218 results on '"Mauvais-Jarvis F"'
Search Results
2. Hyperglycaemia per se does not affect erythrocyte glucose-6-phosphate dehydrogenase activity in ketosis-prone diabetes
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Choukem, S.P., Sobngwi, E., Garnier, J.P., Letellier, S., Mauvais-Jarvis, F., Calvo, F., and Gautier, J.-F.
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- 2015
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3. Efficacy of glucagon-like peptide-1 and estrogen dual agonist in pancreatic islets protection and preclinical models of insulin-deficient diabetes
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Fuselier T, Sa P Mota de, Qadir MMF, Xu B, Allard C, Meyers MM, Tiano JP, Yang BS, Gelfanov V, Lindsey SH, Dimarchi RD, and Mauvais-Jarvis F
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General Economics, Econometrics and Finance - Published
- 2022
4. Oestrogens improve human pancreatic islet transplantation in a mouse model of insulin deficient diabetes
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Liu, S., Kilic, G., Meyers, M. S., Navarro, G., Wang, Y., Oberholzer, J., and Mauvais-Jarvis, F.
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- 2013
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5. The Extranuclear Estrogen Receptor-α Improves Pancreatic Islet Lipid Homeostasis.
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Tiano, JP, primary, Le May, C, additional, Korach, KS, additional, and Mauvais-Jarvis, F, additional
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- 2010
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6. Gender and neurogenin3 influence the pathogenesis of ketosis-prone diabetes
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Louet, J.-F., Smith, S. B., Gautier, J.-F., Molokhia, M., Virally, M.-L., Kevorkian, J.-P., Guillausseau, P.-J., Vexiau, P., Charpentier, G., German, M. S., Vaisse, C., Urbanek, M., and Mauvais-Jarvis, F.
- Published
- 2008
7. Mouse models of insulin resistance and type 2 diabetes
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Postic, C., Mauvais-Jarvis, F., and Girard, J.
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- 2004
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8. Metabolic and immunogenetic prediction of long-term insulin remission in African patients with atypical diabetes
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Sobngwi, E., Vexiau, P., Levy, V., Lepage, V., Mauvais-Jarvis, F., Leblanc, H., Mbanya, J. C., and Gautier, J. F.
- Published
- 2002
9. The polymorphism Gly574Ser in the transcription factor HNF-1α is not a marker of adult-onset ketosis-prone atypical diabetes in Afro-Caribbean patients
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Mauvais-Jarvis, F., Boudou, P., Sobngwi, E., Riveline, J. P., Kevorkian, J. P., Villette, J. M., Porcher, R., Vexiau, P., and Gautier, J. F.
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- 2003
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10. Reduced expression of the murine p85 alpha subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes
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Mauvais-Jarvis F., Ueki K., Fruman D. A., Hirshman M. F., Sakamoto K., Goodyear L. J., Iannacone M., Accili D., Cantley L. C., Ronald Kahn C., Mauvais-Jarvis, F., Ueki, K., Fruman, D. A., Hirshman, M. F., Sakamoto, K., Goodyear, L. J., Iannacone, M., Accili, D., Cantley, L. C., and Ronald Kahn, C.
- Abstract
A critical component of insulin action is the enzyme phosphoinositide (PI) 3-kinase. The major regulatory subunits of PI 3-kinase, p85alpha and its splice variants, are encoded by the Pik3r1 gene. Heterozygous disruption of Pik3r1 improves insulin signaling and glucose homeostasis in normal mice and mice made insulin-resistant by heterozygous deletion of the Insulin receptor and/or insulin receptor substrate-1 (IRS1) genes. Reduced expression of p85 modulates the molecular balance between this protein, the p 110 catalytic subunit of PI 3-kinase, and the IRS proteins. Thus, despite the decrease in p85alpha, PI 3-kinase activation is normal, insulin-stimulated Akt activity is increased, and glucose tolerance and insulin sensitivity are improved. Furthermore, Pik3r1 heterozygosity protects mice with genetic insulin resistance from developing diabetes. These data suggest that regulation of p85alpha levels may provide a novel therapeutic target for the treatment of type 2 diabetes. RI Iannacone, Matteo/B-3342-2008 A critical component of insulin action is the enzyme phosphoinositide (PI) 3-kinase. The major regulatory subunits of PI 3-kinase, p85α and its splice variants, are encoded by the Pik3r1 gene. Heterozygous disruption of Pik3r1 improves insulin signaling and glucose homeostasis in normal mice and mice made insulin-resistant by heterozygous deletion of the Insulin receptor and/or insulin receptor substrate-1 (IRS1) genes. Reduced expression of p85 modulates the molecular balance between this protein, the p110 catalytic subunit of PI 3-kinase, and the IRS proteins. Thus, despite the decrease in p85α, PI 3-kinase activation is normal, insulin-stimulated Akt activity is increased, and glucose tolerance and insulin sensitivity are improved. Furthermore, Pik3r1 heterozygosity protects mice with genetic insulin resistance from developing diabetes. These data suggest that regulation of p85α levels may provide a novel therapeutic target for the treatment of type 2 diabetes.
- Published
- 2002
11. O57 Le récepteur aux œstrogènes ERα nucléaire est nécessaire à la sécrétion d’insuline chez la souris mâle
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Allard, C., primary, Levin, E.R., additional, and Mauvais-Jarvis, F., additional
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- 2015
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12. Diabetes in Africans. Part 2: Ketosis-prone atypical diabetes mellitus
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Sobngwi, E., Mauvais-Jarvis, F., Vexiau, P., Jean Claude N Mbanya, and Gautier, J. -F
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Diabetes Mellitus, Type 1 ,Africa ,Diabetes Mellitus ,Humans - Abstract
Diabetes is increasing with ageing and changes in lifestyle in populations of African ancestry as described in the first part of this review. Apart from classical type 1 and Type 2 diabetes, atypical presentations are observed in these populations, especially "tropical" and "ketosis-prone" atypical diabetes. Ketosis-prone atypical diabetes that has been classified by ADA as idiopathic Type 1 diabetes or Type 1b is the most common atypical form. It is characterised by an acute initial presentation with severe hyperglycaemia and ketosis, as classical Type 1 diabetes. In the subsequent clinical course after initiation of insulin therapy, prolonged remission is often possible with cessation of insulin therapy and maintenance of appropriate metabolic control. Metabolic studies showed a markedly blunted insulin secretory response to glucose, partially reversible with the improvement of blood glucose control. Variable levels of insulin resistance are observed, especially in obese patients. Pancreatic B-cell autoimmunity is an exceptional finding. Association with type 1 susceptibility HLA alleles is variable. The molecular mechanisms underlining the insulin secretory dysfunction are still to be understood and may involve gluco-lipotoxicity processes, glucagon dysregulation, effect of stress, or may be genetically determined. The present review summarises the available clinical and metabolic features and suggests some pathogenetic hypotheses and principles of management for the ketosis-prone atypical diabetes of the Africans.
- Published
- 2002
13. Oestrogens improve human pancreatic islet transplantation in a mouse model of insulin deficient diabetes
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Liu, S., primary, Kilic, G., additional, Meyers, M. S., additional, Navarro, G., additional, Wang, Y., additional, Oberholzer, J., additional, and Mauvais-Jarvis, F., additional
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- 2012
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14. Absence of exercise-induced variations in adiponectin levels despite decreased abdominal adiposity and improved insulin sensitivity in type 2 diabetic men
- Author
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Boudou, P, primary, Sobngwi, E, additional, Mauvais-Jarvis, F, additional, Vexiau, P, additional, and Gautier, JF, additional
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- 2003
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15. A model to explore the interaction between muscle insulin resistance and beta-cell dysfunction in the development of type 2 diabetes.
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Mauvais-Jarvis, F, primary, Virkamaki, A, additional, Michael, M D, additional, Winnay, J N, additional, Zisman, A, additional, Kulkarni, R N, additional, and Kahn, C R, additional
- Published
- 2000
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16. Taux élevés d’antigène carcinoembryonnaire après exérèse d’un cancer : un autre mode de révélation du carcinome médullaire thyroïdien
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Martinez, M, primary, Virally, M.L, additional, Guillausseau-Scholer, C, additional, Vincenot, M, additional, Samuel-Lajeunesse, J, additional, Mauvais-Jarvis, F, additional, Kévorkian, J.P, additional, Porokhov, B, additional, Valleur, P, additional, and Guillausseau, P.J, additional
- Published
- 2000
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17. β- and α-cell dysfunctions in africans with ketosis-prone atypical diabetes during near-normoglycemic remission.
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Choukem SP, Sobngwi E, Boudou P, Fetita LS, Porcher R, Ibrahim F, Blondeau B, Vexiau P, Mauvais-Jarvis F, Calvo F, Gautier JF, Choukem, Siméon-Pierre, Sobngwi, Eugene, Boudou, Philippe, Fetita, Lila-Sabrina, Porcher, Raphael, Ibrahim, Fidaa, Blondeau, Bertrand, Vexiau, Patrick, and Mauvais-Jarvis, Franck
- Abstract
Objective: Ketosis-prone atypical diabetes (KPD) is a subtype of diabetes in which the pathophysiology is yet to be unraveled. The aim of this study was to characterize β- and α-cell functions in Africans with KPD during remission.Research Design and Methods: We characterized β- and α-cell functions in Africans with KPD during remission. The cohort comprised 15 sub-Saharan Africans who had been insulin-free for a median of 6 months. Patients in remission were in good glycemic control (near-normoglycemic) and compared with 15 nondiabetic control subjects matched for age, sex, ethnicity, and BMI. Plasma insulin, C-peptide, and glucagon concentrations were measured in response to oral and intravenous glucose and to combined intravenous arginine and glucose. Early insulin secretion was measured during a 75-g oral glucose tolerance test. Insulin secretion rate and glucagon were assessed in response to intravenous glucose ramping.Results: Early insulin secretion and maximal insulin secretion rate were lower in patients compared with control participants. In response to combined arginine and glucose stimulation, maximal insulin response was reduced. Glucagon suppression was also decreased in response to oral and intravenous glucose but not in response to arginine and insulin.Conclusions: Patients with KPD in protracted near-normoglycemic remission have impaired insulin response to oral and intravenous glucose and to arginine, as well as impaired glucagon suppression. Our results suggest that β- and α-cell dysfunctions both contribute to the pathophysiology of KPD. [ABSTRACT FROM AUTHOR]- Published
- 2013
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18. Importance of oestrogen receptors to preserve functional β-cell mass in diabetes.
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Tiano JP, Mauvais-Jarvis F, Tiano, Joseph P, and Mauvais-Jarvis, Franck
- 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. [ABSTRACT FROM AUTHOR]
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- 2012
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19. Importance of extranuclear estrogen receptor-alpha and membrane G protein-coupled estrogen receptor in pancreatic islet survival.
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Liu S, Le May C, Wong WP, Ward RD, Clegg DJ, Marcelli M, Korach KS, Mauvais-Jarvis F, Liu, Suhuan, Le May, Cedric, Wong, Winifred P S, Ward, Robert D, Clegg, Deborah J, Marcelli, Marco, Korach, Kenneth S, and Mauvais-Jarvis, Franck
- Abstract
Objective: We showed that 17beta-estradiol (E(2)) favors pancreatic beta-cell survival via the estrogen receptor-alpha (ERalpha) in mice. E(2) activates nuclear estrogen receptors via an estrogen response element (ERE). E(2) also activates nongenomic signals via an extranuclear form of ERalpha and the G protein-coupled estrogen receptor (GPER). We studied the contribution of estrogen receptors to islet survival.Research Design and Methods: We used mice and islets deficient in estrogen receptor-alpha (alphaERKO(-/-)), estrogen receptor-beta (betaERKO(-/-)), estrogen receptor-alpha and estrogen receptor-beta (alphabetaERKO(-/-)), and GPER (GPERKO(-/-)); a mouse lacking ERalpha binding to the ERE; and human islets. These mice and islets were studied in combination with receptor-specific pharmacological probes.Results: We show that ERalpha protection of islet survival is ERE independent and that E(2) favors islet survival through extranuclear and membrane estrogen receptor signaling. We show that ERbeta plays a minor cytoprotective role compared to ERalpha. Accordingly, betaERKO(-/-) mice are mildly predisposed to streptozotocin-induced islet apoptosis. However, combined elimination of ERalpha and ERbeta in mice does not synergize to provoke islet apoptosis. In alphabetaERKO(-/-) mice and their islets, E(2) partially prevents apoptosis suggesting that an alternative pathway compensates for ERalpha/ERbeta deficiency. We find that E(2) protection of islet survival is reproduced by a membrane-impermeant E(2) formulation and a selective GPER agonist. Accordingly, GPERKO(-/-) mice are susceptible to streptozotocin-induced insulin deficiency.Conclusions: E(2) protects beta-cell survival through ERalpha and ERbeta via ERE-independent, extra-nuclear mechanisms, as well as GPER-dependent mechanisms. The present study adds a novel dimension to estrogen biology in beta-cells and identifies GPER as a target to protect islet survival. [ABSTRACT FROM AUTHOR]- Published
- 2009
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20. Identification of the rat adapter Grb14 as an inhibitor of insulin actions.
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Kasus-Jacobi, A, Perdereau, D, Auzan, C, Clauser, E, Van Obberghen, E, Mauvais-Jarvis, F, Girard, J, and Burnol, A F
- Abstract
We cloned by interaction with the beta-subunit of the insulin receptor the rat variant of the human adapter Grb14 (rGrb14). rGrb14 is specifically expressed in rat insulin-sensitive tissues and in the brain. The binding of rGrb14 to insulin receptors is insulin-dependent in vivo in Chinese hamster ovary (CHO) cells overexpressing both proteins and importantly, in rat liver expressing physiological levels of proteins. However, rGrb14 is not a substrate of the tyrosine kinase of the receptor. In the two-hybrid system, two domains of rGrb14 can mediate the interaction with insulin receptors: the Src homology 2 (SH2) domain and a region between the PH and SH2 domains that we named PIR (for phosphorylated insulin receptor-interacting region). In vitro interaction assays using deletion mutants of rGrb14 show that the PIR, but not the SH2 domain, is able to coprecipitate insulin receptors, suggesting that the PIR is the major binding domain of rGrb14. The interaction between rGrb14 and the insulin receptors is almost abolished by mutating tyrosine residue Tyr1150 or Tyr1151 of the receptor. The overexpression of rGrb14 in CHO-IR cells decreases insulin stimulation of both DNA and glycogen synthesis. These effects are accompanied by a decrease in insulin-stimulated tyrosine phosphorylation of IRS-1, but insulin receptor autophosphorylation is unaltered. These findings suggest that rGrb14 could be a new downstream signaling component of the insulin-mediated pathways.
- Published
- 1998
21. Diabetes in Africans. Part 1: Epidemiology and clinical specificities
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Sobngwi E, Mauvais-Jarvis F, Vexiau P, Jean Claude N Mbanya, and Jf, Gautier
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Diabetes Complications ,Diabetic Retinopathy ,Diabetic Neuropathies ,Risk Factors ,Africa ,Racial Groups ,Diabetes Mellitus ,Humans ,Coronary Disease ,Diabetic Nephropathies ,Diabetic Angiopathies ,Diabetic Foot - Abstract
The prevalence of diabetes in African communities is increasing with ageing of the population and lifestyle changes associated with rapid urbanisation and westernisation. Traditional rural communities still have very low prevalence, at most 1-2%, except in some specific high-risk groups, whereas 1-13% or more adults in urban communities have diabetes. Type 2 diabetes is the predominant form (70-90%), the rest being represented by typical type 1 patients and patients with atypical presentations that require more pathophysiological insight. Due to the high urban growth rate, dietary changes, reduction in physical activity, and increasing obesity, it is estimated that the prevalence of diabetes is due to triple within the next 25 years. In addition, long-term complications occur early in the course of diabetes and concern a high proportion of patients, probably higher than in other ethnic groups, and that could be partly explained by uncontrolled hypertension, poor metabolic control and possible ethnic predisposition. The combination of the rising prevalence of diabetes and the high rate of long-term complications in Africans will lead to a drastic increase of the burden of diabetes on health systems of African countries. The design and implementation of appropriate strategy for early diagnosis and treatment, and population-based primary prevention of diabetes in these high-risk populations is therefore a public health priority.
22. A novel recognition site for somatostatin-14 on the GABA~A receptor complex
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Vincens, M., Mauvais-Jarvis, F., and Behar, S.
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- 1998
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23. Effect of a diabetic environment in utero on predisposition to type 2 diabetes.
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Sobngwi E, Boudou P, Mauvais-Jarvis F, Leblanc H, Velho G, Vexiau P, Porcher R, Hadjadj S, Pratley R, Tataranni PA, Calvo F, and Gautier J
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- 2003
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24. Upregulation of inflammatory genes and pathways links obesity to severe COVID-19.
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Currey J, Ellsworth C, Khatun MS, Wang C, Chen Z, Liu S, Midkiff C, Xiao M, Ren M, Liu F, Elgazzaz M, Fox S, Maness NJ, Rappaport J, Lazartigues E, Blair R, Kolls JK, Mauvais-Jarvis F, and Qin X
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- Animals, Mice, Humans, Diet, High-Fat adverse effects, Inflammation genetics, Inflammation pathology, Inflammation metabolism, Disease Models, Animal, Interleukin-6 genetics, Interleukin-6 metabolism, Male, Adipose Tissue metabolism, Adipose Tissue pathology, Severity of Illness Index, Angiotensin-Converting Enzyme 2 genetics, Angiotensin-Converting Enzyme 2 metabolism, COVID-19 genetics, COVID-19 virology, COVID-19 metabolism, COVID-19 pathology, Obesity genetics, Obesity metabolism, Obesity complications, SARS-CoV-2, Up-Regulation, Lung metabolism, Lung pathology, Lung virology
- Abstract
Obesity is a risk factor for developing severe COVID-19. However, the mechanism underlying obesity-accelerated COVID-19 remains unclear. Here, we report results from a study in which 2-3-month-old K18-hACE2 (K18) mice were fed a western high-fat diet (WD) or normal chow (NC) over 3 months before intranasal infection with a sublethal dose of SARS-CoV2 WA1 (a strain ancestral to the Wuhan variant). After infection, the WD-fed K18 mice lost significantly more body weight and had more severe lung inflammation than normal chow (NC)-fed mice. Bulk RNA-seq analysis of lungs and adipose tissue revealed a diverse landscape of various immune cells, inflammatory markers, and pathways upregulated in the infected WD-fed K18 mice when compared with the infected NC-fed control mice. The transcript levels of IL-6, an important marker of COVID-19 disease severity, were upregulated in the lung at 6-9 days post-infection in the WD-fed mice when compared to NC-fed mice. Transcriptome analysis of the lung and adipose tissue obtained from deceased COVID-19 patients found that the obese patients had an increase in the expression of genes and the activation of pathways associated with inflammation as compared to normal-weight patients (n = 2). The K18 mouse model and human COVID-19 patient data support a link between inflammation and an obesity-accelerated COVID-19 disease phenotype. These results also indicate that obesity-accelerated severe COVID-19 caused by SARS-CoV-2 WA1 infection in the K18 mouse model would be a suitable model for dissecting the cellular and molecular mechanisms underlying pathogenesis., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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25. Acute estradiol and progesterone therapy in hospitalized adults to reduce COVID-19 severity: a randomized control trial.
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Lovre D, Qadir MMF, Bateman K, Saltzman LY, Sherman M, and Mauvais-Jarvis F
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- Humans, Female, Male, Middle Aged, Adult, SARS-CoV-2 isolation & purification, Double-Blind Method, Severity of Illness Index, Aged, Length of Stay, Treatment Outcome, Progesterone, Estradiol, COVID-19 Drug Treatment, COVID-19, Hospitalization
- Abstract
COVID-19 outcomes are less severe in women than men suggesting that female sex is protective. The steroids estradiol (E2) and progesterone (P4) promote anti-inflammatory immune responses and their therapeutic use for COVID-19 has been under investigation. The aim of the study was to evaluate the efficacy of a short systemic E2 and P4 combination in mitigating COVID-19 severity in hospitalized men and women. In a phase 2, single center, double blind, randomized placebo-controlled trial, ten male and female participants hospitalized for COVID-19 with scores 3-5 on the 9-point WHO ordinal scale were randomized to receive either (1) E2 cypionate (5 mg, IM) and micronized P4 (200 mg, PO), or (2) placebo-equivalent, in addition to standard of care (SOC). The primary outcome was the proportion of patients whose WHO scores improved to 1-2 on the day of discharge. Secondary outcomes included length of hospital stay (LOS), days on oxygen therapy (DOT), readmission rates (RR), adverse events (AEs), and change in circulating biomarkers using untargeted proteomics and cytokine profiling. There were no significant changes between the groups in primary outcome, LOS, DOT, RR or AEs. The E2P4 group exhibited a decrease in biomarker pathways of respiratory and gastrointestinal disease inflammation, infection by coronavirus, and immune cell trafficking and inflammatory response. A short-term E2P4 treatment in patients hospitalized for COVID-19 decreases biomarkers of inflammation. Considering the availability, low cost, and safety of E2 and P4, our results warrant additional studies to explore their effects in mitigating other viral pandemics. Clinical Trial Registration NCT04865029, ClinicalTrials.gov; (First trial registration 29/04/2021)., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
- Published
- 2024
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26. Metabolic benefits afforded by estradiol and testosterone in both sexes: clinical considerations.
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Mauvais-Jarvis F and Lindsey SH
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- Humans, Male, Female, Insulin Resistance, Sex Characteristics, Aging metabolism, Muscle, Skeletal metabolism, Animals, Testosterone metabolism, Estradiol metabolism
- Abstract
Testosterone (T) and 17β-estradiol (E2) are produced in male and female humans and are potent metabolic regulators in both sexes. When E2 and T production stops or decreases during aging, metabolic dysfunction develops and promotes degenerative metabolic and vascular disease. Here, we discuss the shared benefits afforded by E2 and T for metabolic function human females and males. In females, E2 is central to bone and vascular health, subcutaneous adipose tissue distribution, skeletal muscle insulin sensitivity, antiinflammatory immune function, and mitochondrial health. However, T also plays a role in female skeletal, vascular, and metabolic health. In males, T's conversion to E2 is fundamental to bone and vascular health, as well as prevention of excess visceral adiposity and the promotion of insulin sensitivity via activation of the estrogen receptors. However, T and its metabolite dihydrotestosterone also prevent excess visceral adiposity and promote skeletal muscle growth and insulin sensitivity via activation of the androgen receptor. In conclusion, T and E2 are produced in both sexes at sex-specific concentrations and provide similar and potent metabolic benefits. Optimizing levels of both hormones may be beneficial to protect patients from cardiometabolic disease and frailty during aging, which requires further study.
- Published
- 2024
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27. Sex differences in circulating metabolites across glycemic status and risk of coronary heart disease.
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Yoshida Y, Li D, Li X, Fonseca VA, Qi L, and Mauvais-Jarvis F
- Abstract
Background: Women with type 2 diabetes (T2D) have a 50% excess risk of coronary heart disease (CHD) than men with T2D. We compared circulating metabolites and their associations with CHD in men and women across glycemic status., Methods: We used metabolomic data (lipoproteins, fatty acids, amino acids, glycolysis, ketones, inflammation, and fluid balance) for 87,326 CHD-free UK Biobank participants. We used linear regressions to examine the association of sex and metabolites (log) in newly diagnosed T2D (diagnosis<2 yrs from baseline), prediabetes (A1c 5.7-6.5%), and euglycemia, accounting for age, race, Deprivation Index, income, smoking, alcohol drinking, obesity, physical activity, medications for hypertension, hyperlipidemia, and diabetes. We used Cox models to evaluate the association of metabolites and CHD risk by sex, adjusting the same covariates and menopausal status (women). All analyses were FDR-adjusted., Findings: We included 1250 individuals with new T2D, 12,706 with prediabetes, and 83,315 with euglycemia. In adjusted linear regressions, women showed a progressive increase in atherogenic lipid and lipoprotein markers and inflammatory marker, glycoprotein acetyls, compared to men as their glycemic status advanced. However, women had lower levels of albumin during this transition. Menopausal status did not alter these sex differences. In a 10-year follow-up, an SD higher total TG, TG in VLDL, LDL, and HDL, saturated fatty acids (SFA) were positively associated with a higher risk of CHD in women with T2D but not in men (p-interactions 0.03-0.15)., Interpretation: With advancing glycemic status, women exhibited higher levels of atherogenic lipids and lipoproteins, as well as inflammatory markers, but lower circulating albumin. Women with T2D appear to be at a higher risk of CHD associated with TG, VLDL-TG, LDL-TG, and HDL-TG, and SFA than men with T2D.
- Published
- 2024
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28. Single cell regulatory architecture of human pancreatic islets suggests sex differences in β cell function and the pathogenesis of type 2 diabetes.
- Author
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Qadir MMF, Elgamal RM, Song K, Kudtarkar P, Sakamuri SSVP, Katakam PV, El-Dahr SS, Kolls JK, Gaulton KJ, and Mauvais-Jarvis F
- Abstract
Type 2 and type 1 diabetes (T2D, T1D) exhibit sex differences in insulin secretion, the mechanisms of which are unknown. We examined sex differences in human pancreatic islets from 52 donors with and without T2D combining single cell RNA-seq (scRNA-seq), single nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq), hormone secretion, and bioenergetics. In nondiabetic (ND) donors, sex differences in islet cells gene accessibility and expression predominantly involved sex chromosomes. Islets from T2D donors exhibited similar sex differences in sex chromosomes differentially expressed genes (DEGs), but also exhibited sex differences in autosomal genes. Comparing β cells from T2D vs. ND donors, gene enrichment of female β cells showed suppression in mitochondrial respiration, while male β cells exhibited suppressed insulin secretion. Thus, although sex differences in gene accessibility and expression of ND β cells predominantly affect sex chromosomes, the transition to T2D reveals sex differences in autosomes highlighting mitochondrial failure in females., Competing Interests: Declaration of interests: The authors declare no conflict of interest
- Published
- 2024
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29. Testosterone deficiency promotes arterial stiffening independent of sex chromosome complement.
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Sakamuri A, Visniauskas B, Kilanowski-Doroh I, McNally AB, Imulinde A, Kamau A, Sengottaian D, McLachlan J, Anguera M, Mauvais-Jarvis F, Lindsey SH, and Ogola BO
- Subjects
- Animals, Male, Mice, Mice, Inbred C57BL, Blood Pressure, Orchiectomy, Testosterone blood, Testosterone pharmacology, Vascular Stiffness, Sex Chromosomes
- Abstract
Background: Sex hormones and sex chromosomes play a vital role in cardiovascular disease. Testosterone plays a crucial role in men's health. Lower testosterone level is associated with cardiovascular and cardiometabolic diseases, including inflammation, atherosclerosis, and type 2 diabetes. Testosterone replacement is beneficial or neutral to men's cardiovascular health. Testosterone deficiency is associated with cardiovascular events. Testosterone supplementation to hypogonadal men improves libido, increases muscle strength, and enhances mood. We hypothesized that sex chromosomes (XX and XY) interaction with testosterone plays a role in arterial stiffening., Methods: We used four core genotype male mice to understand the inherent contribution of sex hormones and sex chromosome complement in arterial stiffening. Age-matched mice were either gonadal intact or castrated at eight weeks plus an additional eight weeks to clear endogenous sex hormones. This was followed by assessing blood pressure, pulse wave velocity, echocardiography, and ex vivo passive vascular mechanics., Results: Arterial stiffening but not blood pressure was more significant in castrated than testes-intact mice independent of sex chromosome complement. Castrated mice showed a leftward shift in stress-strain curves and carotid wall thinning. Sex chromosome complement (XX) in the absence of testosterone increased collagen deposition in the aorta and Kdm6a gene expression., Conclusion: Testosterone deprivation increases arterial stiffening and vascular wall remodeling. Castration increases Col1α1 in male mice with XX sex chromosome complement. Our study shows decreased aortic contractile genes in castrated mice with XX than XY sex chromosomes., (© 2024. The Author(s).)
- Published
- 2024
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30. UBR1 Promotes Sex-Dependent ACE2 Ubiquitination in Hypertension.
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Elgazzaz M, Lakkappa N, Berdasco C, Mohan UP, Nuzzo A, Restivo L, Martinez A, Scarborough A, Guidry JJ, Sriramula S, Xu J, Daoud H, Mendiola Plá MA, Bowles DE, Beyer AM, Mauvais-Jarvis F, Yue X, Filipeanu CM, and Lazartigues E
- Abstract
Background: Angiotensin (Ang)-II impairs the function of the antihypertensive enzyme ACE2 by promoting its internalization, ubiquitination and degradation thus contributing to hypertension. However, few ACE2 ubiquitination partners have been identified and their role in hypertension remains unknown., Methods: Proteomics and bioinformatic analysis were used to identify ACE2 ubiquitination partners in the brain, heart, and kidney from Ang-II-infused C57BL6/J mice from both sexes and validated the interaction between UBR1 and ACE2 in cells. Central and peripheral UBR1 knockdown was then performed in male mice to investigate its role in the maintenance of hypertension., Results: Proteomics analysis from hypothalamus identified UBR1 as a potential E3 ligase promoting ACE2 ubiquitination. Enhanced UBR1 expression, associated with ACE2 reduction, was confirmed in various tissues from hypertensive male mice and human samples. Treatment of endothelial and smooth muscle cells with testosterone, but not 17β-estradiol, confirmed a sex-specific regulation of UBR1. In vivo silencing of UBR1 using chronic administration of small interference RNA resulted in the restoration of ACE2 levels in hypertensive males. A transient decrease in blood pressure following intracerebroventricular, but not systemic, infusion was also observed. Interestingly, UBR1 knockdown increased the brain activation of Nedd4-2, an E3 ligase promoting ACE2 ubiquitination and reduced expression of SGK1, the kinase inactivating Nedd4-2. Conclusions: These data demonstrate that UBR1 is a novel ubiquitin ligase targeting ACE2 in hypertension. UBR1 and Nedd4-2 E3 ligases appear to work synergistically to ubiquitinate ACE2. Targeting of these ubiquitin ligases may represent a novel strategy to restore ACE2 compensatory activity in hypertension.
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- 2024
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31. Maternal Western diet programs cardiometabolic dysfunction and hypothalamic inflammation via epigenetic mechanisms predominantly in the male offspring.
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Elgazzaz M, Berdasco C, Garai J, Baddoo M, Lu S, Daoud H, Zabaleta J, Mauvais-Jarvis F, and Lazartigues E
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- Pregnancy, Female, Humans, Mice, Animals, Male, Diet, Western, Mice, Inbred C57BL, Epigenesis, Genetic, Hypothalamus metabolism, Inflammation genetics, Inflammation metabolism, Glucose metabolism, Diabetes Mellitus, Type 2 metabolism, Prenatal Exposure Delayed Effects genetics, Prenatal Exposure Delayed Effects metabolism, Hyperglycemia metabolism, MicroRNAs genetics, MicroRNAs metabolism, Hypertension, Cardiovascular Diseases metabolism
- Abstract
Objective: Maternal exposure during pregnancy is a strong determinant of offspring health outcomes. Such exposure induces changes in the offspring epigenome resulting in gene expression and functional changes. In this study, we investigated the effect of maternal Western hypercaloric diet (HCD) programming during the perinatal period on neuronal plasticity and cardiometabolic health in adult offspring., Methods: C57BL/6J dams were fed HCD for 1 month prior to mating with regular diet (RD) sires and kept on the same diet throughout pregnancy and lactation. At weaning, offspring were maintained on either HCD or RD for 3 months resulting in 4 treatment groups that underwent cardiometabolic assessments. DNA and RNA were extracted from the hypothalamus to perform whole genome methylation, mRNA, and miRNA sequencing followed by bioinformatic analyses., Results: Maternal programming resulted in male-specific hypertension and hyperglycemia, with both males and females showing increased sympathetic tone to the vasculature. Surprisingly, programmed male offspring fed HCD in adulthood exhibited lower glucose levels, less insulin resistance, and leptin levels compared to non-programmed HCD-fed male mice. Hypothalamic genes involved in inflammation and type 2 diabetes were targeted by differentially expressed miRNA, while genes involved in glial and astrocytic differentiation were differentially methylated in programmed male offspring. These data were supported by our findings of astrogliosis, microgliosis and increased microglial activation in programmed males in the paraventricular nucleus (PVN). Programming induced a protective effect in male mice fed HCD in adulthood, resulting in lower protein levels of hypothalamic TGFβ2, NF-κB2, NF-κBp65, Ser-pIRS1, and GLP1R compared to non-programmed HCD-fed males. Although TGFβ2 was upregulated in male mice exposed to HCD pre- or post-natally, only blockade of the brain TGFβ receptor in RD-HCD mice improved glucose tolerance and a trend to weight loss., Conclusions: Our study shows that maternal HCD programs neuronal plasticity in the offspring and results in male-specific hypertension and hyperglycemia associated with hypothalamic inflammation in mechanisms and pathways distinct from post-natal HCD exposure. Together, our data unmask a compensatory role of HCD programming, likely via priming of metabolic pathways to handle excess nutrients in a more efficient way., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Eric Lazartigues reports financial support was provided by American Diabetes Association. Franck Mauvais-Jarvis reports financial support was provided by National Institute of Health. Franck Mauvais-Jarvis reports financial support was provided by USDepartment of Veterans Affairs., (Published by Elsevier GmbH.)
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- 2024
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32. Sex differences in energy metabolism: natural selection, mechanisms and consequences.
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Mauvais-Jarvis F
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- Pregnancy, Adult, Humans, Female, Male, Energy Metabolism, Obesity, Glucose, Selection, Genetic, Lipids, Sex Characteristics, Placenta
- Abstract
Metabolic homeostasis operates differently in men and women. This sex asymmetry is the result of evolutionary adaptations that enable women to resist loss of energy stores and protein mass while remaining fertile in times of energy deficit. During starvation or prolonged exercise, women rely on oxidation of lipids, which are a more efficient energy source than carbohydrates, to preserve glucose for neuronal and placental function and spare proteins necessary for organ function. Carbohydrate reliance in men could be an evolutionary adaptation related to defence and hunting, as glucose, unlike lipids, can be used as a fuel for anaerobic high-exertion muscle activity. The larger subcutaneous adipose tissue depots in healthy women than in healthy men provide a mechanism for lipid storage. As female mitochondria have higher functional capacity and greater resistance to oxidative damage than male mitochondria, uniparental inheritance of female mitochondria may reduce the transmission of metabolic disorders. However, in women, starvation resistance and propensity to obesity have evolved in tandem, and the current prevalence of obesity is greater in women than in men. The combination of genetic sex, programming by developmental testosterone in males, and pubertal sex hormones defines sex-specific biological systems in adults that produce phenotypic sex differences in energy homeostasis, metabolic disease and drug responses., (© 2023. Springer Nature Limited.)
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- 2024
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33. Sex Differences in Cardiovascular Risk Associated With Prediabetes and Undiagnosed Diabetes.
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Yoshida Y, Chen Z, Fonseca VA, and Mauvais-Jarvis F
- Abstract
Introduction: Women with Type 2 diabetes (T2D) face up to 50% higher risk of cardiovascular disease than men. This study evaluated the extent to which prediabetes and undiagnosed T2D are associated with a greater excess risk of cardiovascular disease in women versus in men., Methods: Data were pooled from 18,745 cardiovascular disease-free individuals from the Atherosclerosis Risk in Communities Study, the Multi-Ethnic Study of Atherosclerosis, and the Jackson Heart Study. The risk of coronary heart disease, ischemic stroke, and atherosclerotic cardiovascular disease (coronary heart disease or stroke) associated with prediabetes or undiagnosed T2D was estimated using Cox models adjusting for sociodemographic factors, concomitant risk factors, medication use, and menopausal status. Data were collected in 2022, and the analysis was performed in 2023., Results: During a median follow-up of 18.6 years, the associations between prediabetes and risk of atherosclerotic cardiovascular disease were only significant in women (hazard ratio=1.18, 95% CI=1.01, 1.34, p=0.03) but not in men (hazard ratio=1.08, 95% CI=1.00, 1.28, p=0.06) (p-interaction=0.18). The associations between undiagnosed T2D and cardiovascular disease outcomes were significant in both sexes, but the effect was more pronounced in women (coronary heart disease: hazard ratio=1.83, 95% CI=1.4, 2.41, p<0.0001 in women vs hazard ratio=1.6, 95% CI=1.38, 2.07, p=0.007 in men; stroke: hazard ratio=1.99, 95% CI=1.39, 2.72, p<0.0001 vs hazard ratio=1.81, 95% CI=1.36, 2.6, p<0.0001; atherosclerotic cardiovascular disease: hazard ratio=1.86, 95% CI=1.5, 2.28, p<0.0001 vs hazard ratio=1.65, 95% CI=1.4, 1.98, p<0.0001) (all p-interactions≤0.2). Both White and Black patients exhibit similar sex differences., Conclusions: Prediabetes or undiagnosed T2D was associated with a greater excess risk of cardiovascular disease in women than in men. The sex differential in cardiovascular disease risk among those without the T2D diagnosis suggests the need for sex-specific guidelines in T2D screening and treatment., (Copyright © 2023 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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34. Testosterone Deficiency Promotes Arterial Stiffening Independent of Sex Chromosome Complement.
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Sakamuri A, Visniauskas B, Kilanowski-Doroh I, McNally A, Imulinde-Sugi A, Kamau A, Sengottaian D, McLachlan J, Anguera M, Mauvais-Jarvis F, Lindsey S, and Ogola BO
- Abstract
Background: Testosterone plays a vital role in men's health. Lower testosterone level is associated with cardiovascular and cardiometabolic diseases, including inflammation, atherosclerosis, and type 2 diabetes. Testosterone replacement is beneficial or neutral to men's cardiovascular health. Testosterone deficiency is associated with cardiovascular events. Testosterone supplementation to hypogonadal men improves libido, increases muscle strength, and enhances mood. We hypothesized that sex chromosomes (XX and XY) interaction with testosterone plays a role in arterial stiffening., Methods: We used four core genotype male mice to understand the inherent contribution of sex hormones and sex chromosome complement in arterial stiffening. Age-matched mice were either gonadal intact or castrated for eight weeks, followed by an assessment of blood pressure, pulse wave velocity, echocardiography, and ex vivo passive vascular mechanics., Results: Arterial stiffening but not blood pressure was more significant in castrated than testes-intact mice independent of sex chromosome complement. Castrated mice showed a leftward shift in stress-strain curves and carotid wall thinning. Sex chromosome complement (XX) in the absence of testosterone increased collagen deposition in the aorta and Kdm6a gene expression., Conclusion: Testosterone deprivation increases arterial stiffening and vascular wall remodeling. Castration increases Col1α1 in male mice with XX sex chromosome complement. Our study shows decreased aortic contractile genes in castrated mice with XX than XY sex chromosomes., Competing Interests: Competing interest The authors declare no conflict or competing interest.
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- 2023
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35. Sex differences in cardiometabolic biomarkers during the pre-diabetes stage.
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Yoshida Y, Chen Z, Fonseca VA, and Mauvais-Jarvis F
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- Humans, Male, Female, Prospective Studies, Sex Characteristics, Sex Factors, Biomarkers, Lipoproteins, Risk Factors, Prediabetic State complications, Heart Diseases complications, Cardiovascular Diseases epidemiology, Cardiovascular Diseases etiology
- Abstract
Using two large prospective epidemiological studies in the U.S., we examined biomarkers that reflect sex-specific pathophysiological pathways to cardiovascular complications among people with pre-diabetes. Women with pre-diabetes exhibited higher levels of adipokines, while men had lower eGFR. Sex differences in lipoproteins and vascular inflammatory markers during pre-diabetes indicate sex-specific lipoprotein and inflammatory mechanisms to cardiovascular complications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2023
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36. Sex-specific actions of estradiol and testosterone on human fibroblast and endothelial cell proliferation, bioenergetics, and vasculogenesis.
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Martier AT, Maurice YV, Conrad KM, Mauvais-Jarvis F, and Mondrinos MJ
- Abstract
Progress toward the development of sex-specific tissue engineered systems has been hampered by the lack of research efforts to define the effects of sex-specific hormone concentrations on relevant human cell types. Here, we investigated the effects of defined concentrations of estradiol (E2) and dihydrotestosterone (DHT) on primary human dermal and lung fibroblasts (HDF and HLF), and human umbilical vein endothelial cells (HUVEC) from female (XX) and male (XY) donors in both 2D expansion cultures and 3D stromal vascular tissues. Sex-matched E2 and DHT stimulation in 2D expansion cultures significantly increased the proliferation index, mitochondrial membrane potential, and the expression of genes associated with bioenergetics (Na+/K+ ATPase, somatic cytochrome C) and beneficial stress responses (chaperonin) in all cell types tested. Notably, cross sex hormone stimulation, i.e., DHT treatment of XX cells in the absence of E2 and E2 stimulation of XY cells in the absence of DHT, decreased bioenergetic capacity and inhibited cell proliferation. We used a microengineered 3D vasculogenesis assay to assess hormone effects on tissue scale morphogenesis. E2 increased metrics of vascular network complexity compared to vehicle in XX tissues. Conversely, and in line with results from 2D expansion cultures, E2 potently inhibited vasculogenesis compared to vehicle in XY tissues. DHT did not significantly alter vasculogenesis in XX or XY tissues but increased the number of non-participating endothelial cells in both sexes. This study establishes a scientific rationale and adaptable methods for using sex hormone stimulation to develop sex-specific culture systems.
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- 2023
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37. Estetrol Is Safe and Well Tolerated during Treatment of Hospitalized Men and Women with Moderate COVID-19 in a Randomized, Double-Blind Study.
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Foidart JM, Simon K, Utian WH, Mauvais-Jarvis F, Douxfils J, Dixon G, and Barrington P
- Abstract
Epidemiological data suggest that the severe acute respiratory syndrome coronavirus 2 infection rate is higher in women than in men, but the death rate is lower, while women (>50 years) on menopausal hormone therapy (MHT) have a higher survival rate than those not on MHT. Classical oral estrogen enhances the synthesis of coagulation markers and may increase the risk of thromboembolic events that are common in coronavirus disease 2019 (COVID-19). The favorable hemostatic profile of estetrol (E4) might be suitable for use in women who are receiving estrogen treatment and contract COVID-19. A multicenter, randomized, double-blind, placebo-controlled, phase 2 study (NCT04801836) investigated the efficacy, safety, and tolerability of E4 versus placebo in hospitalized patients with moderate COVID-19. Eligible postmenopausal women and men (aged ≥ 18 years old) were randomized to E4 15 mg or placebo, once daily for 21 days, in addition to the standard of care (SoC). The primary efficacy endpoint of improvement in COVID-19 (percentage of patients recovered at day 28) between the placebo and E4 arms was not met. E4 was well tolerated, with no safety signals or thromboembolic events, suggesting that postmenopausal women can safely continue E4-based therapy in cases of moderate COVID-19 managed with SoC.
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- 2023
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38. Architecture of androgen receptor pathways amplifying glucagon-like peptide-1 insulinotropic action in male pancreatic β cells.
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Xu W, Qadir MMF, Nasteska D, Mota de Sa P, Gorvin CM, Blandino-Rosano M, Evans CR, Ho T, Potapenko E, Veluthakal R, Ashford FB, Bitsi S, Fan J, Bhondeley M, Song K, Sure VN, Sakamuri SSVP, Schiffer L, Beatty W, Wyatt R, Frigo DE, Liu X, Katakam PV, Arlt W, Buck J, Levin LR, Hu T, Kolls J, Burant CF, Tomas A, Merrins MJ, Thurmond DC, Bernal-Mizrachi E, Hodson DJ, and Mauvais-Jarvis F
- Subjects
- Male, Mice, Humans, Animals, Glucagon-Like Peptide 1 metabolism, Adenylyl Cyclases metabolism, Receptors, Androgen metabolism, Insulin metabolism, Glucose pharmacology, Glucose metabolism, Testosterone, Peptide Fragments metabolism, Mammals metabolism, Insulin-Secreting Cells metabolism, Islets of Langerhans metabolism
- Abstract
Male mice lacking the androgen receptor (AR) in pancreatic β cells exhibit blunted glucose-stimulated insulin secretion (GSIS), leading to hyperglycemia. Testosterone activates an extranuclear AR in β cells to amplify glucagon-like peptide-1 (GLP-1) insulinotropic action. Here, we examined the architecture of AR targets that regulate GLP-1 insulinotropic action in male β cells. Testosterone cooperates with GLP-1 to enhance cAMP production at the plasma membrane and endosomes via: (1) increased mitochondrial production of CO
2 , activating the HCO3 - -sensitive soluble adenylate cyclase; and (2) increased Gαs recruitment to GLP-1 receptor and AR complexes, activating transmembrane adenylate cyclase. Additionally, testosterone enhances GSIS in human islets via a focal adhesion kinase/SRC/phosphatidylinositol 3-kinase/mammalian target of rapamycin complex 2 actin remodeling cascade. We describe the testosterone-stimulated AR interactome, transcriptome, proteome, and metabolome that contribute to these effects. This study identifies AR genomic and non-genomic actions that enhance GLP-1-stimulated insulin exocytosis in male β cells., Competing Interests: Declaration of interests F.M.-J. received an Investigator-Initiated Study award from Boehringer Ingelheim and Eli Lilly and consulting fees from Mithra Pharmaceutical, Inc. D.E.F. has received research funding from GTx, Inc and has familial relationships with Hummingbird Bioscience, Maia Biotechnology, Alms Therapeutics, Hinova Pharmaceuticals, and Barricade Therapeutics., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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39. Effect of menopausal hormone therapy on COVID-19 severe outcomes in women - A population-based study of the US National COVID Cohort Collaborative (N3C) data.
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Yoshida Y, Chu S, Zu Y, Fox S, and Mauvais-Jarvis F
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- Female, Humans, Estrogen Replacement Therapy, Progestins, Cross-Sectional Studies, Hormone Replacement Therapy, Estrogens, Menopause, COVID-19
- Abstract
Whether menopausal hormone therapy (MHT) lessens the severity of COVID-19 among women is unclear. Leveraging a U.S. national COVID-19 cohort and a cross-sectional analysis, we found MHT use was marginally associated with a lower risk of mortality (odds ratio [OR] 0.73, 95 % CI 0.53-1.01) and significantly associated with a lower risk of prolonged hospital stay (0.7, 0.49-0.99) among inpatient women. When stratifying by MHT type, estrogen-only and estrogen-plus-progestin therapies had a more prominent protective effect than progestin-only therapy, although this difference did not achieve statistical significance. Women with COVID-19 can continue to use MHT. Clinical trials are needed to evaluate MHT's therapeutic effect on COVID-19, especially in terms of severity., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2022. Published by Elsevier B.V.)
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- 2023
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40. Rising Prediabetes, Undiagnosed Diabetes, and Risk Factors in Young Women.
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Yoshida Y, Wang J, Zu Y, Fonseca VA, and Mauvais-Jarvis F
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- Adult, Middle Aged, Male, Female, Humans, Nutrition Surveys, Risk Factors, Obesity complications, Prevalence, Prediabetic State diagnosis, Prediabetic State epidemiology, Hypercholesterolemia diagnosis, Hypercholesterolemia epidemiology, Hypercholesterolemia complications, Diabetes Mellitus diagnosis, Diabetes Mellitus epidemiology, Hypertension complications, Hypertriglyceridemia epidemiology, Hypertriglyceridemia complications
- Abstract
Introduction: Women of reproductive age are less prone to cardiovascular disease than men. However, diabetes mellitus negates this female advantage. The prevalence change of prediabetes (prediabetes mellitus) and diabetes mellitus and diabetes mellitus‒associated cardiovascular risk factors have not been clearly described in women before menopause., Methods: Using National Health and Nutrition Examination Survey data (1999-2018), this study estimated the age-adjusted prevalence of prediabetes mellitus (2005-2018), diagnosed diabetes mellitus, and undiagnosed diabetes mellitus in premenopausal women. Logistic regression was used to examine cardiovascular risk factors, including obesity, central obesity, hypercholesterolemia, hypertension, and hypertriglyceridemia, associated with prediabetes mellitus, diagnosed diabetes mellitus, or undiagnosed diabetes mellitus in premenopausal women. The magnitude of the association among age-matched men and postmenopausal women was compared. The analysis was conducted in 2022., Results: Premenopausal women experienced an increased prevalence of prediabetes mellitus and undiagnosed diabetes mellitus, contrasting with steady trends in all U.S. adults over the last 2 decades. Premenopausal women with prediabetes mellitus or diabetes mellitus (versus those with normoglycemia) have significant obesity risk, and the risk is equivalent to that among age-matched men and higher than that among postmenopausal women. The association between prediabetes mellitus and hypercholesterolemia or hypertriglyceridemia was significant in premenopausal women only. Hypercholesterolemia and hypertension associated with undiagnosed diabetes mellitus were significant in premenopausal women and men of the same age, respectively. Diagnosed and undiagnosed diabetes mellitus was associated with hypertriglyceridemia in men and postmenopausal women, respectively., Conclusions: Premenopausal women had increased prediabetes mellitus and undiagnosed diabetes mellitus in the past 2 decades. They face a considerable cardiovascular risk burden associated with prediabetes mellitus and diabetes mellitus. Cardiometabolic risk screening and patient education should be improved in young and early middle-aged adults, particularly in women., (Copyright © 2022 American Journal of Preventive Medicine. All rights reserved.)
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- 2023
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41. Association Between Metabolic Syndrome Inflammatory Biomarkers and COVID-19 Severity.
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Pham TT, Zu Y, Ghamsari F, Oh J, Mauvais-Jarvis F, Zheng H, Filbin M, and Denson JL
- Abstract
Context: Metabolic syndrome (MetS) is associated with increased risk of severe COVID-19. MetS inflammatory biomarkers share similarities with those of COVID-19, yet this association is poorly explored., Objective: Biomarkers of COVID-19 patients with and without MetS, the combination of diabetes, hypertension, obesity, and/or dyslipidemia, were analyzed to identify biological predictors of COVID-19 severity., Methods: In this prospective observational study, at a large academic emergency department in Boston, Massachusetts, clinical and proteomics data were analyzed from March 24 to April 30, 2020. Patients age ≥18 with a clinical concern for COVID-19 upon arrival and acute respiratory distress were included. The main outcome was severe COVID-19 as defined using World Health Organization COVID-19 outcomes scores ≤4, which describes patients who died, required invasive mechanical ventilation, or required supplemental oxygen., Results: Among 155 COVID-19 patients, 90 (58.1%) met the definition of MetS and 65 (41.9%) were identified as Control. The MetS cohort was more likely to have severe COVID-19 compared with the Control cohort (OR 2.67 [CI 1.09-6.55]). Biomarkers, including CXCL10 (OR 1.94 [CI 1.38-2.73]), CXCL9 (OR 1.79 [CI 1.09-2.93]), HGF (OR 3.30 [CI 1.65-6.58]), and IL6 (OR 2.09 [CI 1.49-2.94]) were associated with severe COVID-19. However, when stratified by MetS, only CXCL10 (OR 2.39 [CI 1.38-4.14]) and IL6 (OR 3.14 [CI 1.53-6.45]) were significantly associated with severe COVID-19., Conclusions: MetS-associated severe COVID-19 is characterized by an immune signature of elevated levels of CXCL10 and IL6. Clinical trials targeting CXCL10 or IL6 antagonism in this population may be warranted., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2023
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42. Sex differences in prognostic role of fasting glucose, Oral glucose tolerance, and HbA1c in diabetic cardiovascular disease.
- Author
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Yoshida Y, Chen Z, Baudier RL, Krousel-Wood M, Anderson AH, Fonseca VA, and Mauvais-Jarvis F
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- Humans, Female, Male, Glucose Tolerance Test, Glycated Hemoglobin, Glucose, Prognosis, Sex Characteristics, Blood Glucose, Fasting, Cardiovascular Diseases diagnosis, Diabetes Mellitus
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- 2023
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43. Sex hormones, sex chromosomes, and microbiota: Identification of Akkermansia muciniphila as an estrogen-responsive microbiota.
- Author
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Sakamuri A, Bardhan P, Tummala R, Mauvais-Jarvis F, Yang T, Joe B, and Ogola BO
- Abstract
Microbiota composition is known to be linked to sex. However, separating sex hormones and sex chromosome roles in gut microbial diversity is yet to be determined. To investigate the sex chromosome role independent of sex hormones, we used the four-core genotype mouse model. In this mouse model, males with testes and females with ovaries have XX or XY sex chromosome complement. In gonadectomized four-core genotype mice, we observed a significant decrease in the levels of estradiol (P<0.001) and progesterone (P<0.03) in female and testosterone (P<0.0001) in male mice plasma samples. Independent of sex chromosome complement, microbial α diversity was increased in gonadectomized female but not male mice compared to sex-matched gonad-intact controls. β diversity analysis showed separation between male (P<0.05) but not female XX and XY mice. Importantly, Akkermansia muciniphila was less abundant in gonadectomized compared to gonadal intact female mice (P<0.0001). In the presence of β-estradiol, Akkermansia muciniphila growth exponentially increased, providing evidence for the identification of a female sex hormone-responsive bacterium (P<0.001)., Competing Interests: Declaration of interest Bina Joe is the Editor-in-Chief of Microbiota and Host. Bina Joe was not involved in the review or editorial process for this paper, on which she is listed as an author. The authors declare no conflict or competing interest.
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- 2023
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44. Gender differences in health protective behaviours and its implications for COVID-19 pandemic in Taiwan: a population-based study.
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Tan J, Yoshida Y, Ma KS, Mauvais-Jarvis F, and Lee CC
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- Child, Female, Humans, Male, Middle Aged, SARS-CoV-2, Sex Factors, Taiwan epidemiology, COVID-19, Pandemics prevention & control
- Abstract
Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection produces more severe symptoms and a higher mortality in men than in women. The role of biological sex in the immune response to SARS-CoV-2 is believed to explain this sex disparity. However, the contribution of gender factors that influence health protective behaviors and therefore health outcomes, remains poorly explored., Methods: We assessed the contributions of gender in attitudes towards the COVID-19 pandemic, using a hypothetical influenza pandemic data from the 2019 Taiwan Social Change Survey. Participants were selected through a stratified, three-stage probability proportional-to-size sampling from across the nation, to fill in questionnaires that asked about their perception of the hypothetical pandemic, and intention to adopt health protective behaviors., Results: A total of 1,990 participants (median age = 45·92 years, 49% were women) were included. Significant gender disparities (p < .001) were observed. The risk perception of pandemic (OR = 1·28, 95% CI [1·21 - 1·35], p < .001), older age (OR = 1·06, 95% CI [1·05 - 1·07], p < .001), female gender (OR = 1·18, 95% CI [1·09-1·27], p < .001), higher education (OR = 1·10, 95% CI [1·06 - 1·13], p < .001), and larger family size (OR = 1·09, 95% CI [1·06 - 1·15], p < .001) were positively associated with health protective behaviors. The risk perception of pandemic (OR = 1·25, 95% CI [1·15 - 1·36]), higher education (OR = 1·07, 95% CI [1·02 - 1·13], p < .05), being married (OR = 1·17, 95% CI [1·01-1·36, p < .05), and larger family size (OR = 1·33, 95% CI [1·25 - 1·42], p < .001), were positively associated with intention to receive a vaccine. However, female gender was negatively associated with intention to receive a vaccine (OR = 0·85, 95% CI [0·75 - 0·90], p < ·01) and to comply with contact-tracing (OR = 0·95, 95% CI [0·90 - 1·00], p < .05) compared to men. Living with children was also negatively associated with intention to receive vaccines (OR = 0·77, 95% CI [0·66 - 0·90], p < .001)., Conclusion: This study unveils gender differences in risk perception, health protective behaviors, vaccine hesitancy, and compliance with contact-tracing using a hypothetical viral pandemic. Gender-specific health education raising awareness of health protective behaviors may be beneficial to prevent future pandemics., (© 2022. The Author(s).)
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- 2022
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45. Sex differences in determinants of COVID-19 severe outcomes - findings from the National COVID Cohort Collaborative (N3C).
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Yoshida Y, Chu S, Fox S, Zu Y, Lovre D, Denson JL, Miele L, and Mauvais-Jarvis F
- Subjects
- Adult, Biomarkers, C-Reactive Protein analysis, Female, Ferritins, Humans, Male, Natriuretic Peptide, Brain, Procalcitonin, Retrospective Studies, Sex Characteristics, COVID-19 epidemiology
- Abstract
Objective: The impact of comorbidities and biomarkers on COVID-19 severity vary by sex but have not yet been verified in population-based studies. We examined the association of comorbidities, inflammatory biomarkers, and severe outcomes in men and women hospitalized for COVID-19., Design: This is a retrospective cohort analysis based on the National COVID Cohort Collaborative (N3C). We included 574,391 adult patients admitted for COVID-19 at hospitals or emergency rooms between 01/01/2020 and 12/31/2021., Methods: We defined comorbidities at or before the first admission for COVID-19 by Charlson Comorbidity Index (CCI) and CCI components. We used the averaged lab values taken within 15 days before or after the admission date to measure biomarkers including c-reactive protein (CRP), ferritin, procalcitonin, N-terminal pro b-type natriuretic peptide (NT proBNP), d-dimer, absolute lymphocyte counts, absolute neutrophil counts, and platelets. Our primary outcome was all-cause mortality; secondary outcomes were invasive mechanical ventilation (IMV) and hospital length of stay (LOS). We used logistic regression adjusted for age, race, ethnicity, visit type, and medications to assess the association of comorbidities, biomarkers, and mortality disaggregating by sex., Results: Moderate to severe liver disease, renal disease, metastatic solid tumor, and myocardial infarction were the top four fatal comorbidities among patients who were hospitalized for COVID-19 (adjusted odds ratio [aOR] > 2). These four comorbid conditions remained the most lethal in both sexes, with a higher magnitude of risk in women than in men (p-interaction < 0.05). Abnormal elevations of CRP, ferritin, procalcitonin, NT proBNP, neutrophil, and platelet counts, and lymphocytopenia were significantly associated with the risk of death, with procalcitonin and NT proBNP as the strongest predictors (aOR > 2). The association between the abnormal biomarkers and death was stronger in women than in men (p-interaction < 0.05)., Conclusion: There are sex differences in inpatient mortality associated with comorbidities and biomarkers. The significant impact of these clinical determinants in women with COVID-19 may be underappreciated as previous studies stressed the increased death rate in male patients that is related to comorbidities or inflammation. Our study highlights the importance and the need for sex-disaggregated research to understand the risk factors of poor outcomes and health disparities in COVID-19., (© 2022. The Author(s).)
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- 2022
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46. Membrane-Initiated Estrogen, Androgen, and Progesterone Receptor Signaling in Health and Disease.
- Author
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Mauvais-Jarvis F, Lange CA, and Levin ER
- Subjects
- Androgens, Estradiol, Estrogens, Humans, Progesterone physiology, Receptors, Androgen, Steroids, Receptors, Progesterone metabolism, Receptors, Steroid metabolism
- Abstract
Rapid effects of steroid hormones were discovered in the early 1950s, but the subject was dominated in the 1970s by discoveries of estradiol and progesterone stimulating protein synthesis. This led to the paradigm that steroid hormones regulate growth, differentiation, and metabolism via binding a receptor in the nucleus. It took 30 years to appreciate not only that some cellular functions arise solely from membrane-localized steroid receptor (SR) actions, but that rapid sex steroid signaling from membrane-localized SRs is a prerequisite for the phosphorylation, nuclear import, and potentiation of the transcriptional activity of nuclear SR counterparts. Here, we provide a review and update on the current state of knowledge of membrane-initiated estrogen (ER), androgen (AR) and progesterone (PR) receptor signaling, the mechanisms of membrane-associated SR potentiation of their nuclear SR homologues, and the importance of this membrane-nuclear SR collaboration in physiology and disease. We also highlight potential clinical implications of pathway-selective modulation of membrane-associated SR., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2022
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47. Sex Differences in the Progression of Metabolic Risk Factors in Diabetes Development.
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Yoshida Y, Chen Z, Baudier RL, Krousel-Wood M, Anderson AH, Fonseca VA, and Mauvais-Jarvis F
- Subjects
- Female, Humans, Male, Risk Factors, Sex Characteristics, Diabetes Mellitus epidemiology, Diabetes Mellitus etiology, Metabolic Syndrome
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- 2022
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48. Efficacy of glucagon-like peptide-1 and estrogen dual agonist in pancreatic islets protection and pre-clinical models of insulin-deficient diabetes.
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Fuselier T, Mota de Sa P, Qadir MMF, Xu B, Allard C, Meyers MM, Tiano JP, Yang BS, Gelfanov V, Lindsey SH, Dimarchi RD, and Mauvais-Jarvis F
- Subjects
- Animals, Estrogen Receptor alpha metabolism, Estrogens metabolism, Glucagon-Like Peptide 1 pharmacology, Insulin metabolism, Insulin, Regular, Human metabolism, Mice, Proteomics, Streptozocin toxicity, Diabetes Mellitus metabolism, Islets of Langerhans metabolism
- Abstract
We study the efficacy of a glucagon-like peptide-1 (GLP-1) and estrogen dual agonist (GLP1-E2) in pancreatic islet protection. GLP1-E2 provides superior protection from insulin-deficient diabetes induced by multiple low-dose streptozotocin (MLD-STZ-diabetes) and by the Akita mutation in mice than a GLP-1 monoagonist. GLP1-E2 does not protect from MLD-STZ-diabetes in estrogen receptor-α (ERα)-deficient mice and fails to prevent diabetes in Akita mice following GLP-1 receptor (GLP-1R) antagonism, demonstrating the requirement of GLP-1R and ERα for GLP1-E2 antidiabetic actions. In the MIN6 β cell model, GLP1-E2 activates estrogen action following clathrin-dependent, GLP-1R-mediated internalization and lysosomal acidification. In cultured human islet, proteomic bioinformatic analysis reveals that GLP1-E2 amplifies the antiapoptotic pathways activated by monoagonists. However, in cultured mouse islets, GLP1-E2 provides antiapoptotic protection similar to monoagonists. Thus, GLP1-E2 promotes GLP-1 and E2 antiapoptotic signals in cultured islets, but in vivo , additional GLP1-E2 actions in non-islet cells expressing GLP-1R are instrumental to prevent diabetes., Competing Interests: F.M.J. received consulting fees from Mithra Pharmaceutical, Inc. R.D. received research funding and is a cofounder of Marcadia biotech. R.D. has a conflict that pertains to IP at Indiana University and its license to Marcadia Biotech with Patents #9,127,088 and #9,783,592 related to this work. Other authors declare no competing financial interest., (© 2022 The Author(s).)
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- 2022
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49. Menopausal hormone therapy and risk of cardiovascular events in women with prediabetes or type 2 diabetes: A pooled analysis of 2917 postmenopausal women.
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Yoshida Y, Chen Z, Baudier RL, Krousel-Wood M, Anderson AH, Fonseca VA, and Mauvais-Jarvis F
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- Female, Humans, Menopause, Postmenopause, Prospective Studies, Risk Assessment, Risk Factors, Cardiovascular Diseases epidemiology, Coronary Disease, Diabetes Mellitus, Type 2 diagnosis, Diabetes Mellitus, Type 2 epidemiology, Prediabetic State diagnosis, Prediabetic State epidemiology
- Abstract
Background and Aims: The effect of MHT on cardiovascular disease (CVD) risk among women with prediabetes or type 2 diabetes (PreDM or T2DM) is unclear. We examined the association between ever or early use MHT and CVD risk in postmenopausal women with PreDM or T2DM, and the potential modifying effect of race., Methods: 2,917 postmenopausal women with PreDM or T2DM were pooled from 3 prospective CVD cohorts (the Atherosclerosis Risk in Communities, the Multi-Ethnic Study of Atherosclerosis, and the Jackson Heart Study). Ever (yes vs no) or early use of MHT (MHT initiated ≤5 vs > 5 years since menopause), and their associations with ischemic stroke, coronary heart disease (CHD), and atherosclerotic cardiovascular disease (ASCVD) were assessed using Cox proportional hazards models., Results: During a median follow-up of 15 years, 264 stroke, 484 CHD, and 659 ASCVD events were observed. In fully adjusted models, ever use of MHT was associated with reduced risk of stroke (hazard ratio 0.86, 95% CI 0.76-0.98), CHD (0.85, 0.74-0.98), and ASCVD (0.83, 0.73-0.95) in white women with PreDM or T2DM. Early use of MHT was associated with reduced risk of stroke (0.82, 0.72-0.95), CHD (0.85, 0.74-0.98), and ASCVD (0.82, 0.70-0.96) in the white group. No risk reduction with ever or early use of MHT was found for black women with PreDM or T2DM., Conclusions: MHT is associated with statistically reduced CVD risk among white but not black women with PreDM or DM. Race is an effect modifier in the association between MHT use and CVD., (Copyright © 2022 Elsevier B.V. All rights reserved.)
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- 2022
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50. Prolonged Islet Allograft Function is Associated With Female Sex in Patients After Islet Transplantation.
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Lemos JRN, Baidal DA, Poggioli R, Fuenmayor V, Chavez C, Alvarez A, Linetsky E, Mauvais-Jarvis F, Ricordi C, and Alejandro R
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- Adult, Female, Glycated Hemoglobin analysis, Humans, Male, Middle Aged, Retrospective Studies, Sex Characteristics, Transplantation, Homologous, Diabetes Mellitus, Type 1 surgery, Graft Survival, Islets of Langerhans Transplantation, Tissue Donors
- Abstract
Background: Islet transplantation (ITx) has proved to be effective in preventing severe hypoglycemia and improving metabolic control in selected subjects with type 1 diabetes. Long-term graft function remains a challenge. Estrogens have been shown to protect β cells from metabolic stresses and improve revascularization of transplanted human islets in the mouse. We aimed to evaluate the influence of sex in allograft survival of ITx recipients., Methods: We analyzed a retrospective cohort of ITx recipients (n = 56) followed-up for up to 20 years. Allograft failure was defined as a stimulated C-peptide <0.3 ng/mL during a mixed-meal tolerance test. Subjects were divided into recipients of at least 1 female donor (group 1) and recipients of male donors only (group 2)., Results: Group 1 subjects (n = 25) were aged 41.5 ± 8.4 years and group 2 subjects (n = 22) 45.9 ± 7.3 years (P = 0.062). Female recipient frequency was 44.8% (n = 13) in group 1 and 55.2% (n = 16) in group 2 (P = 0.145). Group 2 developed graft failure earlier than group 1 (680 [286-1624] vs 1906 [756-3256] days, P = 0.038). We performed additional analyses on female recipients only from each group (group 1, n = 16; group 2, n = 20). Female recipients in group 1 exhibited prolonged allograft function compared with group 2, after adjustment for confounders (odds ratio, 28.6; 95% CI, 1.3-619.1; P < 0.05)., Conclusion: Recipients of islets from at least 1 female donor exhibited prolonged graft survival compared with recipients of islets from exclusively male donors. In addition, female recipients exhibited prolonged survival compared with male recipients following ITx of at least 1 female donor., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2022
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