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      Sex Hormone-Binding Globulin (SHBG) as an Early Biomarker and Therapeutic Target in Polycystic Ovary Syndrome

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          Abstract

          Human sex hormone-binding globulin (SHBG) is a glycoprotein produced by the liver that binds sex steroids with high affinity and specificity. Clinical observations and reports in the literature have suggested a negative correlation between circulating SHBG levels and markers of non-alcoholic fatty liver disease (NAFLD) and insulin resistance. Decreased SHBG levels increase the bioavailability of androgens, which in turn leads to progression of ovarian pathology, anovulation and the phenotypic characteristics of polycystic ovarian syndrome (PCOS). This review will use a case report to illustrate the inter-relationships between SHBG, NAFLD and PCOS. In particular, we will review the evidence that low hepatic SHBG production may be a key step in the pathogenesis of PCOS. Furthermore, there is emerging evidence that serum SHBG levels may be useful as a diagnostic biomarker and therapeutic target for managing women with PCOS.

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          Mechanisms of Insulin Action and Insulin Resistance

          The 1921 discovery of insulin was a Big Bang from which a vast and expanding universe of research into insulin action and resistance has issued. In the intervening century, some discoveries have matured, coalescing into solid and fertile ground for clinical application; others remain incompletely investigated and scientifically controversial. Here, we attempt to synthesize this work to guide further mechanistic investigation and to inform the development of novel therapies for type 2 diabetes (T2D). The rational development of such therapies necessitates detailed knowledge of one of the key pathophysiological processes involved in T2D: insulin resistance. Understanding insulin resistance, in turn, requires knowledge of normal insulin action. In this review, both the physiology of insulin action and the pathophysiology of insulin resistance are described, focusing on three key insulin target tissues: skeletal muscle, liver, and white adipose tissue. We aim to develop an integrated physiological perspective, placing the intricate signaling effectors that carry out the cell-autonomous response to insulin in the context of the tissue-specific functions that generate the coordinated organismal response. First, in section II, the effectors and effects of direct, cell-autonomous insulin action in muscle, liver, and white adipose tissue are reviewed, beginning at the insulin receptor and working downstream. Section III considers the critical and underappreciated role of tissue crosstalk in whole body insulin action, especially the essential interaction between adipose lipolysis and hepatic gluconeogenesis. The pathophysiology of insulin resistance is then described in section IV. Special attention is given to which signaling pathways and functions become insulin resistant in the setting of chronic overnutrition, and an alternative explanation for the phenomenon of ‟selective hepatic insulin resistanceˮ is presented. Sections V, VI, and VII critically examine the evidence for and against several putative mediators of insulin resistance. Section V reviews work linking the bioactive lipids diacylglycerol, ceramide, and acylcarnitine to insulin resistance; section VI considers the impact of nutrient stresses in the endoplasmic reticulum and mitochondria on insulin resistance; and section VII discusses non-cell autonomous factors proposed to induce insulin resistance, including inflammatory mediators, branched-chain amino acids, adipokines, and hepatokines. Finally, in section VIII, we propose an integrated model of insulin resistance that links these mediators to final common pathways of metabolite-driven gluconeogenesis and ectopic lipid accumulation.
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            Adolescence: a foundation for future health

            Adolescence is a life phase in which the opportunities for health are great and future patterns of adult health are established. Health in adolescence is the result of interactions between prenatal and early childhood development and the specific biological and social-role changes that accompany puberty, shaped by social determinants and risk and protective factors that affect the uptake of health-related behaviours. The shape of adolescence is rapidly changing-the age of onset of puberty is decreasing and the age at which mature social roles are achieved is rising. New understandings of the diverse and dynamic effects on adolescent health include insights into the effects of puberty and brain development, together with social media. A focus on adolescence is central to the success of many public health agendas, including the Millennium Development Goals aiming to reduce child and maternal mortality and HIV/AIDS, and the more recent emphases on mental health, injuries, and non-communicable diseases. Greater attention to adolescence is needed within each of these public health domains if global health targets are to be met. Strategies that place the adolescent years centre stage-rather than focusing only on specific health agendas-provide important opportunities to improve health, both in adolescence and later in life. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic Complications

              Obesity is a critical risk factor for the development of type 2 diabetes (T2D), and its prevalence is rising worldwide. White adipose tissue (WAT) has a crucial role in regulating systemic energy homeostasis. Adipose tissue expands by a combination of an increase in adipocyte size (hypertrophy) and number (hyperplasia). The recruitment and differentiation of adipose precursor cells in the subcutaneous adipose tissue (SAT), rather than merely inflating the cells, would be protective from the obesity-associated metabolic complications. In metabolically unhealthy obesity, the storage capacity of SAT, the largest WAT depot, is limited, and further caloric overload leads to the fat accumulation in ectopic tissues (e.g., liver, skeletal muscle, and heart) and in the visceral adipose depots, an event commonly defined as “lipotoxicity.” Excessive ectopic lipid accumulation leads to local inflammation and insulin resistance (IR). Indeed, overnutrition triggers uncontrolled inflammatory responses in WAT, leading to chronic low-grade inflammation, therefore fostering the progression of IR. This review summarizes the current knowledge on WAT dysfunction in obesity and its associated metabolic abnormalities, such as IR. A better understanding of the mechanisms regulating adipose tissue expansion in obesity is required for the development of future therapeutic approaches in obesity-associated metabolic complications.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                01 November 2020
                November 2020
                : 21
                : 21
                : 8191
                Affiliations
                [1 ]School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia
                [2 ]School of Medicine, University of Nottingham, Derby DE22 3DT, UK; richard.donnelly@ 123456nottingham.edu.uk
                Author notes
                [* ]Correspondence: Xianqin.Qu@ 123456uts.edu.au ; Tel.: +61-2-95147852
                Article
                ijms-21-08191
                10.3390/ijms21218191
                7663738
                33139661
                192e45ad-daca-445d-ad10-fe0c5d990d4a
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 01 October 2020
                : 28 October 2020
                Categories
                Review

                Molecular biology
                adolescents,hepatic lipogenesis,human sex hormone-binding globulin,insulin resistance,non-alcoholic fatty liver disease,polycystic ovary syndrome

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