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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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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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Martins FO, Conde SV. Gender Differences in the Context of Obstructive Sleep Apnea and Metabolic Diseases. Front Physiol 2022; 12:792633. [PMID: 34970158 PMCID: PMC8712658 DOI: 10.3389/fphys.2021.792633] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 11/17/2021] [Indexed: 11/13/2022] Open
Abstract
The relationship between obstructive sleep apnea (OSA) and endocrine and metabolic disease is unequivocal. OSA, which is characterized by intermittent hypoxia and sleep fragmentation, leads to and exacerbates obesity, metabolic syndrome, and type 2 diabetes (T2D) as well as endocrine disturbances, such as hypothyroidism and Cushing syndrome, among others. However, this relationship is bidirectional with endocrine and metabolic diseases being considered major risk factors for the development of OSA. For example, polycystic ovary syndrome (PCOS), one of the most common endocrine disorders in women of reproductive age, is significantly associated with OSA in adult patients. Several factors have been postulated to contribute to or be critical in the genesis of dysmetabolic states in OSA including the increase in sympathetic activation, the deregulation of the hypothalamus-pituitary axis, the generation of reactive oxygen species (ROS), insulin resistance, alteration in adipokines levels, and inflammation of the adipose tissue. However, probably the alterations in the hypothalamus-pituitary axis and the altered secretion of hormones from the peripheral endocrine glands could play a major role in the gender differences in the link between OSA-dysmetabolism. In fact, normal sleep is also different between men and women due to the physiologic differences between genders, with sex hormones such as progesterone, androgens, and estrogens, being also connected with breathing pathologies. Moreover, it is very well known that OSA is more prevalent among men than women, however the prevalence in women increases after menopause. At the same time, the step-rise in obesity and its comorbidities goes along with mounting evidence of clinically important sex and gender differences. Metabolic and cardiovascular diseases, seen as a men's illness for decades, presently are more common in women than in men and obesity has a higher association with insulin-resistance-related risk factors in women than in men. In this way, in the present manuscript, we will review the major findings on the overall mechanisms that connect OSA and dysmetabolism giving special attention to the specific regulation of this relationship in each gender. We will also detail the gender-specific effects of hormone replacement therapies on metabolic control and sleep apnea.
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Affiliation(s)
- Fátima O Martins
- Chronic Diseases Research Center (CEDOC), NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal
| | - Sílvia V Conde
- Chronic Diseases Research Center (CEDOC), NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal
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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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Blesson CS, Schutt AK, Vipin VA, Tanchico DT, Mathew PR, Balakrishnan M, Betancourt A, Yallampalli C. In utero low-protein-diet-programmed type 2 diabetes in adult offspring is mediated by sex hormones in rats†. Biol Reprod 2020; 103:1110-1120. [PMID: 32766739 PMCID: PMC7609843 DOI: 10.1093/biolre/ioaa133] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/21/2020] [Accepted: 08/04/2020] [Indexed: 12/11/2022] Open
Abstract
Sex steroids regulate insulin sensitivity and glucose metabolism. We had characterized a lean type 2 diabetes (T2D) rat model using gestational low-protein (LP) diet programming. Our objective was to identify if endocrine dysfunction leading to decreased sex hormone levels will precede the development of T2D and if steroid replacement will prevent the onset of the disease. Pregnant rats were fed control or isocaloric LP diet from gestational day 4 until delivery. Normal diet was given to all mothers after delivery and to pups after weaning. LP offspring developed glucose intolerance and insulin resistance at 4 months. We measured sex steroid hormone profiles and expression of key genes involved in steroidogenesis in testis and ovary. Furthermore, one-month old rats were implanted with 90-day slow release T and E2 pellets for males and females, respectively. Glucose tolerance test (GTT) and euglycemic hyperinsulinemic clamp was performed at 4 months. LP-programmed T2D males had low T levels and females had low E2 levels due to dysregulated gene expression during steroidogenesis in gonads. GTT and euglycemic hyperinsulinemic clamp showed that LP males and females were glucose intolerant and insulin resistant; however, steroid supplementation prevented the onset of glucose intolerance and insulin resistance. Rats that developed T2D by LP programming have compromised gonadal steroidogenesis leading to low T and E2 in males and females, respectively. Sex steroid supplementation prevented the onset of glucose intolerance and insulin resistance indicating low sex steroid levels could cause compromised glucose metabolism ultimately leading to T2D.
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Affiliation(s)
- Chellakkan S Blesson
- Division for Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Baylor College of Medicine, and Family Fertility Center, Texas Children's Hospital, Houston, Texas 77030
| | - Amy K Schutt
- Division for Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Baylor College of Medicine, and Family Fertility Center, Texas Children's Hospital, Houston, Texas 77030
| | - Vidyadharan A Vipin
- Basic Sciences Perinatology Research Laboratories, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA
| | - Daren T Tanchico
- Basic Sciences Perinatology Research Laboratories, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA
| | - Pretty R Mathew
- Basic Sciences Perinatology Research Laboratories, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA
| | - Meena Balakrishnan
- Basic Sciences Perinatology Research Laboratories, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA
| | - Ancizar Betancourt
- Basic Sciences Perinatology Research Laboratories, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA
| | - Chandra Yallampalli
- Basic Sciences Perinatology Research Laboratories, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA
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Christensen A, Liu J, Pike CJ. Aging Reduces Estradiol Protection Against Neural but Not Metabolic Effects of Obesity in Female 3xTg-AD Mice. Front Aging Neurosci 2020; 12:113. [PMID: 32431604 PMCID: PMC7214793 DOI: 10.3389/fnagi.2020.00113] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 04/03/2020] [Indexed: 12/29/2022] Open
Abstract
Vulnerability to Alzheimer's disease (AD) is increased by several risk factors, including midlife obesity, female sex, and the depletion of estrogens in women as a consequence of menopause. Conversely, estrogen-based hormone therapies have been linked with protection from age-related increases in adiposity and dementia risk, although treatment efficacy appears to be affected by the age of initiation. Potential interactions between obesity, AD, aging, and estrogen treatment are likely to have significant impact on optimizing the use of hormone therapies in postmenopausal women. In the current study, we compared how treatment with the primary estrogen, 17β-estradiol (E2), affects levels of AD-like neuropathology, behavioral impairment, and other neural and systemic effects of preexisting diet-induced obesity in female 3xTg-AD mice. Importantly, experiments were conducted at chronological ages associated with both the early and late stages of reproductive senescence. We observed that E2 treatment was generally associated with significantly improved metabolic outcomes, including reductions in body weight, adiposity, and leptin, across both age groups. Conversely, neural benefits of E2 in obese mice, including decreased β-amyloid burden, improved behavioral performance, and reduced microglial activation, were observed only in the early aging group. These results are consistent with the perspective that neural benefits of estrogen-based therapies require initiation of treatment during early rather than later phases of reproductive aging. Further, the discordance between E2 protection against systemic versus neural effects of obesity across age groups suggests that pathways other than general metabolic function, perhaps including reduced microglial activation, contribute to the mechanism(s) of the observed E2 actions. These findings reinforce the potential systemic and neural benefits of estrogen therapies against obesity, while also highlighting the critical role of aging as a mediator of estrogens' protective actions.
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Affiliation(s)
| | | | - Christian J. Pike
- Davis School of Gerontology, University of Southern California, Los Angeles, CA, United States
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Park E, Lim E, Yeo S, Yong Y, Yang J, Jeong SY. Anti-Menopausal Effects of Cornus officinalis and Ribes fasciculatum Extract In Vitro and In Vivo. Nutrients 2020; 12:nu12020369. [PMID: 32019227 PMCID: PMC7071277 DOI: 10.3390/nu12020369] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 01/23/2020] [Accepted: 01/28/2020] [Indexed: 12/21/2022] Open
Abstract
Natural herbal medicines have been developed for the treatment and prevention of women’s menopausal symptoms. In this study, we investigated the anti-menopausal effects of Cornus officinalis (CO) and Ribes fasciculatum (RF) extracts in 3T3-L1 preadipocytes, MC3T3-E1 preosteoblasts, and COV434 granulosa cells in vitro and ovariectomized (OVX) ddY mice in vivo. Combination treatment of CO and RF extract at 7:3 ratio inhibited lipid accumulation via Plin1 and Adipoq downregulation in a cocktail of dexamethasone, 3-isobutyl-1-methylxanthine, and insulin (DMI)-induced differentiated 3T3-L1 cells. In addition, CO + RF treatment significantly enhanced osteoblastic differentiation, with mineralized nodule formation occurring through the upregulation of osteoblast-inducing markers in osteoblastic MC3T3-E1 cells. Increased production of estradiol and mRNA expression of ERα (ESR1) were observed in androstenedione-induced COV434 granulosa cells treated with the CO + RF extract. In CO + RF-treated mice, fatty hepatocyte deposition and abdominal visceral fat tissues reduced with OVX-induced uterine atrophy. Furthermore, bone mineral density and bone mineral content were significantly enhanced by CO + RF in mouse models of ovariectomy-induced femoral bone loss. Taken together, our findings suggested that CO + RF promoted estrogenic activity and had anti-obesity and anti-osteoporotic effects in vitro and in vivo. Thus, a combination of CO and RF extracts may be a good therapeutic strategy for managing women’s menopausal syndromes.
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Affiliation(s)
- Eunkuk Park
- Department of Medical Genetics, Ajou University School of Medicine, Suwon 16499, Korea; (E.P.); (E.L.)
- Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Korea
| | - Eunguk Lim
- Department of Medical Genetics, Ajou University School of Medicine, Suwon 16499, Korea; (E.P.); (E.L.)
- Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Korea
| | - Subin Yeo
- Nine B Co. Ltd., Daejeon 34121, Korea; (S.Y.); (Y.Y.); (J.Y.)
| | - Yoonjoong Yong
- Nine B Co. Ltd., Daejeon 34121, Korea; (S.Y.); (Y.Y.); (J.Y.)
| | - Junga Yang
- Nine B Co. Ltd., Daejeon 34121, Korea; (S.Y.); (Y.Y.); (J.Y.)
| | - Seon-Yong Jeong
- Department of Medical Genetics, Ajou University School of Medicine, Suwon 16499, Korea; (E.P.); (E.L.)
- Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Korea
- Nine B Co. Ltd., Daejeon 34121, Korea; (S.Y.); (Y.Y.); (J.Y.)
- Correspondence: ; Tel.: +82-31-219-4520; Fax: +82-31-219-4521
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Li M, Wang Y, Liu Z, Tang X, Mu P, Tan Y, Wang J, Lin B, Deng J, Peng R, Zhang R, He Z, Li D, Zhang Y, Yang C, Li Y, Chen Y, Liu X, Chen Y. Females with Type 2 Diabetes Mellitus Are Prone to Diabetic Retinopathy: A Twelve-Province Cross-Sectional Study in China. J Diabetes Res 2020; 2020:5814296. [PMID: 32377522 PMCID: PMC7191394 DOI: 10.1155/2020/5814296] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Revised: 03/26/2020] [Accepted: 04/01/2020] [Indexed: 11/28/2022] Open
Abstract
AIMS To investigate the distribution of diabetic retinopathy (DR) by sex in patients with type 2 diabetes mellitus (T2DM) in a twelve-province cross-sectional study in China. METHODS Patients with T2DM, whose ages were ≥18 years, were recruited from 76 cities/counties in 12 provinces in mainland China between January 2015 and December 2018. All participants received a standardized interview, eye examinations, and digital fundus photography. The presence and severity of DR were diagnosed and classified by retina specialists according to the DR domestic typing method. RESULTS A total of 12,766 participants (5963 males and 6803 females) were eligible for this study. The total prevalence of DR was 30.1%. Females exhibited a significantly higher prevalence of DR than males (31.1% vs. 29.0%, P = 0.011). A multivariate logistic regression analysis confirmed that female sex was an independent predictor for a higher prevalence of DR after adjusting for age, the duration of diabetes, economic status, and the presence of hypertension (OR: 1.096, 95% CI: 1.013-1.186, P = 0.023). Even after stratification by the diabetic duration, age, and economic status, female sex was still independently associated with the presence of DR in patients whose T2DM history was more than 10 years, whose ages were over 60 years, or who were in a relatively intermediate economic area. CONCLUSION Females had a higher prevalence of DR than males in T2DM patients with a diabetic history of more than 10 years, ages over 60 years, or a relatively intermediate economic status.
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Affiliation(s)
- Mei Li
- Department of Endocrinology & Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
- VIP Medical Service Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Yina Wang
- VIP Medical Service Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Zifeng Liu
- Clinical Data Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Xixiang Tang
- Department of Endocrinology & Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
- VIP Medical Service Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Panwei Mu
- Department of Endocrinology & Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Ying Tan
- Department of Endocrinology & Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Jing Wang
- Department of Endocrinology, The Third Affiliated Hospital of Sun Yat-sen University, Yuedong Hospital, Meizhou 514021, China
| | - Bairun Lin
- Department of Endocrinology, The Third Affiliated Hospital of Sun Yat-sen University, Yuedong Hospital, Meizhou 514021, China
| | - Juan Deng
- Department of Ophthalmology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Ruiping Peng
- Department of Ophthalmology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Rongyu Zhang
- Guangzhou Da'an Clinical Laboratory Center Co. Ltd., Guangzhou 440100, China
| | - Zhihui He
- Guangdong Provincial Center for Disease Control and Prevention, Guangdong Provincial Institute of Public Health, Guangzhou 510000, China
| | - Dongling Li
- Department of Endocrinology, The Third Affiliated Hospital of Sun Yat-sen University, Yuedong Hospital, Meizhou 514021, China
| | - Yongjun Zhang
- Department of Endocrinology, The Fifth Affiliated Hospital of Zunyi Medical University, Zhuhai 519100, China
| | - Caixian Yang
- Department of Endocrinology & Metabolism, Qingyuan People's Hospital, Qingyuan 511518, China
| | - Yuan Li
- Department of Endocrinology, The Third Affiliated Hospital of Sun Yat-sen University, Yuedong Hospital, Meizhou 514021, China
| | - Yuming Chen
- School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Xun Liu
- Department of Nephrology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Yanming Chen
- Department of Endocrinology & Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
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Blesson CS, Schutt A, Chacko S, Marini JC, Mathew PR, Tanchico D, Balakrishnan M, Yallampalli C. Sex Dependent Dysregulation of Hepatic Glucose Production in Lean Type 2 Diabetic Rats. Front Endocrinol (Lausanne) 2019; 10:538. [PMID: 31447783 PMCID: PMC6691354 DOI: 10.3389/fendo.2019.00538] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 07/19/2019] [Indexed: 12/27/2022] Open
Abstract
We have characterized a lean type 2 diabetic rat model by gestational low protein programming. We aimed to identify if the regulation of hepatic glucose production (HGP) via gluconeogenesis and glycogenolysis is affected and if there are any sex differences. Fasting (6-7 months old) type 2 diabetic rats received 2H2O followed by a primed constant rate infusion of [6,6-2H2] glucose. Blood samples were drawn during steady states after 4 h of fasting and following a euglycemic hyperinsulinemic clamp. HGP and the fraction of glucose derived from gluconeogenesis under fasting and euglycemic states were measured from steady state glucose enrichments after the infusion of [6,6-2H2]glucose and 2H2O tracers. Glycogenolysis was determined by calculating the difference between total HGP and gluconeogenesis rates. Hepatic gene expression of enzymes involved in HGP were quantified using qPCR. HGP rates was similar during fasting in both groups and sexes. However, under simulated fed condition, HGP rate was suppressed in controls but not in type 2 diabetic rats. They also showed inefficient HGP suppression in a simulated fed state. Differential analysis showed that suppression of both gluconeogenesis and glycogenolysis under simulated fed state was affected in these low protein programmed type 2 diabetic rats. These effects were greater in females when compared to males. Further, key genes involved in these processes like G6Pase, Pepck, pyruvate carboxylase, and glycogen phosphorylase in liver were dysregulated. Our data shows impaired suppression of HGP via gluconeogenesis and glycogenolysis in type 2 diabetic rats with greater effects on females.
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Affiliation(s)
- Chellakkan S. Blesson
- Division for Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Baylor College of Medicine and Family Fertility Center, Texas Childrens' Hospital, Houston, TX, United States
| | - Amy Schutt
- Division for Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Baylor College of Medicine and Family Fertility Center, Texas Childrens' Hospital, Houston, TX, United States
| | - Shaji Chacko
- Department of Pediatrics, Baylor College of Medicine, Children's Nutritional Research Center, Houston, TX, United States
| | - Juan C. Marini
- Department of Pediatrics, Baylor College of Medicine, Children's Nutritional Research Center, Houston, TX, United States
- Critical Care Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Pretty Rose Mathew
- Basic Sciences Perinatology Research Laboratories, Department of Obstetrics and Gynecology, Houston, TX, United States
| | - Daren Tanchico
- Basic Sciences Perinatology Research Laboratories, Department of Obstetrics and Gynecology, Houston, TX, United States
| | - Meena Balakrishnan
- Basic Sciences Perinatology Research Laboratories, Department of Obstetrics and Gynecology, Houston, TX, United States
| | - Chandra Yallampalli
- Basic Sciences Perinatology Research Laboratories, Department of Obstetrics and Gynecology, Houston, TX, United States
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Blood pressure in postmenopausal women with a history of polycystic ovary syndrome. MENOPAUSE REVIEW 2019; 18:94-98. [PMID: 31485206 PMCID: PMC6719632 DOI: 10.5114/pm.2019.84039] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 04/10/2019] [Indexed: 12/28/2022]
Abstract
Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder at reproductive age, affecting 6-10% of females in this group. The aetiology of this syndrome is not fully understood. Genetics, endocrinology factors, and the influence of the environment are possible causes of this syndrome. PCOS is characterised by menstrual disorders, hyperandrogenism, and abnormalities in ovarian morphology as well as metabolic disorders. PCOS increases the risk of overweight and obesity, diabetes, endometrial cancer, and cardiovascular diseases such as hypertension along with all its long-term consequences. There are limited studies about cardiovascular disorders, especially hypertension, in postmenopausal women with a history of PCOS. The presented paper is an attempt to briefly summarise literature data concerning the influence of this disease on the incidence of hypertension and blood pressure control in postmenopausal women. Women with PCOS more often present features of metabolic syndrome and have increased cardiovascular risk factors including hypertension. The prevalence of hypertension is 2.5 times higher than in corresponding healthy peers. Furthermore, hyperandrogenaemia is associated with elevated blood pressure independent of the patient's age, insulin resistance, obesity, and dyslipidaemia. In view of this, these patients should be thoroughly screened for hypertensive disorders and educated about the lifestyle modifications that could prevent hypertension later in life.
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Sharma G, Prossnitz ER. G-Protein-Coupled Estrogen Receptor (GPER) and Sex-Specific Metabolic Homeostasis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1043:427-453. [PMID: 29224106 DOI: 10.1007/978-3-319-70178-3_20] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Obesity and metabolic syndrome display disparate prevalence and regulation between males and females. Human, as well as rodent, females with regular menstrual/estrous cycles exhibit protection from weight gain and associated chronic diseases. These beneficial effects are predominantly attributed to the female hormone estrogen, specifically 17β-estradiol (E2). E2 exerts its actions via multiple receptors, nuclear and extranuclear estrogen receptor (ER) α and ERβ, and the G-protein-coupled estrogen receptor (GPER, previously termed GPR30). The roles of GPER in metabolic homeostasis are beginning to emerge but are complex and remain unclear. The discovery of GPER-selective pharmacological agents (agonists and antagonists) and the availability of GPER knockout mice have significantly enhanced our understanding of the functions of GPER in normal physiology and disease. GPER action manifests pleiotropic effects in metabolically active tissues such as the pancreas, adipose, liver, and skeletal muscle. Cellular and animal studies have established that GPER is involved in the regulation of body weight, feeding behavior, inflammation, as well as glucose and lipid homeostasis. GPER deficiency leads to increased adiposity, insulin resistance, and metabolic dysfunction in mice. In contrast, pharmacologic stimulation of GPER in vivo limits weight gain and improves metabolic output, revealing a promising novel therapeutic potential for the treatment of obesity and diabetes.
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Affiliation(s)
- Geetanjali Sharma
- Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
| | - Eric R Prossnitz
- Division of Molecular Medicine, Department of Internal Medicine, and Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
- University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
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12
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Sharma G, Mauvais-Jarvis F, Prossnitz ER. Roles of G protein-coupled estrogen receptor GPER in metabolic regulation. J Steroid Biochem Mol Biol 2018; 176:31-37. [PMID: 28223150 PMCID: PMC5563497 DOI: 10.1016/j.jsbmb.2017.02.012] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 02/13/2017] [Accepted: 02/17/2017] [Indexed: 12/19/2022]
Abstract
Metabolic homeostasis is differentially regulated in males and females. The lower incidence of obesity and associated diseases in pre-menopausal females points towards the beneficial role of the predominant estrogen, 17β-estradiol (E2). The actions of E2 are elicited by nuclear and extra-nuclear estrogen receptor (ER) α and ERβ, as well as the G protein-coupled estrogen receptor (GPER, previously termed GPR30). The roles of GPER in the regulation of metabolism are only beginning to emerge and much remains unclear. The present review highlights recent advances implicating the importance of GPER in metabolic regulation. Assessment of the specific metabolic roles of GPER employing GPER-deficient mice and highly selective GPER-targeted pharmacological agents, agonist G-1 and antagonists G-15 and G36, is also presented. Evidence from in vitro and in vivo studies involving either GPER deficiency or selective activation suggests that GPER is involved in body weight regulation, glucose and lipid homeostasis as well as inflammation. The therapeutic potential of activating GPER signaling through selective ligands for the treatment of obesity and diabetes is also discussed.
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Affiliation(s)
- Geetanjali Sharma
- Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, United States
| | - Franck Mauvais-Jarvis
- Diabetes Discovery and Gender Medicine Laboratory, Section of Endocrinology and Metabolism, Department of Medicine,Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, 70112, United States
| | - Eric R Prossnitz
- Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, United States; University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States.
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13
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Estrogen attenuates AGTR1 expression to reduce pancreatic β-cell death from high glucose. Sci Rep 2017; 7:16639. [PMID: 29192236 PMCID: PMC5709427 DOI: 10.1038/s41598-017-15237-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 10/24/2017] [Indexed: 01/09/2023] Open
Abstract
Chronic exposure of pancreatic β-cells to high glucose levels results in β-cell dysfunction and death. These effects can be protected by estrogen. The local pancreatic renin-angiotensin system (RAS) has been shown as a novel pathological pathway of high-glucose-induced cell death. The effect of estrogen on pancreatic RAS is still unknown. This study examines whether estrogen protects against pancreatic β-cell death caused by glucotoxicity via a decrease in the pancreatic β-cell RAS pathway. When INS-1 cells were cultured in a high glucose medium, cell death was significantly higher than when the cells were cultured in a basal glucose medium; similarly, there were also higher levels of AGTR1 and p47ph°x mRNA, and protein expression. Moreover, the addition of 10−8 M 17β-estradiol to INS-1 cells cultured in a high glucose medium markedly reduced cell death, AGTR1 and p47ph°x mRNA levels, and protein expression. Similar results were demonstrated in the pancreatic islets. The presence of 10−8 M 17β-estradiol, losartan, or a combination of both, in a high glucose medium had similar levels of reduction of p47ph°x mRNA and protein expression, compared with those cultured in high glucose. Taken together, estrogen protected pancreatic β-cells from high-glucose-induced cell death by reducing the AGTR1 pathway.
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14
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Woods SC, May AA, Liu M, Tso P, Begg DP. Using the cerebrospinal fluid to understand ingestive behavior. Physiol Behav 2017; 178:172-178. [PMID: 27923718 PMCID: PMC5944842 DOI: 10.1016/j.physbeh.2016.11.037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 11/22/2016] [Accepted: 11/28/2016] [Indexed: 01/08/2023]
Abstract
The cerebrospinal fluid (CSF) offers a window into the workings of the brain and blood-brain barrier (BBB). Molecules that enter into the central nervous system (CNS) by passive diffusion or receptor-mediated transport through the choroid plexus often appear in the CSF prior to acting within the brain. Other molecules enter the CNS by passing through the BBB into the brain's interstitial fluid prior to appearing in the CSF. This pattern is also often observed for molecules synthesized by neurons or glia within the CNS. The CSF is therefore an important conduit for the entry and clearance of molecules into/from the CNS and thereby constitutes an important window onto brain activity and barrier function. Assessing the CSF basally, under experimental conditions, or in the context of challenges or metabolic diseases can provide powerful insights about brain function. Here, we review important findings made by our labs, as influenced by the late Randall Sakai, by interrogating the CSF.
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Affiliation(s)
- Stephen C Woods
- Department of Psychiatry and Behavioral Neuroscience, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
| | - Aaron A May
- Department of Pathology and Molecular Medicine, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Min Liu
- Department of Pathology and Molecular Medicine, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Patrick Tso
- Department of Pathology and Molecular Medicine, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Denovan P Begg
- School of Psychology, University of New South Wales, Sydney, NSW 2052, Australia
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15
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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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Huffman J, Hoffmann C, Taylor GT. Integrating insulin-like growth factor 1 and sex hormones into neuroprotection: Implications for diabetes. World J Diabetes 2017; 8:45-55. [PMID: 28265342 PMCID: PMC5320748 DOI: 10.4239/wjd.v8.i2.45] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 09/24/2016] [Accepted: 11/22/2016] [Indexed: 02/05/2023] Open
Abstract
Brain integrity and cognitive aptitude are often impaired in patients with diabetes mellitus, presumably a result of the metabolic complications inherent to the disease. However, an increasing body of evidence has demonstrated the central role of insulin-like growth factor 1 (IGF1) and its relation to sex hormones in many neuroprotective processes. Both male and female patients with diabetes display abnormal IGF1 and sex-hormone levels but the comparison of these fluctuations is seldom a topic of interest. It is interesting to note that both IGF1 and sex hormones have the ability to regulate phosphoinositide 3-kinase-Akt and mitogen-activated protein kinases-extracellular signal-related kinase signaling cascades in animal and cell culture models of neuroprotection. Additionally, there is considerable evidence demonstrating the neuroprotective coupling of IGF1 and estrogen. Androgens have also been implicated in many neuroprotective processes that operate on similar signaling cascades as the estrogen-IGF1 relation. Yet, androgens have not been directly linked to the brain IGF1 system and neuroprotection. Despite the sex-specific variations in brain integrity and hormone levels observed in diabetic patients, the IGF1-sex hormone relation in neuroprotection has yet to be fully substantiated in experimental models of diabetes. Taken together, there is a clear need for the comprehensive analysis of sex differences on brain integrity of diabetic patients and the relationship between IGF1 and sex hormones that may influence brain-health outcomes. As such, this review will briefly outline the basic relation of diabetes and IGF1 and its role in neuroprotection. We will also consider the findings on sex hormones and diabetes as a basis for separately analyzing males and females to identify possible hormone-induced brain abnormalities. Finally, we will introduce the neuroprotective interplay of IGF1 and estrogen and how androgen-derived neuroprotection operates through similar signaling cascades. Future research on both neuroprotection and diabetes should include androgens into the interplay of IGF1 and sex hormones.
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17
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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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18
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Michelin RM, Al-Nakkash L, Broderick TL, Plochocki JH. Genistein treatment increases bone mass in obese, hyperglycemic mice. Diabetes Metab Syndr Obes 2016; 9:63-70. [PMID: 27042131 PMCID: PMC4801201 DOI: 10.2147/dmso.s97600] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Obesity and type 2 diabetes mellitus are associated with elevated risk of limb bone fracture. Incidences of these conditions are on the rise worldwide. Genistein, a phytoestrogen, has been shown by several studies to demonstrate bone-protective properties and may improve bone health in obese type 2 diabetics. METHODS In this study, we test the effects of genistein treatment on limb bone and growth plate cartilage histomorphometry in obese, hyperglycemic ob/ob mice. Six-week-old ob/ob mice were divided into control and genistein-treated groups. Genistein-treated mice were fed a diet containing 600 mg genistein/kg for a period of 4 weeks. Cross-sectional geometric and histomorphometric analyses were conducted on tibias. RESULTS Genistein-treated mice remained obese and hyperglycemic. However, histomorphometric comparisons show that genistein-treated mice have greater tibial midshaft diameters and ratios of cortical bone to total tissue area than the controls. Genistein-treated mice also exhibit decreased growth plate thickness of the proximal tibia. CONCLUSION Our results indicate that genistein treatment affects bone of the tibial midshaft in the ob/ob mouse, independent of improvements in the hyperglycemic state and body weight.
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Affiliation(s)
- Richard M Michelin
- Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ, USA
| | - Layla Al-Nakkash
- Department of Physiology, Midwestern University, Glendale, AZ, USA
| | - Tom L Broderick
- Laboratory of Diabetes and Exercise Metabolism, Department of Physiology, Midwestern University, Glendale, AZ, USA
| | - Jeffrey H Plochocki
- Department of Anatomy, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ, 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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MacDonald TL, Ritchie KL, Davies S, Hamilton MJ, Cervone DT, Dyck DJ. Exercise training is an effective alternative to estrogen supplementation for improving glucose homeostasis in ovariectomized rats. Physiol Rep 2015; 3:3/11/e12617. [PMID: 26603453 PMCID: PMC4673645 DOI: 10.14814/phy2.12617] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 10/13/2015] [Indexed: 01/04/2023] Open
Abstract
The irreversible loss of estrogen (specifically 17-β-estradiol; E2) compromises whole-body glucose tolerance in women. Hormone replacement therapy (HRT) is frequently prescribed to treat estrogen deficiency, but has several deleterious side effects. Exercise has been proposed as an HRT substitute, however, their relative abilities to treat glucose intolerance are unknown. Thirty ovariectomized (OVX) and 20 SHAM (control) rats underwent glucose tolerance tests (GTT) 10 weeks post surgery. Area under the curve (AUC) for OVX rats was 60% greater than SHAM controls (P = 0.0005). Rats were then randomly assigned to the following treatment groups: SHAM sedentary (sed) or exercise (ex; 60 min, 5×/weeks), OVX sed, ex, or E2 (28 μg/kg bw/day) for 4 weeks. OVX ex rats experienced a ∼45% improvement in AUC relative to OVX sed rats, whereas OVX E2 underwent a partial reduction (17%; P = 0.08). Maximal insulin-stimulated glucose uptake in soleus and EDL was not impaired in OVX rats, or augmented with exercise or E2. Akt phosphorylation did not differ in soleus, EDL, or liver of any group. However, OVX ex and OVX E2 experienced greater increases in p-Akt Ser473 in VAT and SQ tissues compared with SHAM and OVX sed groups. Mitochondrial markers CS, COXIV, and core1 were increased in soleus posttraining in OVX ex rats. The content of COXIV was reduced by 52% and 61% in SQ of OVX sed and E2 rats, compared to SHAM controls, but fully restored in OVX ex rats. In summary, exercise restores glucose tolerance in OVX rats more effectively than E2. This is not reflected by alterations in muscle maximal insulin response, but increased insulin signaling in adipose depots may underlie whole-body improvements.
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Affiliation(s)
- Tara L MacDonald
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Kerry L Ritchie
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Sarah Davies
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Melissa J Hamilton
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Daniel T Cervone
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
| | - David J Dyck
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
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21
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Estrogens protect male mice from obesity complications and influence glucocorticoid metabolism. Int J Obes (Lond) 2015; 39:1539-47. [PMID: 26032810 PMCID: PMC4564952 DOI: 10.1038/ijo.2015.102] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Revised: 04/06/2015] [Accepted: 05/06/2015] [Indexed: 12/26/2022]
Abstract
BACKGROUND Although the prevalence of obesity is higher among women than men, they are somewhat protected from the associated cardiometabolic consequences. The increase in cardiovascular disease risk seen after the menopause suggests a role for estrogens. There is also growing evidence for the importance of estrogen on body fat and metabolism in males. We hypothesized that that estrogen administration would ameliorate the adverse effects of obesity on metabolic parameters in males. METHODS Male and female C57Bl/6 mice were fed control or obesogenic (DIO) diets from 5 weeks of age until adulthood. Glucose tolerance testing was performed at 13 weeks of age. Mice were killed at 15 weeks of age and liver and adipose tissue were collected for analysis of gene expression. A second cohort of male mice underwent the same experimental design with the addition of estradiol pellet implantation or sham surgery at 6 weeks. RESULTS DIO males had greater mesenteric adipose deposition and more severe increases in plasma glucose, insulin and lipids than females. Treatment of males with estradiol from 6 weeks of age prevented DIO-induced increases in adipose tissue mass and alterations in glucose-insulin homeostasis. We also identified sex differences in the transcript levels and activity of hepatic and adipose glucocorticoid metabolizing enzymes. Estrogen treatment feminized the pattern of DIO-induced changes in glucocorticoid metabolism, rendering males similar to females. CONCLUSIONS Thus, DIO induces sex-specific changes in glucose-insulin homeostasis, which are ameliorated in males treated with estrogen, highlighting the importance of sex steroids in metabolism. Given that altered peripheral glucocorticoid metabolism has been observed in rodent and human obesity, our results also suggest that sexually dimorphic expression and activity of glucocorticoid metabolizing enzymes may have a role in the differential metabolic responses to obesity in males and females.
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22
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Schindler CE, Partap U, Patchen BK, Swoap SJ. Chronic rapamycin treatment causes diabetes in male mice. Am J Physiol Regul Integr Comp Physiol 2014; 307:R434-43. [PMID: 24965794 DOI: 10.1152/ajpregu.00123.2014] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Current evidence indicates that the mammalian target of rapamycin inhibitor rapamycin both increases longevity and, seemingly contradictorily, impairs glucose homeostasis. Most studies exploring the dimensions of this paradox have been based on rapamycin treatment in mice for up to 20 wk. We sought to better understand the metabolic effects of oral rapamycin over a substantially longer period of time in HET3 mice. We observed that treatment with rapamycin for 52 wk induced diabetes in male mice, characterized by hyperglycemia, significant urine glucose levels, and severe glucose and pyruvate intolerance. Glucose intolerance occurred in male mice by 4 wk on rapamycin and could be only partially reversed with cessation of rapamycin treatment. Female mice developed moderate glucose intolerance over 1 yr of rapamycin treatment, but not diabetes. The role of sex hormones in the differential development of diabetic symptoms in male and female mice was further explored. HET3 mice treated with rapamycin for 52 wk were gonadectomized and monitored over 10 wk. Castrated male mice remained glucose intolerant, while ovariectomized females developed significant glucose intolerance over the same time period. Subsequent replacement of 17β-estradiol (E2) in ovariectomized females promoted a recovery of glucose tolerance over a 4-wk period, suggesting the protective role of E2 against rapamycin-induced diabetes. These results indicate that 1) oral rapamycin treatment causes diabetes in male mice, 2) the diabetes is partially reversible with cessation of treatment, and 3) E2 plays a protective role against the development of rapamycin-induced diabetes.
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Affiliation(s)
| | - Uttara Partap
- Department of Biology, Williams College, Williamstown, Massachusetts
| | - Bonnie K Patchen
- Department of Biology, Williams College, Williamstown, Massachusetts
| | - Steven J Swoap
- Department of Biology, Williams College, Williamstown, Massachusetts
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23
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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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Abstract
OBJECTIVE The study objectives were to examine the association between menopause status and diabetes risk among women with glucose intolerance and to determine if menopause status modifies response to diabetes prevention interventions. METHODS The study population included women in premenopause (n = 708), women in natural postmenopause (n = 328), and women with bilateral oophorectomy (n = 201) in the Diabetes Prevention Program, a randomized placebo-controlled trial of lifestyle intervention and metformin among glucose-intolerant adults. Associations between menopause and diabetes risk were evaluated using Cox proportional hazard models that adjusted for demographic variables (age, race/ethnicity, family history of diabetes, history of gestational diabetes mellitus), waist circumference, insulin resistance, and corrected insulin response. Similar models were constructed after stratification by menopause type and hormone therapy use. RESULTS After adjustment for age, there was no association between natural menopause or bilateral oophorectomy and diabetes risk. Differences by study arm were observed in women who reported bilateral oophorectomy. In the lifestyle arm, women with bilateral oophorectomy had a lower adjusted hazard for diabetes (hazard ratio [HR], 0.19; 95% CI, 0.04-0.94), although observations were too few to determine if this was independent of hormone therapy use. No significant differences were seen in the metformin (HR, 1.29; 95% CI, 0.63-2.64) or placebo arms (HR, 1.37; 95% CI, 0.74-2.55). CONCLUSIONS Among women at high risk for diabetes, natural menopause was not associated with diabetes risk and did not affect response to diabetes prevention interventions. In the lifestyle intervention, bilateral oophorectomy was associated with a decreased diabetes risk.
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25
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Gorres BK, Bomhoff GL, Gupte AA, Geiger PC. Altered estrogen receptor expression in skeletal muscle and adipose tissue of female rats fed a high-fat diet. J Appl Physiol (1985) 2011; 110:1046-53. [PMID: 21233345 DOI: 10.1152/japplphysiol.00541.2010] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Estrogen receptors (ERs) are expressed in adipose tissue and skeletal muscle, with potential implications for glucose metabolism and insulin signaling. Previous studies examining the role of ERs in glucose metabolism have primarily used knockout mouse models of ERα and ERβ, and it is unknown whether ER expression is altered in response to an obesity-inducing high-fat diet (HFD). The purpose of the current study was to determine whether modulation of glucose metabolism in response to a HFD in intact and ovariectomized (OVX) female rats is associated with alterations in ER expression. Our results demonstrate that a 6-wk HFD (60% calories from fat) in female rats induces whole body glucose intolerance with tissue-specific effects isolated to the adipose tissue, and no observed differences in insulin-stimulated glucose uptake, GLUT4, or ERα protein expression levels in skeletal muscle. In chow-fed rats, OVX resulted in decreased ERα with a trend toward decreased GLUT4 expression in adipose tissue. Sham-treated and OVX rats fed a HFD demonstrated a decrease in ERα and GLUT4 in adipose tissue. The HFD also increased activation of stress kinases (c-jun NH₂-terminal kinase and inhibitor of κB kinase β) in the sham-treated rats and decreased expression of the protective heat shock protein 72 (HSP72) in both sham-treated and OVX rats. Our findings suggest that decreased glucose metabolism and increased inflammation in adipose tissue with a HFD in female rats could stem from a significant decrease in ERα expression.
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Affiliation(s)
- Brittany K Gorres
- Dept. of Molecular and Integrative Physiology, Univ. of Kansas Medical Center, Kansas City, KS 66160, USA.
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26
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Abstract
Many postmenopausal women live with diabetes mellitus; however, little information is available about how the changes that occur around the time of menopause might uniquely affect management of diabetes mellitus in this population. Although the weight gain that commonly occurs during the menopausal transition is largely attributable to aging rather than the transition itself, changes in body composition have been independently associated with menopausal status. These changes in body composition have, in turn, been associated with alterations in insulin sensitivity and glucose metabolism in postmenopausal women. Hormone therapy seems to have neutral or beneficial effects on the adverse changes in body composition associated with menopause. Whether menopausal status independently influences diabetes risk remains controversial. Nevertheless, consistent findings from large clinical trials suggest that postmenopausal hormone therapy decreases the risk of developing diabetes mellitus. Similarly, many studies suggest that postmenopausal hormone therapy has neutral or beneficial effects on glycemic control among women already diagnosed as having diabetes mellitus. Future studies are needed to elucidate the mechanisms that underlie these relationships and to determine how these observations should influence recommendations for the care of postmenopausal women with diabetes mellitus.
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Affiliation(s)
- Emily D Szmuilowicz
- Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, Chicago, IL, USA
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27
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Charles C, Yuskavage J, Carlson O, John M, Tagalicud AS, Maggio M, Muller DC, Egan J, Basaria S. Effects of high-dose isoflavones on metabolic and inflammatory markers in healthy postmenopausal women. Menopause 2009; 16:395-400. [PMID: 18981951 PMCID: PMC2695501 DOI: 10.1097/gme.0b013e3181857979] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
OBJECTIVE After menopause, women experience changes in body composition, especially an increase in fat mass. In addition, advancing age, decreased physical activity, and increased inflammation may predispose them to develop type 2 diabetes. Isoflavones have been shown to improve metabolic parameters in postmenopausal women. However, the effect of isoflavones on adipokines/cytokines remains unclear. The purpose of this study was to evaluate the effect of high-dose isoflavones on inflammatory and metabolic markers in postmenopausal women. METHODS We measured glucose, insulin, and adipokines/cytokines in 75 healthy postmenopausal women who were randomized to receive 20 g of soy protein with 160 mg of total isoflavones (64 mg genistein, 63 mg daidzein, and 34 mg glycitein) or 20 g of soy protein placebo for 12 weeks. Women taking estrogen discontinued therapy at least 3 months before the study. The supplements were given in a powder form and consumed once daily with milk or other beverages. RESULTS Mean ages in the placebo and active groups were similar (P = 0.4). Average time since menopause was 9 years, and two thirds of the women underwent natural menopause. There was no significant difference in body mass index at baseline between the groups (placebo, 25.1 kg/m; active, 26 kg/m) and it did not change significantly during the study. At baseline, the placebo group had significantly higher levels of tumor necrosis factor alpha (P < 0.0001); otherwise, there was no difference in any other parameter. After 12 weeks of treatment, there were significant positive changes in tumor necrosis factor alpha levels within the placebo group (P < 0.0001) and adiponectin levels within the isoflavone group (P = 0.03). Comparison of pre-post change between the groups showed a small but significant increase in serum adiponectin levels in the isoflavone group (P = 0.03) compared with the placebo group. No significant changes were seen in any other parameter between the two groups. CONCLUSIONS Healthy, normal-weight postmenopausal women may not experience improvement in metabolic parameters when given high-dose isoflavones despite an increase in serum adiponectin levels. The role of isoflavones in obese and insulin-resistant postmenopausal women needs exploration.
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Affiliation(s)
- Cornelia Charles
- Laboratory of Clinical Investigation, Diabetes Section, National Institute on Aging, Baltimore, MD
| | - Julia Yuskavage
- Laboratory of Clinical Investigation, Diabetes Section, National Institute on Aging, Baltimore, MD
| | - Olga Carlson
- Laboratory of Clinical Investigation, Diabetes Section, National Institute on Aging, Baltimore, MD
| | - Majnu John
- Department of Internal Medicine, Division of Endocrinology & Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Arlene S. Tagalicud
- Laboratory of Clinical Investigation, Diabetes Section, National Institute on Aging, Baltimore, MD
| | - Marcello Maggio
- Laboratory of Clinical Investigation, Diabetes Section, National Institute on Aging, Baltimore, MD
| | - Denis C. Muller
- Laboratory of Clinical Investigation, Diabetes Section, National Institute on Aging, Baltimore, MD
| | - Josephine Egan
- Laboratory of Clinical Investigation, Diabetes Section, National Institute on Aging, Baltimore, MD
| | - Shehzad Basaria
- Department of Internal Medicine, Division of Endocrinology & Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD
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Abstract
BACKGROUND Across all ages, the incidence and rate of progression of most nondiabetic renal diseases are markedly higher in men compared with age-matched women. These observations suggest that female sex may be renoprotective. In the setting of diabetes, however, this female protection against the development and progression of renal disease is diminished. OBJECTIVE This review aimed to summarize our current understanding of sex differences in the development and progression of diabetic renal disease, and of the contribution of sex hormones, particularly estrogens, to the pathophysiology of this disease. We also attempted to answer why female sex does not protect the diabetic kidney. METHODS Using terms such as gender, sex, diabetes, diabetic nephropathy, estrogens, and sex hormones, the PubMed database was searched for English-language articles; targeted searches were conducted using terms such as gender/sex differences in diabetic renal disease. No restrictions were imposed on publication dates. RESULTS Although the existing data regarding the sex differences in the incidence and progression of diabetic renal disease are inconclusive, the undisputed fact is that women with either type 1 or type 2 diabetes mellitus exhibit a much higher incidence of renal disease compared with nondiabetic women. It is conceivable that the loss of female sex as a renoprotective factor in diabetes may be related to the abnormal regulation of sex hormone concentrations. Both clinical and experimental data suggest that diabetes may be associated with an imbalance in estradiol concentrations. Supplementation with 17beta-estradiol or administration of selective estrogen receptor modulators reduces the incidence of diabetes and attenuates the progression of diabetic renal disease. CONCLUSIONS Serum concentrations of ovarian hormones may provide a new means for predicting future risk of renal complications in diabetes. Exogenous steroid hormones may be an effective treatment for attenuating the progression of diabetic nephropathy.
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Affiliation(s)
- Christine Maric
- Department of Medicine, Georgetown University Medical Center, Washington, DC 20057, USA.
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Campagnoli C, Clavel-Chapelon F, Kaaks R, Peris C, Berrino F. Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. J Steroid Biochem Mol Biol 2005; 96:95-108. [PMID: 15908197 PMCID: PMC1974841 DOI: 10.1016/j.jsbmb.2005.02.014] [Citation(s) in RCA: 93] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2004] [Accepted: 02/04/2005] [Indexed: 01/29/2023]
Abstract
Controlled studies and most observational studies published over the last 5 years suggest that the addition of synthetic progestins to estrogen in hormone replacement therapy (HRT), particularly in continuous-combined regimen, increases the breast cancer (BC) risk compared to estrogen alone. By contrast, a recent study suggests that the addition of natural progesterone in cyclic regimens does not affect BC risk. This finding is consistent with in vivo data suggesting that progesterone does not have a detrimental effect on breast tissue. The increased BC risk found with the addition of synthetic progestins to estrogen could be due to the regimen and/or the kind of progestin used. Continuous-combined regimen inhibits the sloughing of mammary epithelium that occurs after progesterone withdrawal in a cyclic regimen. More importantly, the progestins used (medroxyprogesterone acetate and 19-Nortestosterone-derivatives) are endowed with some non-progesterone-like effects, which can potentiate the proliferative action of estrogens. Particularly relevant seem to be the metabolic and hepatocellular effects (decreased insulin sensitivity, increased levels and activity of insulin-like growth factor-I, and decreased levels of SHBG), which contrast the opposite effects induced by oral estrogen.
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Affiliation(s)
- Carlo Campagnoli
- Unit of Endocrinological Gynecology, Sant'Anna Gynecological Hospital, Corso Spezia 60, 10126 Torino, Italy.
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30
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Garris DR. Diabetes (db/db) mutation-induced endometrial epithelial lipoapoptosis: ultrastructural and cytochemical analysis of reproductive tract atrophy. Reprod Biol Endocrinol 2005; 3:15. [PMID: 15857516 PMCID: PMC1097758 DOI: 10.1186/1477-7827-3-15] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2005] [Accepted: 04/27/2005] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The diabetes (db/db) mutation in C57BL/KsJ mice promotes a progressive cytolipidemia within the endometrial epithelial (EE) layer of the female reproductive tract which results in premature cellular and organ atrophy. The current studies focus on the ultrastructural and cytochemical changes which promote nuclear apoptosis and cytostructural disruption following the expression of endometrial hypercytolipidemia which promotes diabetes-associated organoinvolution and manifest infertility. METHODS Control (normal:+/+) and diabetes (db/db) genotype groups were prepared for high resolution light microscopic analysis of cytolipidemia and nuclear apoptosis (TUNEL-labeled 3'-DNA fragmentation) indices and compared to the transmission electron (TEM) microscopic analysis of endometrial tissue samples collected from 8-16 week-old groups. RESULTS Compared to controls, db/db mutation expression induced a dramatic increase in EE cytolipid vacuole volume and density within the epithelial endometrial layer. TEM analysis revealed that cytolipid vacuole accumulations initially aggregated at the baso-polar regions of UEE cells in response to the systemic hyperglycemic/hypertriglyceridemic conditions which characterized the (db/db) groups. Progressive cytoplasmic movement of the lipid pools into perinuclear compartments of affected EE cells induced nuclear isolation from organelles that were displaced towards peripheral cytoplasmic compartments. Cytochemical analysis of lipid vacuole accumulations indicated attraction towards, and incorporation within, the nuclear envelope of hyperlipidemic cells. Co-localization of nuclear apoptotic 3'-DNA fragments within identified hyperlipidemic EE cells was coincident with the cytochemical and ultrastructural identification of lipid penetration through the nuclear envelope in db/db mutants. CONCLUSION These results are the first cytochemical indication that the metabolic disturbances in db/db mutants which promote hypercytolipidemia are coincident with lipoapoptosis-induced nuclear dissolution, as denoted by DNA fragmentation analysis. The lipidemia-induced alterations in intracellular organelle and nuclear architectures suggests that the metabolic disturbances in glucose and lipid metabolic cascades in diabetes (db/db) mutants disrupts cytointegrity, culminating in nuclear disregulation (as indicated by lipoapoptosis) and eventual premature reproductive tract organoinvolution and resultant, manifest, reproductive sterility.
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Affiliation(s)
- David R Garris
- Division of Cell Biology and Biophysics, School of Biological Sciences, University of Missouri-Kansas City, Kansas City, Missouri 64110, USA.
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31
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Louet JF, LeMay C, Mauvais-Jarvis F. Antidiabetic actions of estrogen: insight from human and genetic mouse models. Curr Atheroscler Rep 2004; 6:180-5. [PMID: 15068742 DOI: 10.1007/s11883-004-0030-9] [Citation(s) in RCA: 211] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
There is increasing evidence both in humans and rodents linking the endogenous estrogen 17b-estradiol (E2) to the maintenance of glucose homeostasis. Postmenopausal women develop visceral obesity and insulin resistance and are at increased risk for type 2 diabetes mellitus, but hormone replacement therapy leads to a reduction in the incidence of diabetes. In various spontaneous rodent models of type 2 diabetes, female rodents are protected against hyperglycemia unless they are ovariectomized, and E2 perfusion reverses diabetes in male rodents. Finally, the study of transgenic mice and mice with genetic alteration of E2 secretion or E2 action has shed light on the antidiabetic properties of E2 at a tissue-specific level. Thus, E2 secretion and action in rodents seems to be implicated 1) in adipose tissue biology and the prevention of obesity, 2) in the stimulation of liver fatty acid metabolism and suppression of hepatic glucose production, and 3) in the protection of pancreatic b-cell function/survival and insulin secretion in conditions of oxidative stress.
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Affiliation(s)
- Jean-Francois Louet
- Department of Medicine, Division of Diabetes, Endocrinology & Metabolism, Baylor College of Medicine, One Baylor Plaza, 520B, Houston, TX 77030, USA
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Margolis KL, Bonds DE, Rodabough RJ, Tinker L, Phillips LS, Allen C, Bassford T, Burke G, Torrens J, Howard BV. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women's Health Initiative Hormone Trial. Diabetologia 2004; 47:1175-1187. [PMID: 15252707 DOI: 10.1007/s00125-004-1448-x] [Citation(s) in RCA: 420] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2004] [Accepted: 04/22/2004] [Indexed: 12/28/2022]
Abstract
AIMS/HYPOTHESIS Studies examining the effect of postmenopausal hormone therapy on concentrations of glucose, insulin and diabetes incidence have been inconclusive, in part because many of the studies were too small. We examined the effect of oestrogen plus progestin on diabetes incidence and insulin resistance. METHODS The study was a randomised, double-blind trial comparing the effect of daily 0.625 mg conjugated equine oestrogens plus 2.5 mg medroxyprogesterone acetate with that of placebo during 5.6 years of follow-up. The participants were 15,641 postmenopausal women enrolled in the Women's Health Initiative Hormone Trial. These women were aged 50 to 79 and all had an intact uterus. Diabetes incidence was ascertained by self-report of treatment with insulin or oral hypoglycaemic medication. Fasting glucose, insulin, and lipoproteins were measured in a random sample at baseline and at 1 and 3 years. RESULTS The cumulative incidence of treated diabetes was 3.5% in the hormone therapy group and 4.2% in the placebo group (hazard ratio 0.79, 95% CI 0.67-0.93, p=0.004). There was little change in the hazard ratio after adjustment for changes in BMI and waist circumference. During the first year of follow-up, changes in fasting glucose and insulin indicated a significant fall in insulin resistance in actively treated women compared to the control subjects (Year 1 to baseline between-group difference -0.22+/-0.10, p=0.03). INTERPRETATIONS/CONCLUSION: These data suggest that combined therapy with oestrogen and progestin reduces the incidence of diabetes, possibly mediated by a decrease in insulin resistance unrelated to body size. Future studies of alternative postmenopausal hormone therapy regimens and selective oestrogen agonists and/or antagonists should consider the effects of these regimens on insulin resistance and diabetes.
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Affiliation(s)
- K L Margolis
- Hennepin County Medical Center, Minneapolis, Minnesota, USA.
- Berman Center for Outcomes and Clinical Research, 825 S. 8th Street, Suite 440, Minneapolis, MN 55404, USA.
| | - D E Bonds
- Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - R J Rodabough
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - L Tinker
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | | | - C Allen
- University of Wisconsin, Madison, Wisconsin, USA
| | - T Bassford
- University of Arizona, Tucson, Arizona, USA
| | - G Burke
- Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - J Torrens
- University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA
| | - B V Howard
- MedStar Research Institute/Howard University, Washington, District of Columbia, USA
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Løkkegaard E, Pedersen AT, Heitmann BL, Jovanovic Z, Keiding N, Hundrup YA, Obel EB, Ottesen B. Relation between hormone replacement therapy and ischaemic heart disease in women: prospective observational study. BMJ 2003; 326:426. [PMID: 12595383 PMCID: PMC149444 DOI: 10.1136/bmj.326.7386.426] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
OBJECTIVE To investigate the risk of ischaemic heart disease and myocardial infarction among women using hormone replacement therapy, especially the potential modifying effect of cardiovascular risk factors. DESIGN Prospective observational study. SETTING Denmark. PARTICIPANTS 19 898 nurses aged 45 and over completing a questionnaire on lifestyle and use of hormone replacement therapy in 1993. MAIN OUTCOME MEASURES All cases of death and incident cases of ischaemic heart disease and myocardial infarction until the end of 1998. RESULTS Current users of hormone replacement therapy smoked more, consumed more alcohol, had lower self rated health, but were slimmer and had a lower prevalence of diabetes than never users. In current users compared with never users, hormone replacement therapy had no protective effect on ischaemic heart disease (hazard ratio 1.2, 0.9 to 1.7) or myocardial infarction (1.0, 0.6 to 1.7), whereas current users with diabetes had an increased risk of death (3.2, 1.4 to 7.5), ischaemic heart disease (4.2, 1.4 to 12.5), and myocardial infarction (9.2, 2.0 to 41.4) compared with never users with diabetes. CONCLUSION Hormone replacement therapy showed no protective effect on ischaemic heart disease, but there was a significantly increased risk of death from all causes and ischaemic heart disease among women with diabetes.
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Affiliation(s)
- E Løkkegaard
- Department of Obstetrics and Gynaecology, Hvidovre University Hospital, Kettegård alle 30, DK-2650 Hvidovre, Denmark.
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Kim C, Siscovick DS, Sidney S, Lewis CE, Kiefe CI, Koepsell TD. Oral contraceptive use and association with glucose, insulin, and diabetes in young adult women: the CARDIA Study. Coronary Artery Risk Development in Young Adults. Diabetes Care 2002; 25:1027-32. [PMID: 12032110 DOI: 10.2337/diacare.25.6.1027] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE We studied the associations between 1) current use of oral contraceptives (OCs) and 2) glucose levels, insulin levels, and diabetes in young women. RESEARCH DESIGN AND METHODS Subjects were women (n = 1,940) in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective observational study of African-Americans and whites aged 18-30 years at enrollment in 1985-1986. We analyzed the cross-sectional associations between 1) current use of OCs and 2) fasting glucose, fasting insulin, and presence of diabetes using generalized estimating equations to adjust for repeated measures. We also examined the effect of current use of OCs on incident diabetes at year 10 of the study. RESULTS In unadjusted analyses, current use was associated with lower fasting glucose levels [-3.1 mg/dl, 95% CI (-3.7, -2.5)] and reduction in the odds of diabetes [odds ratio 0.56 (0.32, 0.97)], but not lower fasting insulin levels [-0.01 microU/ml (-0.03, 0.02)], compared with nonuse in both African-American and white women. After adjustment for covariates, current use of OCs was still associated with lower fasting glucose levels [-1.8 mg/dl (-2.4, -1.3)] and lower odds of diabetes [odds ratio 0.56 (0.33, 0.95)], although the associations were attenuated. After adjustment, current use of OCs was associated with higher insulin levels [0.12 microU/ml (0.006, 0.23)]. No association existed between pattern of use of OCs and incident diabetes at year 10, although the total number of new persons with diabetes at year 10 was small (n = 17). CONCLUSIONS Current use of OCs is associated with lower glucose levels in young African-American and white women and may be associated with lower odds of diabetes.
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Affiliation(s)
- Catherine Kim
- Robert Wood Johnson Clinical Scholars Program, University of Washington, Seattle, Washington, USA.
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