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The Role of Estrogen in Insulin Resistance

A Review of Clinical and Preclinical Data
  • Monica De Paoli
    Affiliations
    Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada

    Department of Medicine, McMaster University, Hamilton, Ontario, Canada
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  • Alexander Zakharia
    Affiliations
    Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada

    Department of Medicine, McMaster University, Hamilton, Ontario, Canada
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  • Geoff H. Werstuck
    Correspondence
    Address correspondence to Geoff H. Werstuck, Ph.D., Thrombosis and Atherosclerosis Research Institute, 237 Barton St. E., Hamilton, ON, Canada L8L 2X2.
    Affiliations
    Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada

    Department of Medicine, McMaster University, Hamilton, Ontario, Canada
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      Insulin resistance results when peripheral tissues, including adipose, skeletal muscle, and liver, do not respond appropriately to insulin, causing the ineffective uptake of glucose. This represents a risk factor for the development of type 2 diabetes mellitus. Along with abdominal obesity, hypertension, high levels of triglycerides, and low levels of high-density lipoproteins, insulin resistance is a component of a condition known as the metabolic syndrome, which significantly increases the risk of developing cardiometabolic disorders. Accumulating evidence shows that biological sex has a major influence in the development of cardiometabolic disturbances, with females being more protected than males. This protection appears to be driven by female sex hormones (estrogens), as it tends to disappear with the onset of menopause but can be re-established with hormone replacement therapy. This review evaluates current knowledge on the protective role of estrogens in the relevant pathways associated with insulin resistance. The importance of increasing our understanding of sex as a biological variable in cardiometabolic research to promote the development of more effective preventative strategies is emphasized.
      The aim of this review is to summarize the current knowledge on the protective effect of estrogens in maintaining insulin sensitivity, with a specific focus on current preclinical studies. It provides an overview of insulin signaling, as well as its correlation with diabetes mellitus and cardiovascular diseases. The second part of the review specifically focuses on preclinical studies looking at the various insulin-sensitive tissues and delineates relevant pathways that might be influenced by estrogens (estradiol).

      Insulin: Mechanisms of Action

      Postprandial elevations in blood glucose concentration are sensed by pancreatic β-cells, which release insulin into the circulation. Circulating insulin binds to insulin receptors (IRs) that are expressed by virtually all mammalian cells (Figure 1). The IR is a heterotetrameric glycoprotein composed of two αβ dimers. Insulin binds to the α-subunits, inducing autophosphorylation at sites along the β-subunits. Autophosphorylation of Y1158, Y1160, and Y1162 is of particular significance as this activates the catalytic domain of the IR tyrosine kinase.
      • White M.F.
      Insulin signaling in health and disease.
      Insulin receptor substrates (IRSs) 1 to 4, as well as other cellular proteins, are targeted for phosphorylation by the activated IR.
      • Guo S.
      Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models to disease mechanisms.
      The IRSs are signaling adaptor proteins responsible for mediating interactions between the activated IR and components involved in the intracellular signal cascades, such as Src-homology 2 domain-containing cellular proteins.
      • Bansal P.
      • Wang S.
      • Liu S.
      • Xiang Y.-Y.
      • Lu W.-Y.
      GABA coordinates with insulin in regulating secretory function in pancreatic INS-1 b-cells.
      Despite the underlying homology of IRS isoforms, the functions of the major IRS proteins, IRS1 and IRS2, are distinct; IRS1 is necessary for insulin-mediated glucose uptake and metabolism, whereas IRS2 plays a role in the regulation of lipid metabolism.
      • Bouzakri K.
      • Zachrisson A.
      • Al-Khalili L.
      • Zhang B.B.
      • Koistinen H.A.
      • Krook A.
      • Zierath J.R.
      siRNA-based gene silencing reveals specialized roles of IRS-1/Akt2 and IRS-2/Akt1 in glucose and lipid metabolism in human skeletal muscle.
      Figure thumbnail gr1
      Figure 1Insulin associates with the extracellular α-subunits of the insulin receptor (IR), facilitating autophosphorylation of β-subunits, in turn activating the catalytic domain of the IR tyrosine kinase, which phosphorylates insulin receptor substrates (IRSs). IRS isoforms associate with the Src-homology 2 domain of class I phosphatidylinositol 3-kinase (CI-PI3K). CI-PI3K associates with Ras GTPase and is activated by Ras GTPase-mediated phosphorylation. Activation of CI-PI3K permits phosphatidylinositol(4,5)-bisphosphate (PIP2) phosphorylation to generate phosphatidylinositol(3,4,5)-trisphosphate (PIP3). PIP3 associates with the pleckstrin homology (PH) domain of 3-phosphoinositide–dependent protein kinase 1 (PDK1), thereby activating it and facilitating its subsequent phosphorylation of PIP3-bound Akt protein kinase. Mechanistic target of rapamycin (mTOR) serine/threonine kinase associated with rapamycin-insensitive companion of mTOR (rictor; mTOR complex 2) synergistically phosphorylates Akt to enhance its activation. Akt further facilitates insulin action via phosphorylation of Akt substrate of 160 kDa (pAS160), glycogen synthase kinase-3 (pGSK3), and forkhead box O (pFoxO) transcription factors, which function to increase glycogenesis and lipid biosynthesis and/or decrease gluconeogenesis. Image generated with BioRender.com (Toronto, ON, Canada).
      Src-homology 2 domain-containing cellular proteins that can associate with the IRS homologs include the class I phosphatidylinositol 3-kinase (PI3K) enzymes. Activated class I PI3K catalyzes the phosphorylation of the inositol ring in membrane-bound phosphatidylinositol(4,5)-bisphosphate to phosphatidylinositol(3,4,5)-trisphosphate.
      • Kumar A.
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      New functions for PI3K in the control of cell division.
      Phosphatidylinositol(3,4,5)-trisphosphate, in turn, recruits intracellular molecules with pleckstrin homology (PH) domains, including 3-phosphoinositide–dependent protein kinase 1.
      • Kikani C.K.
      • Dong L.Q.
      • Liu F.
      “New”-clear functions of PDK1: beyond a master kinase?.
      Activated 3-phosphoinositide–dependent protein kinase 1 phosphorylates phosphatidylinositol (3,4,5)-trisphosphate–bound Akt protein kinase at Y308 of the catalytic activation loop.
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      “New”-clear functions of PDK1: beyond a master kinase?.
      Synergistic activation of Akt by mechanistic target of rapamycin (mTOR) significantly enhances its kinase activity.
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      • Hemmings B.A.
      PIKKing on PKB: regulation of PKB activity by phosphorylation.
      mTOR is a serine/threonine kinase that can form complexes with regulatory-associated protein of mTOR (raptor) or rapamycin-insensitive companion of mTOR (rictor), forming mTOR complex 1 or mTOR complex 2, respectively. Notably, mTOR complex 2 is responsible for the full activation of Akt.
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      PIKKing on PKB: regulation of PKB activity by phosphorylation.
      The association of class I PI3K and IRS and the subsequent series of phosphorylation events are illustrated in Figure 1.
      Akt facilitates insulin action via phosphorylation of the protein Akt substrate of 160 kDa,
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      AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain.
      glycogen synthase kinase-3,
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      • Leslie N.R.
      GSK3 and its interactions with the PI3K/AKT/mTOR signalling network.
      and forkhead box O (FoxO) transcription factors
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      • Dobson M.
      • Ramakrishnan G.
      FoxO transcription factors; regulation by AKT and 14-3-3 proteins.
      (Figure 1). Akt-mediated phosphorylation of Akt substrate of 160 kDa inhibits its GTPase-activating protein activity, causing an increased concentration of GTP-bound Rab proteins that are involved in mediating vesicle translocation of glucose transporter protein (GLUT) 4 proteins.
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      AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain.
      As a result, GLUT4 translocates to the plasma membrane, and increases glucose uptake.
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      • Klip A.
      Update on GLUT4 vesicle traffic: a cornerstone of insulin action.
      In the absence of insulin signaling, glycogen synthase kinase-3 phosphorylates and inhibits glycogen synthase.
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      • Leslie N.R.
      GSK3 and its interactions with the PI3K/AKT/mTOR signalling network.
      However, in the presence of insulin, Akt-mediated phosphorylation of glycogen synthase kinase-3 inhibits its kinase activity, resulting in the activation of glycogen synthase, facilitating the storage of intracellular glucose as glycogen.
      • Hermida M.A.
      • Dinesh Kumar J.
      • Leslie N.R.
      GSK3 and its interactions with the PI3K/AKT/mTOR signalling network.
      The Akt-dependent inactivation of glycogen synthase kinase-3 also leads to the activation of sterol-regulatory element binding protein transcription factors, which promote the expression of factors involved in fatty acid and triglyceride biosynthesis.
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      The Akt-SREBP nexus: cell signaling meets lipid metabolism.
      The FoxO family of transcription factors (FoxO1, FoxO3, FoxO4, and FoxO6) contains three potential Akt phosphorylation motifs (RxRxxS/T), except for FoxO6, which lacks a phosphorylation site at the COOH-terminal.
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      FoxO transcription factors; regulation by AKT and 14-3-3 proteins.
      The FoxO family promotes the transcription of a variety of gene targets that are dependent on the specific cell type. In the liver, FoxO1 promotes the transcription of glucose-6-phosphatase, phosphoenolpyruvate carboxykinase, and pyruvate dehydrogenase kinase-4, specifically up-regulating gluconeogenesis.
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      Regulation of glucose-6-phosphatase gene expression by protein kinase Balpha and the forkhead transcription factor FKHR: evidence for insulin response unit-dependent and -independent effects of insulin on promoter activity.
      ,
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      Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation.
      Activation of IR down-regulates FoxO activity, thereby decreasing gluconeogenesis.
      To summarize, insulin-dependent IR activation leads to an increased glucose transport via GLUT translocation/activation, increased glycogenesis via activation of glycogen synthase, increased lipid biosynthesis associated with activation of sterol-regulatory element binding proteins, and decreased gluconeogenesis via diminished FoxO activity and enhanced sterol-regulatory element binding protein activity.

      Insulin Resistance, Mechanisms of Action, and Correlation with Diabetes and Cardiovascular Disease

      Insulin resistance is characterized by the inability of circulating insulin to effectively regulate the uptake and/or utilization of glucose by insulin-sensitive tissues and organs. In normal conditions, an increase in blood glucose levels stimulates insulin production from pancreatic β-cells, as well as the inhibition of glucose production in the liver. However, insulin-resistant individuals do not respond to this signaling process, and paradoxically show an increase in both hepatic glucose production and insulin secretion, which can induce or aggravate hyperglycemia.
      • Santoleri D.
      • Titchenell P.M.
      Resolving the paradox of hepatic insulin resistance.
      The factors that promote the emergence of insulin resistance include altered insulin signaling, hyperinsulinemia, hyperlipidemia, and obesity. These factors are also associated with chronic low-grade inflammation characteristic of type 2 diabetes mellitus.
      In addition to the regulation of blood glucose levels, insulin is also involved in the regulation of lipid metabolism, particularly in hepatic cells and adipocytes. In the liver, insulin resistance can increase lipogenesis, resulting in the development of nonalcoholic fatty liver disease.
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      • Titchenell P.M.
      Resolving the paradox of hepatic insulin resistance.
      Nonalcoholic fatty liver disease involves the accumulation of fat in the liver, and it is recognized as a central component of the metabolic syndrome.
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      17β-Estradiol ameliorates lipotoxicity-induced hepatic mitochondrial oxidative stress and insulin resistance.
      Impaired lipid metabolism results in the deposition of surplus lipids in nonadipose tissues, which impairs insulin signaling and promotes β-cell hyperplasia.
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      Overexpression of vesicle-associated membrane protein (VAMP) 3, but not VAMP2, protects glucose transporter (GLUT) 4 protein translocation in an in vitro model of cardiac insulin resistance.
      As a result, insulin resistance–induced β-cell glucolipotoxicity interferes with an effective insulin secretion response, further exacerbating insulin resistance as well as glucose and lipid regulation.
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      Overexpression of vesicle-associated membrane protein (VAMP) 3, but not VAMP2, protects glucose transporter (GLUT) 4 protein translocation in an in vitro model of cardiac insulin resistance.
      Obesity is another factor that is strongly associated with the development of insulin resistance, and fat distribution plays a determinant role in the pathogenesis. Specifically, the accumulation of visceral abdominal fat is considered a risk factor for metabolic syndrome and cardiovascular diseases (CVDs),
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      Sex differences in metabolic regulation and diabetes susceptibility.
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      Association between insulin resistance and the development of cardiovascular disease.
      and surgical reduction of visceral abdominal fat can significantly improve insulin sensitivity.
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      Sex differences in metabolic regulation and diabetes susceptibility.
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      Depot-specific hormonal characteristics of subcutaneous and visceral adipose tissue and their relation to the metabolic syndrome.
      Compromised insulin action and/or insulin secretion contributes to the development and sustenance of hyperglycemia, hyperlipidemia, hypertension, and obesity, which are all characteristic of metabolic syndrome.
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      The metabolic syndrome: insulin resistance.
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      Association between diabetes mellitus with metabolic syndrome and diabetic microangiopathy.
      The major consequence of metabolic syndrome is a significantly elevated risk of developing type 2 diabetes mellitus and/or CVDs.
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      Insulin resistance: review of the underlying molecular mechanisms.

      Overview of Sex Differences in Insulin Resistance

      Men are more susceptible to develop metabolic syndrome than premenopausal women; however, protection in women is significantly reduced when estrogen levels decrease.
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      Menopause and the metabolic syndrome: the Study of Women's Health Across the Nation.
      Consistent with these findings, when compared with premenopausal women, women after menopause and the respective age-matched men present with increased insulin resistance, as measured by homeostatic model assessment–insulin resistance.
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      Effects of age on insulin resistance and secretion in subjects without diabetes.
      Menopause is a potential risk factor for developing insulin resistance independent of age, likely due to the reduction in circulating estrogens.
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      Metabolic syndrome in menopause and associated factors: a meta-analysis.
      In support of this hypothesis, it has been shown that surgically induced menopause increases the risk of developing insulin resistance and metabolic syndrome.
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      • Hasan H.
      • De Souza L.R.
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      The effect of menopause on metabolic syndrome: cross-sectional results from the Canadian Longitudinal Study on Aging.
      Clinical studies show that post-menopausal women are more susceptible than premenopausal women to develop dyslipidemia, an increase in body weight (evaluated through body mass index and waist circumference), and impaired glucose tolerance (as shown by their levels of hyperinsulinemia and increased fasting glucose levels).
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      Metabolic syndrome in menopause and associated factors: a meta-analysis.
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      • Hasan H.
      • De Souza L.R.
      • Shirreff L.
      The effect of menopause on metabolic syndrome: cross-sectional results from the Canadian Longitudinal Study on Aging.
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      • Park J.
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      The effect of menopause on the metabolic syndrome among Korean women: the Korean National Health and Nutrition Examination Survey, 2001.
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      The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988-1994.
      Metabolic disturbances, such as insulin resistance, tend to dramatically increase with the onset of menopause, and estrogen replacement therapy significantly reduces the risk of metabolic syndrome.
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      Metabolic syndrome in menopause and associated factors: a meta-analysis.
      ,
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      • Lee J.
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      • Kang D.
      • Choi J.-Y.
      Associations of postmenopausal hormone therapy with metabolic syndrome among diabetic and non-diabetic women.
      However, there have been conflicting results regarding the effect of hormone replacement therapy (HRT) on glucose homeostasis and insulin sensitivity. These results can be explained by differences in the population examined, the type of hormonal regimen in HRT, differences in the way of administering HRT, as well as differences in measuring insulin sensitivity.
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      Effects of hormone replacement therapy on insulin resistance in postmenopausal diabetic women.
      Moreover, the timing of HRT matters; treatment with HRT in early menopausal women has beneficial effects compared with HRT started in established postmenopausal women, in whom hormone treatment has no effect or even detrimental effect in terms of glucose homeostasis and insulin sensitivity.
      • Gupte A.A.
      • Pownall H.J.
      • Hamilton D.J.
      Estrogen: an emerging regulator of insulin action and mitochondrial function.
      Despite these controversial results, a meta-analysis of the available data has shown that exogenous estrogen confers a significant improvement in insulin sensitivity and a reduction of new onset of diabetes in women receiving estrogen replacement therapy.
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      • Greyber E.
      • Buckley N.S.
      • Salpeter E.E.
      Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women.
      Consistent with these findings, a recently published cross-sectional analysis on the effect of hormonal replacement therapy on metabolic syndrome in Korean women with or without diabetes showed that estrogens significantly alleviate etiological factors of the metabolic syndrome in both groups.
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      • Lee J.
      • Shin A.
      • Park S.M.
      • Kang D.
      • Choi J.-Y.
      Associations of postmenopausal hormone therapy with metabolic syndrome among diabetic and non-diabetic women.
      Taken together, these studies highlight the protective role of estrogens in women's metabolic health, specifically with respect to distribution of body fat mass, mobilization of fatty acids, as well as the response to glucose by the various glucose-sensitive tissues and organs.
      • Adeyanju O.A.
      • Soetan O.A.
      • Soladoye A.O.
      • Olatunji L.A.
      Oral hormonal therapy with ethinylestradiol-levonorgestrel improves insulin resistance, obesity, and glycogen synthase kinase-3 independent of circulating mineralocorticoid in estrogen-deficient rats.
      ,
      • Mauvais-Jarvis F.
      • Clegg D.J.
      • Hevener A.L.
      The role of estrogens in control of energy balance and glucose homeostasis.
      Furthermore, reductions in estrogens can significantly impact energy metabolism and general metabolic homeostasis.

      Association between Insulin Resistance and Low-Grade Inflammatory State and the Role of Estrogens

      Organs and tissues involved in glucose metabolism both express and respond to inflammatory mediators.
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      • Teixeira D.
      • Calhau C.
      Estrogen signaling in metabolic inflammation.
      The immune system is significantly influenced by metabolic stimuli and relies on energetic support by inducing catabolism and repressing anabolic processes induced by insulin.
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      • Teixeira D.
      • Calhau C.
      Estrogen signaling in metabolic inflammation.
      Insulin resistance is associated with a low-grade inflammatory state, which may lead to an increased risk of cardiometabolic diseases.
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      • Dekker J.M.
      Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) Investigators
      Low-grade chronic inflammation in the relationship between insulin sensitivity and cardiovascular disease (RISC) population: associations with insulin resistance and cardiometabolic risk profile.
      Estrogens are involved in the regulation of metabolic processes related to energy balance, and can influence inflammatory responses.
      • de Rooij S.R.
      • Nijpels G.
      • Nilsson P.M.
      • Nolan J.J.
      • Gabriel R.
      • Bobbioni-Harsch E.
      • Mingrone G.
      • Dekker J.M.
      Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) Investigators
      Low-grade chronic inflammation in the relationship between insulin sensitivity and cardiovascular disease (RISC) population: associations with insulin resistance and cardiometabolic risk profile.
      Many inflammatory components, such as macrophages and monocytes, are activated by estrogen through estrogen receptors expressed in these cells.
      • de Rooij S.R.
      • Nijpels G.
      • Nilsson P.M.
      • Nolan J.J.
      • Gabriel R.
      • Bobbioni-Harsch E.
      • Mingrone G.
      • Dekker J.M.
      Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) Investigators
      Low-grade chronic inflammation in the relationship between insulin sensitivity and cardiovascular disease (RISC) population: associations with insulin resistance and cardiometabolic risk profile.
      Furthermore, there is an association between reduced levels of estrogen in post-menopausal women and an increased inflammatory state. Post-menopausal women have increased lymphocyte and monocyte counts, increased expression of proinflammatory cytokines, and increased senescent inflammatory cells, which is usually associated with an improper immunologic function, compared with premenopausal women.
      • Abildgaard J.
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      • Zhao Y.
      • Hartling H.J.
      • Pedersen A.T.
      • Lindegaard B.
      • Dam Nielsen S.
      Increased systemic inflammation and altered distribution of T-cell subsets in postmenopausal women.
      These results are in accordance with other clinical studies that confirm the association between reduced levels of estrogens and an increased proinflammatory state.
      • Abu-Taha M.
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      • Cerda-Nicolas J.-M.
      • Issekutz A.C.
      • Jose P.J.
      • Cortijo J.
      • Morcillo E.J.
      • Sanz M.-J.
      Menopause and ovariectomy cause a low grade of systemic inflammation that may be prevented by chronic treatment with low doses of estrogen or losartan.
      ,
      • Cushman M.
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      • Stefanick M.L.
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      • Sakkinen P.A.
      • Tracy R.P.
      Effect of postmenopausal hormones on inflammation-sensitive proteins: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Study.
      Taken together, these findings suggest that estrogens might protect from the development of insulin resistance by both modulating the metabolic processes involved in energy balance and down-regulating and/or repressing inflammation.

      Analysis of Sex Differences in Insulin Resistance Using Animal Models

      Several mouse models of insulin resistance have been generated, and an extensive description of their characteristics and associated advantages and disadvantages has been published in a review by Nandi et al.
      • Nandi A.
      • Kitamura Y.
      • Kahn C.R.
      • Accili D.
      Mouse models of insulin resistance.
      Ovariectomies are often performed in animal models to study the underlying mechanisms by which sexual dimorphisms affect biochemical processes.
      • De Paoli M.
      • Werstuck G.H.
      Role of estrogen in type 1 and type 2 diabetes mellitus: a review of clinical and preclinical data.
      This procedure results in a significant reduction in circulating estrogen levels and represents a viable option to study the impact of female sex hormones in metabolic disorders and insulin resistance in any animal model.
      • Santos R.S.
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      • Clegg D.J.
      • Carneiro E.M.
      Lacking of estradiol reduces insulin exocytosis from pancreatic β-cells and increases hepatic insulin degradation.
      Alternatively, treatment with exogenous sex hormones can be used to study the effects of increasing estrogen concentrations. In general, the results from experiments performed in such animal models appear to approximate observations from clinical studies in humans.

      Sex Differences in Insulin Resistance in the Pancreas

      Hyperinsulinemia is an early indicator of the development of insulin resistance. This condition is established when there is increased insulin secretion by pancreatic β-cells in response to increased blood glucose levels. Impaired lipid metabolism, induced by insulin resistance, leads to adaptive β-cell hyperplasia in a compensatory attempt to increase insulin production.
      • Ye R.
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      • Herz J.
      • Scherer P.E.
      Intracellular lipid metabolism impairs β cell compensation during diet-induced obesity.
      Hyperglycemic and hyperlipidemic conditions, along with a chronically increased demand for insulin, can significantly compromise the function and viability of β-cells.
      • van Raalte D.H.
      • Diamant M.
      Glucolipotoxicity and beta cells in type 2 diabetes mellitus: target for durable therapy?.
      Ovariectomized C57BL/6 mice develop impaired glucose tolerance when compared with sham-operated controls.
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      • Morato P.N.
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      • Wanschel A.C.B.A.
      • Clegg D.J.
      • Carneiro E.M.
      Lacking of estradiol reduces insulin exocytosis from pancreatic β-cells and increases hepatic insulin degradation.
      Total pancreatic β-cell insulin content, as well as glucose-stimulated insulin secretion from isolated pancreatic islets, is significantly lower in ovariectomized mice relative to their respective sham controls. Supplementation with exogenous estradiol rescues these effects.
      • Santos R.S.
      • Batista T.M.
      • Camargo R.L.
      • Morato P.N.
      • Borck P.C.
      • Leite N.C.
      • Kurauti M.A.
      • Wanschel A.C.B.A.
      • Clegg D.J.
      • Carneiro E.M.
      Lacking of estradiol reduces insulin exocytosis from pancreatic β-cells and increases hepatic insulin degradation.
      The Zucker diabetic fatty rat is a rodent model that presents with sexual dimorphism. Male obese rats become diabetic, and female counterparts remain normoglycemic.
      • De Paoli M.
      • Werstuck G.H.
      Role of estrogen in type 1 and type 2 diabetes mellitus: a review of clinical and preclinical data.
      Male Zucker diabetic fatty rats have a significant impairment in glucose-stimulated insulin secretion that can be remarkably improved with estradiol supplementation.
      • Tiano J.P.
      • Delghingaro-Augusto V.
      • Le May C.
      • Liu S.
      • Kaw M.K.
      • Khuder S.S.
      • Latour M.G.
      • Bhatt S.A.
      • Korach K.S.
      • Najjar S.M.
      • Prentki M.
      • Mauvais-Jarvis F.
      Estrogen receptor activation reduces lipid synthesis in pancreatic islets and prevents β cell failure in rodent models of type 2 diabetes.
      Male Zucker diabetic fatty rats treated with estradiol also have reduced levels of free fatty acids (FFAs) and triglycerides in the pancreatic islets, suggesting a reduction of lipotoxicity and β-cell failure.
      • Tiano J.P.
      • Delghingaro-Augusto V.
      • Le May C.
      • Liu S.
      • Kaw M.K.
      • Khuder S.S.
      • Latour M.G.
      • Bhatt S.A.
      • Korach K.S.
      • Najjar S.M.
      • Prentki M.
      • Mauvais-Jarvis F.
      Estrogen receptor activation reduces lipid synthesis in pancreatic islets and prevents β cell failure in rodent models of type 2 diabetes.
      Similar to the Zucker diabetic fatty rats, male New Zealand obese (NZO) mice develop overt diabetes when compared with their female counterparts, which remain normoglycemic.
      • De Paoli M.
      • Werstuck G.H.
      Role of estrogen in type 1 and type 2 diabetes mellitus: a review of clinical and preclinical data.
      Estrogen deficiency (ovariectomy) in the female NZO mice promotes the development of a diabetic phenotype, with mice showing impaired oral glucose tolerance, and a significant reduction of β-cell mass, when compared with sham-operated females.
      • Vogel H.
      • Mirhashemi F.
      • Liehl B.
      • Taugner F.
      • Kluth O.
      • Kluge R.
      • Joost H.-G.
      • Schürmann A.
      Estrogen deficiency aggravates insulin resistance and induces β-cell loss and diabetes in female New Zealand obese mice.
      The observed phenotype in ovariectomized female NZO mice is similar to what is observed in male NZO mice.
      • Vogel H.
      • Mirhashemi F.
      • Liehl B.
      • Taugner F.
      • Kluth O.
      • Kluge R.
      • Joost H.-G.
      • Schürmann A.
      Estrogen deficiency aggravates insulin resistance and induces β-cell loss and diabetes in female New Zealand obese mice.
      Ovariectomized NZO mice fed a high-fat and carbohydrate-free diet show significant body weight gain when compared with sham-operated female controls. Insulin levels are also significantly higher in the ovariectomized group when compared with sham controls, indicating that the loss of estrogens plays a role in the development of insulin resistance.
      • Vogel H.
      • Mirhashemi F.
      • Liehl B.
      • Taugner F.
      • Kluth O.
      • Kluge R.
      • Joost H.-G.
      • Schürmann A.
      Estrogen deficiency aggravates insulin resistance and induces β-cell loss and diabetes in female New Zealand obese mice.
      Consistent with these findings, glucose tolerance and insulin sensitivity are impaired in ovariectomized NZO females, compared with the sham-operated controls. Estrogen supplementation improves glucose tolerance, reduces fasting levels of insulinemia, and reduces insulin resistance (homeostatic model assessment–insulin resistance) assessments in ovariectomized Wistar rats, compared with the ovariectomized nonsupplemented controls.
      • Adeyanju O.A.
      • Soetan O.A.
      • Soladoye A.O.
      • Olatunji L.A.
      Oral hormonal therapy with ethinylestradiol-levonorgestrel improves insulin resistance, obesity, and glycogen synthase kinase-3 independent of circulating mineralocorticoid in estrogen-deficient rats.

      Sex Differences in Insulin Resistance in the Liver

      The liver plays an important role in glucose homeostasis as it is a central tissue for glucose production through both gluconeogenesis and glycogenolysis. Hepatic glucose production is mainly regulated by FoxO1, a transcription factor that promotes the expression of glucose-6-phosphatase.
      • O-Sullivan I.
      • Zhang W.
      • Wasserman D.H.
      • Liew C.W.
      • Liu J.
      • Paik J.
      • DePinho R.A.
      • Stolz D.B.
      • Kahn C.R.
      • Schwartz M.W.
      • Unterman T.G.
      FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization.
      Insulin signaling can attenuate hepatic glucose production by inhibiting FoxO1 via downstream Akt activation.
      • Matsuzaki H.
      • Daitoku H.
      • Hatta M.
      • Tanaka K.
      • Fukamizu A.
      Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation.
      In liver-specific FoxO1 knockout mice, glucose tolerance is impaired in both males and females, suggesting that FoxO1 plays an important role in modulating gluconeogenesis.
      • Yan H.
      • Yang W.
      • Zhou F.
      • Li X.
      • Pan Q.
      • Shen Z.
      • Han G.
      • Newell-Fugate A.
      • Tian Y.
      • Majeti R.
      • Liu W.
      • Xu Y.
      • Wu C.
      • Allred K.
      • Allred C.
      • Sun Y.
      • Guo S.
      Estrogen improves insulin sensitivity and suppresses gluconeogenesis via the transcription factor Foxo1.
      Treatment with estrogen pellets in liver-specific FoxO1 knockout males and ovariectomized females significantly improved glucose tolerance.
      • Yan H.
      • Yang W.
      • Zhou F.
      • Li X.
      • Pan Q.
      • Shen Z.
      • Han G.
      • Newell-Fugate A.
      • Tian Y.
      • Majeti R.
      • Liu W.
      • Xu Y.
      • Wu C.
      • Allred K.
      • Allred C.
      • Sun Y.
      • Guo S.
      Estrogen improves insulin sensitivity and suppresses gluconeogenesis via the transcription factor Foxo1.
      This suggests that estrogen may signal through the estrogen receptor-α present in hepatic cells. These results are consistent with other studies that show a protective effect of estrogen in terms of hepatic insulin resistance and glucose production by signaling through estrogen receptor-α.
      • Gao H.
      • Fält S.
      • Sandelin A.
      • Gustafsson J.-A.
      • Dahlman-Wright K.
      Genome-wide identification of estrogen receptor alpha-binding sites in mouse liver.
      • Qiu S.
      • Vazquez J.T.
      • Boulger E.
      • Liu H.
      • Xue P.
      • Hussain M.A.
      • Wolfe A.
      Hepatic estrogen receptor α is critical for regulation of gluconeogenesis and lipid metabolism in males.
      • Zhu L.
      • Brown W.C.
      • Cai Q.
      • Krust A.
      • Chambon P.
      • McGuinness O.P.
      • Stafford J.M.
      Estrogen treatment after ovariectomy protects against fatty liver and may improve pathway-selective insulin resistance.
      Male Wistar rats fed a high-fat diet develop insulin resistance, whereas females do not experience a significant induction.
      • Galmés-Pascual B.M.
      • Martínez-Cignoni M.R.
      • Morán-Costoya A.
      • Bauza-Thorbrügge M.
      • Sbert-Roig M.
      • Valle A.
      • Proenza A.M.
      • Lladó I.
      • Gianotti M.
      17β-Estradiol ameliorates lipotoxicity-induced hepatic mitochondrial oxidative stress and insulin resistance.
      Additionally male, but not female, Wistar rats accumulate hepatic lipid, a hallmark of nonalcoholic fatty liver disease, and have an impaired hepatic insulin response, as measured with homeostatic model assessment–insulin resistance. Lipogenesis also induces an increase in fatty acid synthesis, in turn causing an increase in triglycerides in the form of very-low-density lipoprotein.
      • Camporez J.P.
      • Lyu K.
      • Goldberg E.L.
      • Zhang D.
      • Cline G.W.
      • Jurczak M.J.
      • Dixit V.D.
      • Petersen K.F.
      • Shulman G.I.
      Anti-inflammatory effects of oestrogen mediate the sexual dimorphic response to lipid-induced insulin resistance.
      ,
      • Mittendorfer B.
      Insulin resistance: sex matters.
      The excess of circulating lipids can have detrimental effects on other tissues and promote CVDs. A study in C57BL/6 mice showed that ovariectomized mice fed a high-fat diet developed insulin resistance along with increased hepatic glucose and triglyceride production. Treatment with estradiol significantly improved insulin resistance and prevented triglyceride accumulation.
      • Camporez J.P.
      • Lyu K.
      • Goldberg E.L.
      • Zhang D.
      • Cline G.W.
      • Jurczak M.J.
      • Dixit V.D.
      • Petersen K.F.
      • Shulman G.I.
      Anti-inflammatory effects of oestrogen mediate the sexual dimorphic response to lipid-induced insulin resistance.
      Similarly, C57BL/6 mice treated with estradiol have reduced lipid accumulation and reduced insulin resistance when compared with untreated male controls.
      • Zhu L.
      • Brown W.C.
      • Cai Q.
      • Krust A.
      • Chambon P.
      • McGuinness O.P.
      • Stafford J.M.
      Estrogen treatment after ovariectomy protects against fatty liver and may improve pathway-selective insulin resistance.
      Finally, the concentration of circulating insulin is regulated by the degradation of hepatic insulin, primarily by the insulin-degrading enzyme in the liver. Enhanced insulin degradation can promote insulin resistance. Ovariectomized C57BL/6 mice present with higher insulin-degrading enzyme levels when compared with the sham controls. Exogenous estrogen supplementation significantly decreases insulin-degrading enzyme levels.
      • Santos R.S.
      • Batista T.M.
      • Camargo R.L.
      • Morato P.N.
      • Borck P.C.
      • Leite N.C.
      • Kurauti M.A.
      • Wanschel A.C.B.A.
      • Clegg D.J.
      • Carneiro E.M.
      Lacking of estradiol reduces insulin exocytosis from pancreatic β-cells and increases hepatic insulin degradation.

      Sex Differences in Insulin Resistance in the Adipose Tissue

      Estrogens can prevent the accumulation of visceral abdominal fat in premenopausal women, although this protection is lost following menopause.
      • Sam S.
      Differential effect of subcutaneous abdominal and visceral adipose tissue on cardiometabolic risk.
      Consistent with these findings, premenopausal obese women are less prone to develop insulin resistance and altered glucose tolerance than lean age-matched men, hinting that estrogen might exert its protective effect by influencing the pathways that control fat distribution.
      • Mittendorfer B.
      Insulin resistance: sex matters.
      • Jazet I.M.
      • Pijl H.
      • Meinders A.E.
      Adipose tissue as an endocrine organ: impact on insulin resistance.
      • Geer E.B.
      • Shen W.
      Gender differences in insulin resistance, body composition, and energy balance.
      It is now understood that adipose tissue is an endocrine organ and that adipocytes can directly regulate the pathways involved in energy homeostasis.
      • Jazet I.M.
      • Pijl H.
      • Meinders A.E.
      Adipose tissue as an endocrine organ: impact on insulin resistance.
      ,
      • Geer E.B.
      • Shen W.
      Gender differences in insulin resistance, body composition, and energy balance.
      Adipocytes of the intra-abdominal depot of C57BL/6 female mice are more insulin-sensitive than those of male mice as they have significantly enhanced activation of Akt and extracellular signal-regulated kinases compared with males, when stimulated with low doses of insulin.
      • Macotela Y.
      • Boucher J.
      • Tran T.T.
      • Kahn C.R.
      Sex and depot differences in adipocyte insulin sensitivity and glucose metabolism.
      Additionally, female adipocytes highly express genes involved in glucose and lipid metabolism compared with males.
      • Macotela Y.
      • Boucher J.
      • Tran T.T.
      • Kahn C.R.
      Sex and depot differences in adipocyte insulin sensitivity and glucose metabolism.
      Male and ovariectomized female C57BL/6J mice fed with high-fat diet present with insulin resistance, have increased adipocyte size, and are less protected from adipocyte oxidative stress compared with sham-operated females or ovariectomized females supplemented with estrogen.
      • Stubbins R.E.
      • Najjar K.
      • Holcomb V.B.
      • Hong J.
      • Núñez N.P.
      Oestrogen alters adipocyte biology and protects female mice from adipocyte inflammation and insulin resistance.

      Sex Differences in Insulin Resistance in the Skeletal Muscle

      Skeletal muscle plays a key role in insulin-stimulated glucose absorption: approximately 85% to 90% of all postprandial glucose uptake occurs at the skeletal muscle tissue.
      • DeFronzo R.A.
      • Jacot E.
      • Jequier E.
      • Maeder E.
      • Wahren J.
      • Felber J.P.
      The effect of insulin on the disposal of intravenous glucose: results from indirect calorimetry and hepatic and femoral venous catheterization.
      ,
      • Huang X.
      • Liu G.
      • Guo J.
      • Su Z.
      The PI3K/AKT pathway in obesity and type 2 diabetes.
      Therefore, this tissue is a significant contributor to the development of insulin resistance. Glucose and FFA are transported into skeletal muscle tissue via GLUT4 and CD36, respectively.
      • Abdul-Ghani M.A.
      • Defronzo R.A.
      Pathogenesis of insulin resistance in skeletal muscle.
      Hyperlipidemia has been shown to suppress CD36 translocation in skeletal muscle tissue, and consequently heightens the risk of type 2 diabetes mellitus because of impaired lipid metabolism and increased FFA concentration.
      • Hevener A.
      • Reichart D.
      • Janez A.
      • Olefsky J.
      Female rats do not exhibit free fatty acid–induced insulin resistance.
      Sex differences in insulin action have been investigated by Hevener et al
      • Hevener A.
      • Reichart D.
      • Janez A.
      • Olefsky J.
      Female rats do not exhibit free fatty acid–induced insulin resistance.
      using Wistar rats infused with a lipid emulsion (liposyn) to increase FFA levels. The liposyn infusion rate to attain a fourfold increase in FFA is approximately one-third higher among female rats when compared with males, indicating that female Wistar rats have a substantially greater FFA clearance compared with males.
      • Hevener A.
      • Reichart D.
      • Janez A.
      • Olefsky J.
      Female rats do not exhibit free fatty acid–induced insulin resistance.
      After liposyn infusion, IRS1 activation is decreased by 30% and class I PI3K activity is decreased by 48% among male rats when compared with female rats, suggesting the potential role of estrogens in improving insulin sensitivity.
      • Hevener A.
      • Reichart D.
      • Janez A.
      • Olefsky J.
      Female rats do not exhibit free fatty acid–induced insulin resistance.
      A potential determinant of sex differences in insulin resistance in the skeletal muscle tissue is through γABAB receptor impairment.
      • Bonaventura M.M.
      • Rodriguez D.
      • Ferreira M.L.
      • Crivello M.
      • Repetto E.M.
      • Bettler B.
      • Libertun C.
      • Lux-Lantos V.A.
      Sex differences in insulin resistance in GABAB1 knockout mice.
      γABAB receptor is crucial for the maintenance of glucose-stimulated insulin secretion and glucose homeostasis. Male BALB/c γABAB1R subunit knockout mice are more susceptible to insulin resistance in skeletal muscle tissue than female BALB/c γABAB1R subunit knockout mice.
      • Bonaventura M.M.
      • Rodriguez D.
      • Ferreira M.L.
      • Crivello M.
      • Repetto E.M.
      • Bettler B.
      • Libertun C.
      • Lux-Lantos V.A.
      Sex differences in insulin resistance in GABAB1 knockout mice.
      ,
      • Bonaventura M.M.
      • Catalano P.N.
      • Chamson-Reig A.
      • Arany E.
      • Hill D.
      • Bettler B.
      • Saravia F.
      • Libertun C.
      • Lux-Lantos V.A.
      GABAB receptors and glucose homeostasis: evaluation in GABAB receptor knockout mice.
      Mitochondrial dysfunction may play a role in the development of insulin resistance in the skeletal muscle. Male Wistar rats fed a high-fat diet have significantly more oxidative damage in their skeletal muscle tissues than females.
      • Gómez-Pérez Y.
      • Capllonch-Amer G.
      • Gianotti M.
      • Lladó I.
      • Proenza A.M.
      Long-term high-fat-diet feeding induces skeletal muscle mitochondrial biogenesis in rats in a sex-dependent and muscle-type specific manner.
      This is associated with higher mitochondrial biogenesis in males when compared with female controls as a way to compensate the deleterious effects of insulin resistance on oxidative metabolism.
      • Gómez-Pérez Y.
      • Capllonch-Amer G.
      • Gianotti M.
      • Lladó I.
      • Proenza A.M.
      Long-term high-fat-diet feeding induces skeletal muscle mitochondrial biogenesis in rats in a sex-dependent and muscle-type specific manner.
      Another study investigated the protective effects of estrogen in the skeletal muscle by measuring glucose uptake in the skeletal muscle tissue of male, female, and ovariectomized Sprague-Dawley rats.
      • Rattanavichit Y.
      • Chukijrungroat N.
      • Saengsirisuwan V.
      Sex differences in the metabolic dysfunction and insulin resistance of skeletal muscle glucose transport following high fructose ingestion.
      Autoradiographic analysis of glucose transport activity in soleus muscle strips from the legs of the experimental rats on a high-fructose diet revealed that the female rats had significantly greater glucose uptake in the skeletal muscle tissue compared with males or ovariectomized female rats, suggesting the presence of sex differences in skeletal muscle tissue insulin sensitivity.
      • Rattanavichit Y.
      • Chukijrungroat N.
      • Saengsirisuwan V.
      Sex differences in the metabolic dysfunction and insulin resistance of skeletal muscle glucose transport following high fructose ingestion.
      Additionally, females showed significantly greater insulin-stimulated activation of IRβ, IRS1 phosphorylation, Akt phosphorylation, and Akt substrate of 160 kDa phosphorylation when compared with males.
      • Rattanavichit Y.
      • Chukijrungroat N.
      • Saengsirisuwan V.
      Sex differences in the metabolic dysfunction and insulin resistance of skeletal muscle glucose transport following high fructose ingestion.
      This finding is supported by another study that observed a significant overexpression of GLUT4 among female Wistar rats fed a high-fat diet, when compared with male Wistar rats.
      • Gómez-Pérez Y.
      • Amengual-Cladera E.
      • Català-Niell A.
      • Thomàs-Moyà E.
      • Gianotti M.
      • Proenza A.M.
      • Lladó I.
      Gender dimorphism in high-fat-diet-induced insulin resistance in skeletal muscle of aged rats.
      A recent study further elaborated on the mechanism of sex differences in obesity-induced insulin resistance using male and female C57BL/6 mice fed either a high-fat diet or a regular chow diet.
      • Camporez J.P.
      • Lyu K.
      • Goldberg E.L.
      • Zhang D.
      • Cline G.W.
      • Jurczak M.J.
      • Dixit V.D.
      • Petersen K.F.
      • Shulman G.I.
      Anti-inflammatory effects of oestrogen mediate the sexual dimorphic response to lipid-induced insulin resistance.
      Increased insulin sensitivity in skeletal muscle and greater adiposity were associated with significantly greater glucose uptake among the female mice, thus consolidating previously discussed mechanisms of sex differences in insulin resistance in the skeletal muscle tissue.
      • Camporez J.P.
      • Lyu K.
      • Goldberg E.L.
      • Zhang D.
      • Cline G.W.
      • Jurczak M.J.
      • Dixit V.D.
      • Petersen K.F.
      • Shulman G.I.
      Anti-inflammatory effects of oestrogen mediate the sexual dimorphic response to lipid-induced insulin resistance.
      Furthermore, quantification of ectopic diacylglycerol and triacylglycerol levels by liquid chromatography–tandem mass spectrometry analysis revealed significant reductions in the skeletal muscle tissue of female mice, which is likely a result of unhindered FFA metabolism.
      • Camporez J.P.
      • Lyu K.
      • Goldberg E.L.
      • Zhang D.
      • Cline G.W.
      • Jurczak M.J.
      • Dixit V.D.
      • Petersen K.F.
      • Shulman G.I.
      Anti-inflammatory effects of oestrogen mediate the sexual dimorphic response to lipid-induced insulin resistance.
      Estradiol supplementation improved insulin sensitivity in the skeletal muscle tissue with associated enhanced IRS1 phosphorylation and Akt2 phosphorylation in both male and female mice.
      • Camporez J.P.
      • Lyu K.
      • Goldberg E.L.
      • Zhang D.
      • Cline G.W.
      • Jurczak M.J.
      • Dixit V.D.
      • Petersen K.F.
      • Shulman G.I.
      Anti-inflammatory effects of oestrogen mediate the sexual dimorphic response to lipid-induced insulin resistance.

      Sex Differences in Insulin Resistance in the Cardiac Tissue

      Insulin resistance is a main driving factor in the development of diabetic cardiomyopathy, a complication of diabetes that can lead to heart failure independent of other cardiovascular risk factors.
      • Jia G.
      • Whaley-Connell A.
      • Sowers J.R.
      Diabetic cardiomyopathy: a hyperglycaemia- and insulin-resistance-induced heart disease.
      The hallmark of diabetic cardiomyopathy is diastolic dysfunction.
      • Roedebusch R.
      • Belenchia A.
      • Pulakat L.
      Diabetic cardiomyopathy: impact of biological sex on disease development and molecular signatures.
      The effect of estrogen treatment on cardiac function in bilateral ovariectomized, insulin-resistant Wistar rats shows that cardiac ejection fraction and fractional shortening are significantly reduced among ovariectomized rats, indicating that loss of estrogens in an insulin-resistant background results in cardiac contractile dysfunction.
      • Sivasinprasasn S.
      • Tanajak P.
      • Pongkan W.
      • Pratchayasakul W.
      • Chattipakorn S.C.
      • Chattipakorn N.
      DPP-4 inhibitor and estrogen share similar efficacy against cardiac ischemic-reperfusion injury in obese-insulin resistant and estrogen-deprived female rats.
      Estrogen supplementation in these mice significantly attenuates cardiac autonomic dysfunction, restores systolic blood pressure, and improves cardiac contractile performance.
      • Sivasinprasasn S.
      • Tanajak P.
      • Pongkan W.
      • Pratchayasakul W.
      • Chattipakorn S.C.
      • Chattipakorn N.
      DPP-4 inhibitor and estrogen share similar efficacy against cardiac ischemic-reperfusion injury in obese-insulin resistant and estrogen-deprived female rats.
      Moreover, Western blot analysis indicates that ovariectomized rats treated with estrogen have significantly higher expression of B-cell lymphoma 2, an anti-apoptotic protein, while simultaneously decreasing expression of bcl-2–like protein 4, a pro-apoptotic protein, thereby highlighting the role of attenuating cardiomyocyte apoptosis among insulin-resistant rats.
      • Sivasinprasasn S.
      • Tanajak P.
      • Pongkan W.
      • Pratchayasakul W.
      • Chattipakorn S.C.
      • Chattipakorn N.
      DPP-4 inhibitor and estrogen share similar efficacy against cardiac ischemic-reperfusion injury in obese-insulin resistant and estrogen-deprived female rats.
      A protective role for estrogen in the attenuation of cardiac dysfunction and rescue of insulin action can be seen in studies performed in insulin-resistant H9c2 cardiomyocytes, db/db mice, and ovariectomized Wistar rats, whose results are consistent with the existence of female sex differences protecting against insulin resistance in cardiac tissue.
      • Sivasinprasasn S.
      • Tanajak P.
      • Pongkan W.
      • Pratchayasakul W.
      • Chattipakorn S.C.
      • Chattipakorn N.
      DPP-4 inhibitor and estrogen share similar efficacy against cardiac ischemic-reperfusion injury in obese-insulin resistant and estrogen-deprived female rats.
      ,
      • Zhang B.
      • Zhang J.
      • Zhang C.
      • Zhang X.
      • Ye J.
      • Kuang S.
      • Sun G.
      • Sun X.
      Notoginsenoside R1 protects against diabetic cardiomyopathy through activating estrogen receptor α and its downstream signaling.
      Additional clinical and preclinical research focusing primarily on sex differences in the pathology of insulin resistance in the cardiac tissue and the respective role of estrogen are needed to further our understanding of the extent of these effects.

      Sex Differences in Insulin Resistance in the Endothelium

      Insulin promotes endothelial nitric oxide production via signaling through the PI3K-Akt pathway. Nitric oxide induces the vasodilation of blood vessels, thereby increasing blood flow and glucose uptake by the various organs and tissues.
      • Vincent M.A.
      • Montagnani M.
      • Quon M.J.
      Molecular and physiologic actions of insulin related to production of nitric oxide in vascular endothelium.
      ,
      • Muniyappa R.
      • Quon M.J.
      Insulin action and insulin resistance in vascular endothelium.
      Nitric oxide also prevents leukocyte adhesion and platelet aggregation as well as smooth muscle cell proliferation.
      • Vincent M.A.
      • Montagnani M.
      • Quon M.J.
      Molecular and physiologic actions of insulin related to production of nitric oxide in vascular endothelium.
      ,
      • Muniyappa R.
      • Quon M.J.
      Insulin action and insulin resistance in vascular endothelium.
      Endothelial dysfunction is a feature of insulin resistance and is characterized by a reduced production of nitric oxide by endothelial cells, which can trigger the processes that lead to atherosclerosis and to the development of CVDs.
      • Zhang B.
      • Zhang J.
      • Zhang C.
      • Zhang X.
      • Ye J.
      • Kuang S.
      • Sun G.
      • Sun X.
      Notoginsenoside R1 protects against diabetic cardiomyopathy through activating estrogen receptor α and its downstream signaling.
      ,
      • Muniyappa R.
      • Quon M.J.
      Insulin action and insulin resistance in vascular endothelium.
      Several clinical trials have shown that post-menopausal women have significant endothelial dysfunction compared with premenopausal women, suggesting that depletion of estrogens might be detrimental to the endothelial vascular tissue.
      • Meadows J.L.
      • Vaughan D.E.
      Endothelial biology in the post-menopausal obese woman.
      • van Sloten T.T.
      • Henry R.M.
      • Dekker J.M.
      • Nijpels G.
      • Unger T.
      • Schram M.T.
      • Stehouwer C.D.
      Endothelial dysfunction plays a key role in increasing cardiovascular risk in type 2 diabetes.
      • Benjamin E.J.
      • Larson M.G.
      • Keyes M.J.
      • Mitchell G.F.
      • Vasan R.S.
      • Keaney J.F.
      • Lehman B.T.
      • Fan S.
      • Osypiuk E.
      • Vita J.A.
      Clinical correlates and heritability of flow-mediated dilation in the community: the Framingham Heart Study.
      Studies conducted in women with polycystic ovary syndrome, a condition characterized by hyperandrogenism where most patients present with insulin resistance, show significant alterations in endothelial function.
      • Paradisi G.
      • Steinberg H.O.
      • Hempfling A.
      • Cronin J.
      • Hook G.
      • Shepard M.K.
      • Baron A.D.
      Polycystic ovary syndrome is associated with endothelial dysfunction.
      ,
      • Dube R.
      Does endothelial dysfunction correlate with endocrinal abnormalities in patients with polycystic ovary syndrome?.
      These findings suggest that a reduction in estrogens along with insulin resistance could be detrimental and significantly increase the risk of developing CVDs.
      • Paradisi G.
      • Steinberg H.O.
      • Hempfling A.
      • Cronin J.
      • Hook G.
      • Shepard M.K.
      • Baron A.D.
      Polycystic ovary syndrome is associated with endothelial dysfunction.
      ,
      • Dube R.
      Does endothelial dysfunction correlate with endocrinal abnormalities in patients with polycystic ovary syndrome?.
      Research conducted on male insulin-resistant Zucker rats treated with estradiol showed a significant improvement in endothelial function by reducing vasoconstriction and increasing vasodilation responses as well as inducing nitric oxide synthase expression.
      • Brooks-Asplund E.M.
      • Shoukas A.A.
      • Kim S.-Y.
      • Burke S.A.
      • Berkowitz D.E.
      Estrogen has opposing effects on vascular reactivity in obese, insulin-resistant male Zucker rats.
      Consistent with these results, ovariectomized Wistar rats treated with estradiol showed a reduced vasoconstrictor response of mesenteric arteries compared with the ovariectomized Wistar rats without estrogen treatment.
      • Song D.
      • Yuen V.G.
      • Yao L.
      • McNeill J.H.
      Chronic estrogen treatment reduces vaso-constrictor responses in insulin resistant rats.

      Conclusion

      Insulin resistance is one of the main components of the metabolic syndrome, a condition that increases the risk of developing type 2 diabetes mellitus and cardiovascular diseases. Accumulating clinical and preclinical data suggest that sex differences in cardiometabolic risk do exist; however, this is still an underrepresented and understudied area of research. Estrogen seems to play a role on various insulin-sensitive tissues and organs by improving and/or modulating glucose homeostasis (Table 1).
      • Yan H.
      • Yang W.
      • Zhou F.
      • Li X.
      • Pan Q.
      • Shen Z.
      • Han G.
      • Newell-Fugate A.
      • Tian Y.
      • Majeti R.
      • Liu W.
      • Xu Y.
      • Wu C.
      • Allred K.
      • Allred C.
      • Sun Y.
      • Guo S.
      Estrogen improves insulin sensitivity and suppresses gluconeogenesis via the transcription factor Foxo1.
      Table 1Summary of the Protective Effects of Estrogens on Specific Organs and Tissues
      Organ/tissueEffects of estrogen
      Pancreas
      • Improves fasting insulinemia
      • Improves GSIS
      Liver
      • Modulates gluconeogenesis
      • Improves hepatic insulin response
      • Reduces hepatic insulin degradation
      Adipose tissue
      • Improves insulin sensitivity in adipocytes
      • Reduces adipocyte oxidative stress
      Skeletal muscle
      • Improves insulin-stimulated glucose absorption
      Cardiac tissue
      • Mitigates insulin resistance–induced cardiomyopathy
      • Improves cardiac function
      Vascular endothelium
      • Improves nitric oxide production
      • Increases vasodilation response
      GSIS, glucose-stimulated insulin secretion.
      However, the specific action in these organs and tissues as well as the underlying mechanisms and pathways are yet to be identified. This review summarizes current knowledge on the potential protective role of estrogen in the development of insulin resistance and its consequences. We acknowledge that there is a considerable gap in understanding the molecular mechanisms underlying how these protective effects are exerted, and more studies are needed to delineate these pathways. This highlights the importance of including sex as a biological variable in preclinical studies, as stated by the NIH’s mandate,
      • Miller L.R.
      • Marks C.
      • Becker J.B.
      • Hurn P.D.
      • Chen W.-J.
      • Woodruff T.
      • McCarthy M.M.
      • Sohrabji F.
      • Schiebinger L.
      • Wetherington C.L.
      • Makris S.
      • Arnold A.P.
      • Einstein G.
      • Miller V.M.
      • Sandberg K.
      • Maier S.
      • Cornelison T.L.
      • Clayton J.A.
      Considering sex as a biological variable in preclinical research.
      which will lead to a more detailed comprehension of the pathogenesis of cardiometabolic diseases and subsequently improve contemporary management and prevention of these conditions.

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