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Ravi H, Das S, Devi Rajeswari V, Venkatraman G, Choudhury AA, Chakraborty S, Ramanathan G. Hormonal regulation in diabetes: Special emphasis on sex hormones and metabolic traits. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 142:257-291. [PMID: 39059988 DOI: 10.1016/bs.apcsb.2023.12.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/28/2024]
Abstract
Diabetes constitutes a significant global public health challenge that is rapidly reaching epidemic proportions. Among the non-communicable diseases, the incidence of diabetes is rising at an alarming rate. The International Diabetes Federation has documented a 9.09% prevalence of diabetes among individuals aged between 20 and 79 years. The interplay of gonadal hormones and gender differences is critical in regulating insulin sensitivity and glucose tolerance, and this dynamic is particularly crucial because of the escalating incidence of diabetes. Variations in insulin sensitivity are observed across genders, levels of adiposity, and age groups. Both estrogen and testosterone are seen to influence glucose metabolism and insulin sensitivity. This chapter surveys the present knowledge of sex differences, sex hormones, and chromosomes on insulin imbalance and diabetes development. It further highlights the influence of metabolic traits in diabetes and changes in sex hormones during diabetic pregnancy. Notably, even stressful lifestyles have been acknowledged to induce hormonal imbalances. Furthermore, it discusses the potential of hormonal therapy to help stabilize sex hormones in diabetic individuals and focuses on the most recent research investigating the correlation between sex hormones and diabetes.
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Affiliation(s)
- Harini Ravi
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Soumik Das
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - V Devi Rajeswari
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Ganesh Venkatraman
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Abbas Alam Choudhury
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Shreya Chakraborty
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Gnanasambandan Ramanathan
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India.
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Ahanchi NS, Khatami F, Llanaj E, Quezada-Pinedo HG, Dizdari H, Bano A, Glisic M, Eisenga MF, Vidal PM, Muka T. The complementary roles of iron and estrogen in menopausal differences in cardiometabolic outcomes. Clin Nutr 2024; 43:1136-1150. [PMID: 38593499 DOI: 10.1016/j.clnu.2024.03.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 02/25/2024] [Accepted: 03/24/2024] [Indexed: 04/11/2024]
Abstract
Biological hormonal changes are frequently cited as an explanatory factor of sex and menopause differences in cardiometabolic diseases (CMD) and its associated risk factors. However, iron metabolism which varies between sexes and among women of different reproductive stages could also play a role. Recent evidence suggest that iron may contribute to CMD risk by modulating oxidative stress pathways and inflammatory responses, offering insights into the mechanistic interplay between iron and CMD development. In the current review, we provide a critical appraisal of the existing evidence on sex and menopausal differences in CMD, discuss the pitfall of current estrogen hypothesis as sole explanation, and the emerging role of iron in CMD as complementary pathway. Prior to menopause, body iron stores are lower in females as compared to males, but the increase during and after menopause, is tandem with an increased CMD risk. Importantly, basic science experiments show that an increased iron status is related to the development of type 2 diabetes (T2D), and different cardiovascular diseases (CVD). While epidemiological studies have consistently reported associations between heme iron intake and some iron biomarkers such as ferritin and transferrin saturation with the risk of T2D, the evidence regarding their connection to CVD remains controversial. We delve into the factors contributing to this inconsistency, and the limitation of relying on observational evidence, as it does not necessarily imply causation. In conclusion, we provide recommendations for future studies on evaluating the potential role of iron in elucidating the sex and menopausal differences observed in CMD.
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Affiliation(s)
- Noushin Sadat Ahanchi
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; Graduate School for Health Sciences, University of Bern, Bern, Switzerland; Department of Internal Medicine, Internal Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Farnaz Khatami
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; Graduate School for Health Sciences, University of Bern, Bern, Switzerland; Community Medicine Department, Tehran University of Medical Sciences, Tehran, Iran
| | - Erand Llanaj
- Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Hugo G Quezada-Pinedo
- Department of Cardiology, Bern University Hospital, University of Bern, Bern, Switzerland; The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Pediatrics Erasmus MC-Sophia Children's Hospital University, Rotterdam, the Netherlands
| | - Helga Dizdari
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
| | - Arjola Bano
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; Department of Cardiology, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Marija Glisic
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; Swiss Paraplegic Research, Nottwil, Switzerland
| | - Michele F Eisenga
- Division of Nephrology, Department of Internal Medicine, University of Groningen, Groningen, Netherlands
| | - Pedro-Marques Vidal
- Department of Internal Medicine, Internal Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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Mkhize BC, Mosili P, Ngubane PS, Sibiya NH, Khathi A. The Relationship between Renin-Angiotensin-Aldosterone System (RAAS) Activity, Osteoporosis and Estrogen Deficiency in Type 2 Diabetes. Int J Mol Sci 2023; 24:11963. [PMID: 37569338 PMCID: PMC10419188 DOI: 10.3390/ijms241511963] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/15/2023] [Accepted: 07/21/2023] [Indexed: 08/13/2023] Open
Abstract
Type 2 diabetes (T2D) is associated with a plethora of comorbidities, including osteoporosis, which occurs due to an imbalance between bone resorption and formation. Numerous mechanisms have been explored to understand this association, including the renin-angiotensin-aldosterone system (RAAS). An upregulated RAAS has been positively correlated with T2D and estrogen deficiency in comorbidities such as osteoporosis in humans and experimental studies. Therefore, research has focused on these associations in order to find ways to improve glucose handling, osteoporosis and the downstream effects of estrogen deficiency. Upregulation of RAAS may alter the bone microenvironment by altering the bone marrow inflammatory status by shifting the osteoprotegerin (OPG)/nuclear factor kappa-Β ligand (RANKL) ratio. The angiotensin-converting-enzyme/angiotensin II/Angiotensin II type 1 receptor (ACE/Ang II/AT1R) has been evidenced to promote osteoclastogenesis and decrease osteoblast formation and differentiation. ACE/Ang II/AT1R inhibits the wingless-related integration site (Wnt)/β-catenin pathway, which is integral in bone formation. While a lot of literature exists on the effects of RAAS and osteoporosis on T2D, the work is yet to be consolidated. Therefore, this review looks at RAAS activity in relation to osteoporosis and T2D. This review also highlights the relationship between RAAS activity, osteoporosis and estrogen deficiency in T2D.
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Affiliation(s)
- Bongeka Cassandra Mkhize
- Human Physiology, Health Science, Westville Campus, University of KwaZulu-Natal, Westville 4041, South Africa; (B.C.M.); (P.M.); (P.S.N.)
| | - Palesa Mosili
- Human Physiology, Health Science, Westville Campus, University of KwaZulu-Natal, Westville 4041, South Africa; (B.C.M.); (P.M.); (P.S.N.)
| | - Phikelelani Sethu Ngubane
- Human Physiology, Health Science, Westville Campus, University of KwaZulu-Natal, Westville 4041, South Africa; (B.C.M.); (P.M.); (P.S.N.)
| | | | - Andile Khathi
- Human Physiology, Health Science, Westville Campus, University of KwaZulu-Natal, Westville 4041, South Africa; (B.C.M.); (P.M.); (P.S.N.)
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He L, Fan B, Li C, Qu Y, Liu Y, Zhang T. Association between Body Mass Index and Diabetes Mellitus Are Mediated through Endogenous Serum Sex Hormones among Menopause Transition Women: A Longitudinal Cohort Study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2023; 20:1831. [PMID: 36767197 PMCID: PMC9914507 DOI: 10.3390/ijerph20031831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/10/2023] [Accepted: 01/16/2023] [Indexed: 06/18/2023]
Abstract
OBJECTIVE To explore whether and to what extent endogenous sex hormones mediate the association between overweight and diabetes risk in menopausal transition women. METHODS Premenopausal women were from the Study of Women's Health Across the Nation, with measurements of serum sex hormone including sex hormone binding globulin (SHBG), testosterone (T), estradiol (E2), follicle-stimulating hormone (FSH), and dehydroepiandrosterone sulfate (DHAS) in first postmenopausal follow-up. At the last postmenopausal follow-up, hyperglycemia status was confirmed. The partial least squares (PLS) regression method was used to extract hormonal signals associated with body mass index (BMI). Hyperglycemia was defined as individuals with prediabetes or diabetes; overweight was defined as BMI ≥ 25 kg/m2. Causal mediation analysis was used to examine the mediation effect on the association between perimenopause overweight and post-menopause hyperglycemia through PLS score and individual sex hormones. RESULTS The longitudinal study included 1438 normal glucose women with a baseline mean age (SD) of 46.5 (2.6) years and a mean follow-up period of 9.9 years. During the follow-up period, 145 (10.1) cases of hyperglycemia occurred. Compared with normal-weight participants, overweight women were associated with a higher hyperglycemia risk during the transition period (OR = 4.06, 95% CI: 2.52 to 6.80). Overweight women had higher T, E2, and lower SHBG, FSH, and DAHS concentrations (β = 0.26, 0.38, -0.52, -0.52, and -0.13, p < 0.05 for all). After adjusting for overweight and covariates, lower SHBG and FSH levels were associated with higher hyperglycemia risk (OR = 0.70 and 0.69, all p < 0.05). As a linear combination of sex hormones, the PLS score was positively associated with T, E2, and negatively with SHBG, FSH, and DHAS. PLS score interpreted 36.50% (p < 0.001) of the overweight-hyperglycemia association. Considering single-sex hormones, the mediation proportion of SHBG and FSH were 21.38% (p < 0.001) and 24.08% (p < 0.001). CONCLUSIONS Sex hormones mediated the association of overweight and diabetes risk in menopause transition women. SHBG and FSH have the dominant mediation effect.
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Affiliation(s)
- Li He
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
- Institute for Medical Dataology, Shandong University, Jinan 250002, China
| | - Bingbing Fan
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
- Institute for Medical Dataology, Shandong University, Jinan 250002, China
| | - Chunxia Li
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
- Institute for Medical Dataology, Shandong University, Jinan 250002, China
| | - Yanlin Qu
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
- Institute for Medical Dataology, Shandong University, Jinan 250002, China
| | - Ying Liu
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
- Institute for Medical Dataology, Shandong University, Jinan 250002, China
| | - Tao Zhang
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
- Institute for Medical Dataology, Shandong University, Jinan 250002, China
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Identification of repurposed drugs targeting significant long non-coding RNAs in the cross-talk between diabetes mellitus and Alzheimer's disease. Sci Rep 2022; 12:18332. [PMID: 36316461 PMCID: PMC9622874 DOI: 10.1038/s41598-022-22822-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 10/19/2022] [Indexed: 11/14/2022] Open
Abstract
The relationship between diabetes mellitus (DM) and Alzheimer's disease (AD) is so strong that scientists called it "brain diabetes". According to several studies, the critical factor in this relationship is brain insulin resistance. Due to the rapid global spread of both diseases, overcoming this cross-talk has a significant impact on societies. Long non-coding RNAs (lncRNAs), on the other hand, have a substantial impact on complex diseases due to their ability to influence gene expression via a variety of mechanisms. Consequently, the regulation of lncRNA expression in chronic diseases permits the development of innovative therapeutic techniques. However, developing a new drug requires considerable time and money. Recently repurposing existing drugs has gained popularity due to the use of low-risk compounds, which may result in cost and time savings. in this study, we identified drug repurposing candidates capable of controlling the expression of common lncRNAs in the cross-talk between DM and AD. We also utilized drugs that interfered with this cross-talk. To do this, high degree common lncRNAs were extracted from microRNA-lncRNA bipartite network. The drugs that interact with the specified lncRNAs were then collected from multiple data sources. These drugs, referred to as set D, were classified in to positive (D+) and negative (D-) groups based on their effects on the expression of the interacting lncRNAs. A feature selection algorithm was used to select six important features for D. Using a random forest classifier, these features were capable of classifying D+ and D- with an accuracy of 82.5%. Finally, the same six features were extracted for the most recently Food and Drug Administration (FDA) approved drugs in order to identify those with the highest likelihood of belonging to D+ or D-. The most significant FDA-approved positive drugs, chromium nicotinate and tapentadol, were presented as repurposing candidates, while cefepime and dihydro-alpha-ergocryptine were recommended as significant adverse drugs. Moreover, two natural compounds, curcumin and quercetin, were recommended to prevent this cross-talk. According to the previous studies, less attention has been paid to the role of lncRNAs in this cross-talk. Our research not only did identify important lncRNAs, but it also suggested potential repurposed drugs to control them.
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Kobayashi K, Tang YT, Sasaki K. Paeoniflorin, a constituent of Kami-shoyo-san, suppresses blood glucose levels in postmenopausal diabetic mice by promoting the secretion of estradiol from adipocytes. Biochem Biophys Rep 2022; 32:101335. [PMID: 36510583 PMCID: PMC9734273 DOI: 10.1016/j.bbrep.2022.101335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/19/2022] [Accepted: 08/22/2022] [Indexed: 12/16/2022] Open
Abstract
Ovarian functional deterioration in women with climacteric disorders increases the prevalence of type 2 diabetes (T2D). Therefore, we revealed that paeoniflorin (PF), an ingredient of paeony root (PR), which is a constituent of Kami-shoyo-san (KS), promotes glucose uptake by increasing estradiol secretion from adipocytes. Adipocytes differentiated from 3T3-L1 cells were incubated in culture medium containing the extracts of KS, PR, KS excluding PR (KS-PR), or PF for 5 d at 37 °C and 5% CO2. The estradiol and glucose concentrations in the medium were determined using enzyme-linked immunosorbent assay (ELISA). Next, PF (1 or 10 mg/kg) was subcutaneously injected into ovariectomized mice (12-week-old, ICR strain) once daily for 19 d to perform the glucose tolerance test and determine blood estradiol and adiponectin levels. The release of estradiol from 3T3-L1 adipocytes was significantly increased by KS, PR, KS-PR, and PF, and the increased estradiol level caused by KS was significantly decreased by excluding PF from KS (KS-PR). Glucose concentration in the medium was significantly decreased by KS and PF. In in vivo experiments, the 10 mg/kg PF-treated group showed significantly suppressed blood glucose levels at 0 and 30 min after d-glucose loading by intraperitoneal injection. These findings indicate that KS, which includes PR-containing PF as the main ingredient, may have the potential to prevent T2D caused by ovarian dysfunction in menopausal women by increasing estradiol secretion from adipocytes.
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Affiliation(s)
- Kyoko Kobayashi
- Corresponding author. Department of Pharmacognosy, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-1 Komatsushima 4-Chome, Aoba-Ku, Sendai, Miyagi, 981-8558, Japan.
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Alemany M. Estrogens and the regulation of glucose metabolism. World J Diabetes 2021; 12:1622-1654. [PMID: 34754368 PMCID: PMC8554369 DOI: 10.4239/wjd.v12.i10.1622] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/10/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
The main estrogens: estradiol, estrone, and their acyl-esters have been studied essentially related to their classical estrogenic and pharmacologic functions. However, their main effect in the body is probably the sustained control of core energy metabolism. Estrogen nuclear and membrane receptors show an extraordinary flexibility in the modulation of metabolic responses, and largely explain gender and age differences in energy metabolism: part of these mechanisms is already sufficiently known to justify both. With regard to energy, the estrogen molecular species act essentially through four key functions: (1) Facilitation of insulin secretion and control of glucose availability; (2) Modulation of energy partition, favoring the use of lipid as the main energy substrate when more available than carbohydrates; (3) Functional protection through antioxidant mechanisms; and (4) Central effects (largely through neural modulation) on whole body energy management. Analyzing the different actions of estrone, estradiol and their acyl esters, a tentative classification based on structure/effects has been postulated. Either separately or as a group, estrogens provide a comprehensive explanation that not all their quite diverse actions are related solely to specific molecules. As a group, they constitute a powerful synergic action complex. In consequence, estrogens may be considered wardens of energy homeostasis.
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Affiliation(s)
- Marià Alemany
- Faculty of Biology, University of Barcelona, Barcelona 08028, Catalonia, Spain
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Busquets-Cortés C, Bennasar-Veny M, López-González AA, Fresneda S, Aguiló A, Yanez A. Fatty liver index and progression to type 2 diabetes: a 5-year longitudinal study in Spanish workers with pre-diabetes. BMJ Open 2021; 11:e045498. [PMID: 34433590 PMCID: PMC8388308 DOI: 10.1136/bmjopen-2020-045498] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE The main aim of the study was to evaluate the association between non-alcoholic fatty liver disease (NAFLD), estimated by fatty liver index (FLI), and the development of type 2 diabetes (T2D) in a large cohort of adult workers with pre-diabetes. DESIGN Prospective cohort study. SETTING Occupational health services from Spain. PARTICIPANTS 16 648 adult workers (aged 20-65 years) with pre-diabetes (fasting plasma glucose (FPG) of 100-125 mg/dL). OUTCOME AND MEASURES FLI was calculated based on measurements of triglycerides, body mass index, waist circumference and γ-glutamyltransferase. The population was classified into three categories: FLI<30 (no hepatic steatosis), FLI 30-60 (intermediate status) and FLI>60 (hepatic steatosis). Sociodemographic, anthropometric, dietary habits, physical activity and clinical data were collected from all subjects. The incidence rate of T2D was determined after 5 years of follow-up. RESULTS After 5 years of follow-up, 3706 of the 16 648 participants (22.2%) were diagnosed with T2D, corresponding to an annual rate of progression of 4.5%. FLI was strongly associated with T2D conversion. The incidence rates of T2D in the FLI<30, FLI 30-60 and FLI>60 groups were significantly different after 5 years of follow-up were 19/6,421 (0.3%), 338/4,318 (7.8%) and 3,349/5,909 (56.7%), respectively. This association remained significant for FLI>60 after adjustment for, age, diet, physical activity, FPG, blood pressure, social class and smoking habits (adjusted HR=6.879; 95% CI 5.873 to 8.057 for men, and HR=5.806; 95% CI 4.863 to 6.932 for women). CONCLUSION NAFLD assessed by FLI independently predicted the risk of conversion to T2D among people with pre-diabetes. FLI may be an easily determined and valuable early predictor for T2D in people with pre-diabetes. FLI-based assessment of NAFLD in subjects with pre-diabetes in routine clinical practice could allow the adoption of effective measures to prevent and reduce their progression to T2D.
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Affiliation(s)
- Carla Busquets-Cortés
- Nursing and Physiotherapy Department, University of the Balearic Islands, Palma de Mallorca, Illes Balears, Spain
- Escuela Universitaria ADEMA, Palma, Illes Balears, Spain
| | - Miquel Bennasar-Veny
- Nursing and Physiotherapy Department, University of the Balearic Islands, Palma de Mallorca, Illes Balears, Spain
- Global Health and Lifestyles research group, Insitut d'Investigació Sanitària Illes Balears (IdISBa), Palma, Spain
- CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Angel-Arturo López-González
- Escuela Universitaria ADEMA, Palma, Illes Balears, Spain
- Prevention of Occupational Risks in Health Services, Balearic Islands Health Services, Palma de Mallorca, Illes Balears, Spain
| | - Sergio Fresneda
- Nursing and Physiotherapy Department, University of the Balearic Islands, Palma de Mallorca, Illes Balears, Spain
- Global Health and Lifestyles research group, Insitut d'Investigació Sanitària Illes Balears (IdISBa), Palma, Spain
| | - Antoni Aguiló
- Nursing and Physiotherapy Department, University of the Balearic Islands, Palma de Mallorca, Illes Balears, Spain
- Global Health and Lifestyles research group, Insitut d'Investigació Sanitària Illes Balears (IdISBa), Palma, Spain
| | - Aina Yanez
- Nursing and Physiotherapy Department, University of the Balearic Islands, Palma de Mallorca, Illes Balears, Spain
- Global Health and Lifestyles research group, Insitut d'Investigació Sanitària Illes Balears (IdISBa), Palma, Spain
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Fashe M, Yi M, Sueyoshi T, Negishi M. Sex-specific expression mechanism of hepatic estrogen inactivating enzyme and transporters in diabetic women. Biochem Pharmacol 2021; 190:114662. [PMID: 34157297 DOI: 10.1016/j.bcp.2021.114662] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 06/17/2021] [Accepted: 06/17/2021] [Indexed: 12/21/2022]
Abstract
Circulating estrogens levels significantly decrease in menopause and levels off in postmenopausal women. Accordingly, the liver represses levels of enzymes and membrane transporters, thereby decreasing capability of inactivating and excreting estrogens. Women increasingly develop type 2 diabetes during or after menopause. Estrogens are known to promote liver diseases in these women. Here, we have found that the estrogen inactivating sulfotransferase (SULT1E1) and an ATP-binding cassette subfamily G member 2 (ABCG2), a gene encoding breast cancer resistance protein that exports sulfated estrogens, increased their expression levels in diabetic women but not men. For the sulfotransferase gene, phosphorylated nuclear receptors ERα and RORα, at Ser212 and Ser100, respectively, bind their response elements to activate the SULT1E1 promoter in women. This coordinated increase in estrogen inactivation and excretion, and the phosphorylated nuclear receptor-mediated gene activation could be a defense mechanism against toxicities of estrogens through inactivation and excretion in the livers of women.
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Affiliation(s)
- Muluneh Fashe
- Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
| | - MyeongJin Yi
- Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Tatsuya Sueyoshi
- Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Masahiko Negishi
- Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
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Buscemi C, Ferro Y, Pujia R, Mazza E, Boragina G, Sciacqua A, Piro S, Pujia A, Sesti G, Buscemi S, Montalcini T. Sarcopenia and Appendicular Muscle Mass as Predictors of Impaired Fasting Glucose/Type 2 Diabetes in Elderly Women. Nutrients 2021; 13:nu13061909. [PMID: 34199375 PMCID: PMC8227668 DOI: 10.3390/nu13061909] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 05/26/2021] [Accepted: 05/29/2021] [Indexed: 12/18/2022] Open
Abstract
Elderly women exhibit a high risk of type 2 diabetes (T2D), but no definitive data exist about the possible role of postmenopausal increases in visceral adiposity, the loss of lean body mass, or decreases in the sum of the lean mass of arms and legs (appendicular skeletal muscle mass (ASMM)). This retrospective, longitudinal study investigated whether body composition (bioelectrical impedance analysis) predicted the development of impaired fasting glucose (IFG) or T2D in a cohort of 159 elderly women (age: 71 ± 5 years, follow-up: 94 months) from southern Italy (Clinical Nutrition and Geriatric Units of the “Mater Domini” University Hospital in Catanzaro, Calabria region, and the “P. Giaccone ”University Hospital in Palermo, Sicily region). Sarcopenia was defined in a subgroup of 128 women according to the EWGSOP criteria as the presence of low muscle strength (handgrip strength <16 kg) plus low muscle mass (reported as appendicular skeletal muscle mass <15 kg). Participants with a low ASMM had a higher IFG/T2D incidence than those with a normal ASMM (17% vs. 6%, p-adjusted = 0.044); this finding was independent of BMI, fat mass, waist circumference, and habitual fat intake (OR = 3.81, p = 0.034). A higher incidence of IFG/T2D was observed in the subgroup with sarcopenia than those without sarcopenia (33% vs. 7%, p-adjusted = 0.005) independent of BMI and fat mass (OR = 6.75, p = 0.007). In conclusion, this study demonstrates that elderly women with low ASMM had a higher probability of developing IFG/T2D. Further studies are needed to confirm these results in men and in other age groups.
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Affiliation(s)
- Carola Buscemi
- Department of Clinical and Molecular Medicine, Postgraduate Specialization School in Geriatrics, University of Catania, 95100 Catania, Italy; (C.B.); (S.P.)
- Unit of Clinical Nutrition, Dipartimento di Promozione della Salute, Materno-Infantile, Medicina Interna e Specialistica di Eccellenza (PROMISE), University of Palermo, AOU Policlinico “P. Giaccone”, 90127 Palermo, Italy;
| | - Yvelise Ferro
- Department of Medical and Surgical Science, University Magna Graecia, 88100 Catanzaro, Italy; (Y.F.); (R.P.); (E.M.); (G.B.); (A.S.); (A.P.)
| | - Roberta Pujia
- Department of Medical and Surgical Science, University Magna Graecia, 88100 Catanzaro, Italy; (Y.F.); (R.P.); (E.M.); (G.B.); (A.S.); (A.P.)
| | - Elisa Mazza
- Department of Medical and Surgical Science, University Magna Graecia, 88100 Catanzaro, Italy; (Y.F.); (R.P.); (E.M.); (G.B.); (A.S.); (A.P.)
| | - Giada Boragina
- Department of Medical and Surgical Science, University Magna Graecia, 88100 Catanzaro, Italy; (Y.F.); (R.P.); (E.M.); (G.B.); (A.S.); (A.P.)
| | - Angela Sciacqua
- Department of Medical and Surgical Science, University Magna Graecia, 88100 Catanzaro, Italy; (Y.F.); (R.P.); (E.M.); (G.B.); (A.S.); (A.P.)
| | - Salvatore Piro
- Department of Clinical and Molecular Medicine, Postgraduate Specialization School in Geriatrics, University of Catania, 95100 Catania, Italy; (C.B.); (S.P.)
| | - Arturo Pujia
- Department of Medical and Surgical Science, University Magna Graecia, 88100 Catanzaro, Italy; (Y.F.); (R.P.); (E.M.); (G.B.); (A.S.); (A.P.)
| | - Giorgio Sesti
- Dipartimento di Medicina clinica e molecolare, Università la Sapienza, 00185 Roma, Italy;
| | - Silvio Buscemi
- Unit of Clinical Nutrition, Dipartimento di Promozione della Salute, Materno-Infantile, Medicina Interna e Specialistica di Eccellenza (PROMISE), University of Palermo, AOU Policlinico “P. Giaccone”, 90127 Palermo, Italy;
| | - Tiziana Montalcini
- Department of Clinical and Experimental Medicine, University Magna Grecia, 88100 Catanzaro, Italy
- Correspondence:
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11
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Hang D, He X, Kværner AS, Chan AT, Wu K, Ogino S, Hu Z, Shen H, Giovannucci EL, Song M. Plasma sex hormones and risk of conventional and serrated precursors of colorectal cancer in postmenopausal women. BMC Med 2021; 19:18. [PMID: 33504335 PMCID: PMC7841996 DOI: 10.1186/s12916-020-01895-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 12/22/2020] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Sex hormones have been suggested to play a role in colorectal cancer (CRC), but their influence on early initiation of CRC remains unknown. METHODS We retrospectively examined the associations with risk of CRC precursors, including conventional adenomas and serrated polyps, for plasma estrone, estradiol, free estradiol, testosterone, free testosterone, sex hormone-binding globulin (SHBG), and the ratio of estradiol to testosterone among 5404 postmenopausal women from the Nurses' Health Study I and II. Multivariable logistic regression was used to calculate the odds ratio (OR) and 95% confidence intervals (CI). Given multiple testing, P < 0.005 was considered statistically significant. RESULTS During 20 years of follow-up, we documented 535 conventional adenoma cases and 402 serrated polyp cases. Higher concentrations of SHBG were associated with lower risk of conventional adenomas, particularly advanced adenomas (multivariable OR comparing the highest to the lowest quartile, 0.40, 95% CI 0.24-0.67, P for trend < 0.0001). A nominally significant association was found for SHBG with lower risk of large serrated polyps (≥ 10 mm) (OR, 0.47, 95% CI 0.17-1.35, P for trend = 0.02) as well as free estradiol and free testosterone with higher risk of conventional adenomas (OR, 1.54, 95% CI 1.02-2.31, P for trend = 0.03 and OR, 1.33, 95% CI 0.99-1.78, P for trend = 0.03, respectively). CONCLUSIONS The findings suggest a potential role of sex hormones, particularly SHBG, in early colorectal carcinogenesis.
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Affiliation(s)
- Dong Hang
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
- Department of Nutrition, Harvard T.H. Chan School of Public Health, 667 Huntington Avenue, Kresge 906A, Boston, MA, 02115, USA
| | - Xiaosheng He
- Clinical and Translational Epidemiology Unit and Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Department of Colorectal Surgery, The Six Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ane Sørlie Kværner
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Andrew T Chan
- Clinical and Translational Epidemiology Unit and Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Kana Wu
- Department of Nutrition, Harvard T.H. Chan School of Public Health, 667 Huntington Avenue, Kresge 906A, Boston, MA, 02115, USA
| | - Shuji Ogino
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Zhibin Hu
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Hongbing Shen
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Edward L Giovannucci
- Department of Nutrition, Harvard T.H. Chan School of Public Health, 667 Huntington Avenue, Kresge 906A, Boston, MA, 02115, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Mingyang Song
- Department of Nutrition, Harvard T.H. Chan School of Public Health, 667 Huntington Avenue, Kresge 906A, Boston, MA, 02115, USA.
- Clinical and Translational Epidemiology Unit and Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
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12
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Ramírez-Alarcón K, Victoriano M, Mardones L, Villagran M, Al-Harrasi A, Al-Rawahi A, Cruz-Martins N, Sharifi-Rad J, Martorell M. Phytochemicals as Potential Epidrugs in Type 2 Diabetes Mellitus. Front Endocrinol (Lausanne) 2021; 12:656978. [PMID: 34140928 PMCID: PMC8204854 DOI: 10.3389/fendo.2021.656978] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 03/31/2021] [Indexed: 11/13/2022] Open
Abstract
Type 2 diabetes Mellitus (T2DM) prevalence has significantly increased worldwide in recent years due to population age, obesity, and modern sedentary lifestyles. The projections estimate that 439 million people will be diabetic in 2030. T2DM is characterized by an impaired β-pancreatic cell function and insulin secretion, hyperglycemia and insulin resistance, and recently the epigenetic regulation of β-pancreatic cells differentiation has been underlined as being involved. It is currently known that several bioactive molecules, widely abundant in plants used as food or infusions, have a key role in histone modification and DNA methylation, and constituted potential epidrugs candidates against T2DM. In this sense, in this review the epigenetic mechanisms involved in T2DM and protein targets are reviewed, with special focus in studies addressing the potential use of phytochemicals as epidrugs that prevent and/or control T2DM in vivo and in vitro. As main findings, and although some controversial results have been found, bioactive molecules with epigenetic regulatory function, appear to be a potential replacement/complementary therapy of pharmacological hypoglycemic drugs, with minimal side effects. Indeed, natural epidrugs have shown to prevent or delay the T2DM development and the morbidity associated to dysfunction of blood vessels, eyes and kidneys due to sustained hyperglycemia in T2DM patients.
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Affiliation(s)
- Karina Ramírez-Alarcón
- Department of Nutrition and Dietetics, Faculty of Pharmacy, University of Concepción, Concepción, Chile
| | - Montserrat Victoriano
- Department of Nutrition and Dietetics, Faculty of Pharmacy, University of Concepción, Concepción, Chile
| | - Lorena Mardones
- Department of Basic Science, Faculty of Medicine, Universidad Catolica de la Santisima Concepcion, Concepción, Chile
| | - Marcelo Villagran
- Department of Basic Science, Faculty of Medicine, Universidad Catolica de la Santisima Concepcion, Concepción, Chile
- Scientific-Technological Center for the Sustainable Development of the Coastline, Universidad Catolica de la Santisima Concepcion, Concepción, Chile
| | - Ahmed Al-Harrasi
- Natural and Medical Sciences Research Centre, University of Nizwa, Birkat Al Mouz, Oman
- *Correspondence: Ahmed Al-Harrasi, ; Natália Cruz-Martins, ; Javad Sharifi-Rad, ; Miquel Martorell,
| | - Ahmed Al-Rawahi
- Natural and Medical Sciences Research Centre, University of Nizwa, Birkat Al Mouz, Oman
| | - Natália Cruz-Martins
- Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, Porto, Portugal
- Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal
- Laboratory of Neuropsychophysiology, Faculty of Psychology and Education Sciences, University of Porto, Porto, Portugal
- *Correspondence: Ahmed Al-Harrasi, ; Natália Cruz-Martins, ; Javad Sharifi-Rad, ; Miquel Martorell,
| | - Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Facultad de Medicina, Universidad del Azuay, Cuenca, Ecuador
- *Correspondence: Ahmed Al-Harrasi, ; Natália Cruz-Martins, ; Javad Sharifi-Rad, ; Miquel Martorell,
| | - Miquel Martorell
- Department of Nutrition and Dietetics, Faculty of Pharmacy, University of Concepción, Concepción, Chile
- Centre for Healthy Living, University of Concepción, Concepción, Chile
- Universidad de Concepción, Unidad de Desarrollo Tecnológico, UDT, Concepción, Chile
- *Correspondence: Ahmed Al-Harrasi, ; Natália Cruz-Martins, ; Javad Sharifi-Rad, ; Miquel Martorell,
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13
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Affiliation(s)
- Zulvikar Syambani Ulhaq
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Maulana Malik Ibrahim Islamic State University of Malang, Batu, Indonesia
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14
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Metabolic and Epigenetic Action Mechanisms of Antidiabetic Medicinal Plants. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 2019:3583067. [PMID: 31191707 PMCID: PMC6525884 DOI: 10.1155/2019/3583067] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Accepted: 04/17/2019] [Indexed: 12/14/2022]
Abstract
Diabetes is a predominant metabolic disease nowadays due to the off-beam lifestyle of diet and reduced physical activity. Complications of the illness include the gene-environment interactions and the downstream genetic and epigenetic consequences, e.g., cardiovascular diseases, tumor progression, retinopathy, nephropathy, neuropathy, polydipsia, polyphagia, polyuria, and weight loss. This review sheds the light on the mechanistic insights of antidiabetic medicinal plants in targeting key organs and tissues involved in regulating blood glucose homeostasis including the pancreas, liver, muscles, adipose tissues, and glucose absorption in the intestine. Diabetes is also involved in modulating major epigenetic pathways such as DNA methylation and histone modification. In this respect, we will discuss the phytochemicals as current and future epigenetic drugs in the treatment of diabetes. In addition, several proteins are common targets for the treatment of diabetes. Some phytochemicals are expected to directly interact with these targets. We lastly uncover modeling studies that predict such plausible interactions. In conclusion, this review article presents the mechanistic insight of phytochemicals in the treatment of diabetes by combining both the cellular systems biology and molecular modeling.
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15
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Crooke ST, Baker BF, Xia S, Yu RZ, Viney NJ, Wang Y, Tsimikas S, Geary RS. Integrated Assessment of the Clinical Performance of GalNAc 3-Conjugated 2'-O-Methoxyethyl Chimeric Antisense Oligonucleotides: I. Human Volunteer Experience. Nucleic Acid Ther 2018; 29:16-32. [PMID: 30570431 PMCID: PMC6386089 DOI: 10.1089/nat.2018.0753] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Advances in medicinal chemistry have produced new chemical classes of antisense oligonucleotides (ASOs) with enhanced therapeutic properties. Conjugation of the triantennary N-acetylgalactosamine (GalNAc3) moiety to the extensively characterized phosphorothioate (PS)-modified 2′-O-methoxyethyl (2′MOE) ASO exemplifies such an advance. This structure-activity optimized moiety effects receptor-mediated uptake of the ASO prodrug through the asialoglycoprotein receptor 1 to support selective targeting of RNAs expressed by hepatocytes. In this study we report the integrated assessment of data available from randomized placebo-controlled dose-ranging studies of this chemical class of ASOs administered systemically to healthy human volunteers. First, we compare the pharmacokinetic and pharmacodynamic profiles of a subset of the GalNAc3-conjugated PS-modified 2′MOE ASOs to the parent PS-modified 2′MOE ASOs for which plasma analytes are available. We then evaluate the safety profile of the full set of GalNAc3-conjugated PS-modified 2′MOE ASO conjugates by the incidence of signals in standardized laboratory tests and by the mean laboratory test results as a function of dose level over time. With hepatocyte targeted delivery, the ED50 for the GalNAc3-conjugated PS-modified 2′MOE ASO subset ranges from 4 to 10 mg/week, up to 30-fold more potent than the parent PS-modified 2′MOE ASO. No GalNAc3-conjugated PS-modified 2′MOE ASO class effects were identified from the assessment of the integrated laboratory test data across all doses tested with either single or multidose regimens. The increase in potency supports an increase in the safety margin for this new chemical class of ASOs now under broad investigation in the clinic. Although the total exposure is limited in the initial phase 1 trials, ongoing and future investigations in patient populations will support evaluation of the effects of long-term exposure.
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Affiliation(s)
| | | | - Shuting Xia
- Ionis Pharmaceuticals, Inc., Carlsbad, California
| | - Rosie Z Yu
- Ionis Pharmaceuticals, Inc., Carlsbad, California
| | | | - Yanfeng Wang
- Ionis Pharmaceuticals, Inc., Carlsbad, California
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16
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Marchand GB, Carreau AM, Weisnagel SJ, Bergeron J, Labrie F, Lemieux S, Tchernof A. Increased body fat mass explains the positive association between circulating estradiol and insulin resistance in postmenopausal women. Am J Physiol Endocrinol Metab 2018; 314:E448-E456. [PMID: 29208612 DOI: 10.1152/ajpendo.00293.2017] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The relationship between circulating estrogen levels and cardiometabolic risk factors such as insulin resistance is unclear in postmenopausal women. High estradiol (E2) levels have been reported to predict increased risk of type 2 diabetes in this population. We aimed to examine associations among estrogen levels, adiposity measurements, and cardiometabolic risk variables including insulin resistance in postmenopausal women. One hundred-one healthy participants (mean ± SD: age 57 ± 4 yr, BMI 27.9 ± 4.8 kg/m2) were included in the analysis. Fifteen plasma steroids or metabolites were measured by liquid chromatography-tandem mass spectrometry. Insulin sensitivity was assessed with a hyperinsulinemic-euglycemic clamp. Body composition and fat distribution were determined with hydrostatic weighing and computed tomography, respectively. Blood lipids and circulating cytokines were also measured. Circulating E2 was positively correlated with all adiposity indexes ( r = 0.62 to 0.42, P < 0.0001) except waist-to-hip ratio. E2 was positively correlated with VLDL-cholesterol, plasma-, VLDL-, and HDL-triglyceride levels ( r = 0.31 to 0.24, P < 0.02) as well as with hs-CRP and IL-6 ( r = 0.52 and 0.29, P < 0.005) and negatively with HDL-cholesterol, adiponectin, and insulin sensitivity ( r = -0.36 to -0.20, P < 0.02). With adjustments for percent body fat, correlations between E2 and metabolic risk variables were no longer significant. Similar results were observed for circulating estrone (E1) and estrone-sulfate (E1-S) levels. In conclusion, circulating estrogen concentrations are proportional to adipose mass in postmenopausal women, although they remain in the low range. Insulin resistance as well as altered blood lipids and cytokines are observed when circulating estrogen levels are high within that range, but these differences are explained by concomitant variation in total adiposity.
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Affiliation(s)
- Geneviève B Marchand
- School of Nutrition, Laval University , Quebec City, Quebec , Canada
- Quebec Heart and Lung Institute , Quebec City, Quebec , Canada
| | - Anne-Marie Carreau
- Quebec Heart and Lung Institute , Quebec City, Quebec , Canada
- Department of Medicine, University of Sherbrooke , Sherbrooke , Canada
| | - S John Weisnagel
- CHU de Quebec-Université Laval Research Center , Quebec City, Quebec , Canada
| | - Jean Bergeron
- CHU de Quebec-Université Laval Research Center , Quebec City, Quebec , Canada
| | | | - Simone Lemieux
- School of Nutrition, Laval University , Quebec City, Quebec , Canada
- Institute of Nutrition and Functional Foods , Quebec City, Quebec , Canada
| | - André Tchernof
- School of Nutrition, Laval University , Quebec City, Quebec , Canada
- Quebec Heart and Lung Institute , Quebec City, Quebec , Canada
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17
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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: 206] [Impact Index Per Article: 25.8] [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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