose after OGTT and E(2) was present in TS. CONCLUSIONS Our results indicate that adult patients with TS under HRT are connoted by higher frequency of central obesity, insulin resistance, hypercholesterolemia, and hypertension.
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Affiliation(s)
- Roberta Giordano
- Department of Clinical and Biological Sciences, University of Turin, 10126 Turin, Italy
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Endocrine factors in the hypothalamic regulation of food intake in females: a review of the physiological roles and interactions of ghrelin, leptin, thyroid hormones, oestrogen and insulin. Nutr Res Rev 2011; 24:132-54. [DOI: 10.1017/s0954422411000035] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Controlling energy homeostasis involves modulating the desire to eat and regulating energy expenditure. The controlling machinery includes a complex interplay of hormones secreted at various peripheral endocrine endpoints, such as the gastrointestinal tract, the adipose tissue, thyroid gland and thyroid hormone-exporting organs, the ovary and the pancreas, and, last but not least, the brain itself. The peripheral hormones that are the focus of the present review (ghrelin, leptin, thyroid hormones, oestrogen and insulin) play integrated regulatory roles in and provide feedback information on the nutritional and energetic status of the body. As peripheral signals, these hormones modulate central pathways in the brain, including the hypothalamus, to influence food intake, energy expenditure and to maintain energy homeostasis. Since the growth of the literature on the role of various hormones in the regulation of energy homeostasis shows a remarkable and dynamic expansion, it is now becoming increasingly difficult to understand the individual and interactive roles of hormonal mechanisms in their true complexity. Therefore, our goal is to review, in the context of general physiology, the roles of the five best-known peripheral trophic hormones (ghrelin, leptin, thyroid hormones, oestrogen and insulin, respectively) and discuss their interactions in the hypothalamic regulation of food intake.
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