The Role of Estrogen in Insulin Resistance
2021; Elsevier BV; Volume: 191; Issue: 9 Linguagem: Inglês
10.1016/j.ajpath.2021.05.011
ISSN1525-2191
AutoresMonica De Paoli, Alexander Zakharia, Geoff H. Werstuck,
Tópico(s)Retinoids in leukemia and cellular processes
ResumoInsulin 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. 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). 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.1White M.F. Insulin signaling in health and disease.Science. 2003; 302: 1710-1711Crossref PubMed Scopus (531) Google Scholar Insulin receptor substrates (IRSs) 1 to 4, as well as other cellular proteins, are targeted for phosphorylation by the activated IR.2Guo S. Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models to disease mechanisms.J Endocrinol. 2014; 220: T1-T23Crossref PubMed Scopus (9) Google Scholar 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.3Bansal 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.PLoS One. 2011; 6: 26225Crossref PubMed Scopus (41) Google Scholar 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.4Bouzakri 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.Cell Metab. 2006; 4: 89-96Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar 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.5Kumar A. Carrera A.C. New functions for PI3K in the control of cell division.Cell Cycle. 2007; 6: 1696-1698Crossref PubMed Scopus (19) Google Scholar Phosphatidylinositol(3,4,5)-trisphosphate, in turn, recruits intracellular molecules with pleckstrin homology (PH) domains, including 3-phosphoinositide–dependent protein kinase 1.6Kikani C.K. Dong L.Q. Liu F. “New”-clear functions of PDK1: beyond a master kinase?.J Cell Biochem. 2005; 96: 1157-1162Crossref PubMed Scopus (51) Google Scholar Activated 3-phosphoinositide–dependent protein kinase 1 phosphorylates phosphatidylinositol (3,4,5)-trisphosphate–bound Akt protein kinase at Y308 of the catalytic activation loop.6Kikani C.K. Dong L.Q. 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Hemmings B.A. PIKKing on PKB: regulation of PKB activity by phosphorylation.Curr Opin Cell Biol. 2009; 21: 256-261Crossref PubMed Scopus (168) Google Scholar 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,8Mîinea C.P. Sano H. Kane S. Sano E. Fukuda M. Peränen J. Lane W.S. Lienhard G.E. AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain.Biochem J. 2005; 391: 87-93Crossref PubMed Scopus (302) Google Scholar glycogen synthase kinase-3,9Hermida M.A. Dinesh Kumar J. Leslie N.R. GSK3 and its interactions with the PI3K/AKT/mTOR signalling network.Adv Biol Regul. 2017; 65: 5-15Crossref PubMed Scopus (172) Google Scholar and forkhead box O (FoxO) transcription factors10Tzivion G. Dobson M. Ramakrishnan G. FoxO transcription factors; regulation by AKT and 14-3-3 proteins.Biochim Biophys Acta. 2011; 1813: 1938-1945Crossref PubMed Scopus (449) Google Scholar (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.8Mîinea C.P. Sano H. Kane S. Sano E. Fukuda M. Peränen J. Lane W.S. Lienhard G.E. AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain.Biochem J. 2005; 391: 87-93Crossref PubMed Scopus (302) Google Scholar As a result, GLUT4 translocates to the plasma membrane, and increases glucose uptake.11Jaldin-Fincati J.R. Pavarotti M. Frendo-Cumbo S. Bilan P.J. Klip A. Update on GLUT4 vesicle traffic: a cornerstone of insulin action.Trends Endocrinol Metab. 2017; 28: 597-611Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar In the absence of insulin signaling, glycogen synthase kinase-3 phosphorylates and inhibits glycogen synthase.9Hermida M.A. Dinesh Kumar J. Leslie N.R. GSK3 and its interactions with the PI3K/AKT/mTOR signalling network.Adv Biol Regul. 2017; 65: 5-15Crossref PubMed Scopus (172) Google Scholar 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.9Hermida M.A. Dinesh Kumar J. Leslie N.R. GSK3 and its interactions with the PI3K/AKT/mTOR signalling network.Adv Biol Regul. 2017; 65: 5-15Crossref PubMed Scopus (172) Google Scholar 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.12Krycer J.R. Sharpe L.J. Luu W. Brown A.J. The Akt-SREBP nexus: cell signaling meets lipid metabolism.Trends Endocrinol Metab. 2010; 21: 268-276Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar 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.10Tzivion G. Dobson M. Ramakrishnan G. FoxO transcription factors; regulation by AKT and 14-3-3 proteins.Biochim Biophys Acta. 2011; 1813: 1938-1945Crossref PubMed Scopus (449) Google Scholar 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.13Schmoll D. Walker K.S. Alessi D.R. Grempler R. Burchell A. Guo S. Walther R. Unterman T.G. 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.J Biol Chem. 2000; 275: 36324-36333Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar,14Matsuzaki H. Daitoku H. Hatta M. Tanaka K. Fukamizu A. 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The role of estrogens in control of energy balance and glucose homeostasis.Endocr Rev. 2013; 34: 309-338Crossref PubMed Scopus (619) Google Scholar Furthermore, reductions in estrogens can significantly impact energy metabolism and general metabolic homeostasis. Organs and tissues involved in glucose metabolism both express and respond to inflammatory mediators.38Monteiro R. Teixeira D. Calhau C. Estrogen signaling in metabolic inflammation.Mediators Inflamm. 2014; 2014: 615917Crossref PubMed Scopus (93) Google Scholar The immune system is significantly influenced by metabolic stimuli and relies on energetic support by inducing catabolism and repressing anabolic processes induced by insulin.38Monteiro R. Teixeira D. Calhau C. Estrogen signaling in metabolic inflammation.Mediators Inflamm. 2014; 2014: 615917Crossref PubMed Scopus (93) Google Scholar Insulin resistance is associated with a low-grade inflammatory state, which may lead to an increased risk of cardiometabolic diseases.39de 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) InvestigatorsLow-grade chronic inflammation in the relationship between insulin sensitivity and cardiovascular disease (RISC) population: associations with insulin resistance and cardiometabolic risk profile.Diabetes Care. 2009; 32: 1295-1301Crossref PubMed Scopus (66) Google Scholar Estrogens are involved in the regulation of metabolic processes related to energy balance, and can influence inflammatory responses.39de Rooij S.R. Nijpels G. Nilsson P.M. Nolan J.J. Gabriel R. Bobbioni-Harsch E. Mingrone G. Dekker J.M. 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Increased systemic inflammation and altered distribution of T-cell subsets in postmenopausal women.PLoS One. 2020; 15: e0235174Crossref PubMed Scopus (6) Google Scholar These results are in accordance with other clinical studies that confirm the association between reduced levels of estrogens and an increased proinflammatory state.41Abu-Taha M. Rius C. Hermenegildo C. Noguera I. 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.J Immunol. 2009; 183: 1393-1402Crossref PubMed Scopus (114) Google Scholar,42Cushman M. Legault C. Barrett-Connor E. Stefanick M.L. Kessler C. Judd H.L. Sakkinen P.A. Tracy R.P. 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Role of estrogen in type 1 and type 2 diabetes mellitus: a review of clinical and preclinical data.Can J Diabetes. 2020; 44: 448-452Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar 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.45Santos 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.Steroids. 2016; 114: 16-24Crossref PubMed Scopus (11) Google Scholar 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.
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