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  • Pulmonary function and sleep breathing: two new targets for type 2 diabetes care.
    Endocr. Rev. (IF 15.745) Pub Date : 2017-09-04
    Albert Lecube, Rafael Simó, Maria Pallayova, Naresh M Punjabi, Carolina López-Cano, Cecilia Turino, Cristina Hernández, Ferran Barbé

    Population based studies showing the negative impact of type 2 diabetes (T2D) on lung function are overviewed. Among the well-recognized pathophysiological mechanisms, the metabolic pathways related to insulin resistance, low-grade chronic inflammation, leptin resistance, microvascular damage, and autonomic neuropathy are emphasized. Histopathological changes are exposed, and findings reported from experimental models are clearly differentiated from those described in humans. The accelerated decline in pulmonary function that appears in patients with cystic fibrosis with related abnormalities of glucose tolerance and diabetes is considered as an example to further investigate the relationship between T2D and the lung. Furthermore, a possible causal link between antihyperglycemic therapies and pulmonary function is examined.

  • Taming the flames: targeting white adipose tissue browning in hypermetabolic conditions
    Endocr. Rev. (IF 15.745) Pub Date : 2017-08-30
    Abdikarim Abdullahi, Marc G Jeschke

    In this era of increased obesity and diabetes prevalence, the browning of white adipose tissue (WAT) has emerged as a promising therapeutic target to induce weight loss and improve insulin sensitivity in this population. The browning process entails a shift in the WAT from primarily storing excess energy to the dissipation of energy as heat. However, this idealistic view of WAT browning being the saviour of the metabolic syndrome has been criticized by studies in burns and cancer patients that have shown browning to be detrimental rather than being beneficial. In fact, in the context of hypermetabolic states the browning of WAT has presented with substantial clinical adverse outcomes related to cachexia, hepatic steatosis, and muscle catabolism. Therefore, the previous thought construct of understanding browning as an all-beneficial physiologic event has now been met with scepticism. In this review we focus on current knowledge of browning of WAT and its adverse metabolic alterations during hypermetabolic states. We also discuss the regulators and signaling pathways involved in the browning process and their potential for being targeted by new or existing drugs to inhibit or alleviate browning potentially leading to decreased hypermetabolism and improved clinical outcomes. Lastly, the imminent clinical applications of pharmacological agents are explored in the perspective of attenuating WAT browning and its associated adverse side effects reported in burn patients.

  • New Perspectives on Pheochromocytoma and Paraganglioma: Towards a Molecular Classification
    Endocr. Rev. (IF 15.745) Pub Date : 2017-08-04
    Joakim Crona, David Taïeb, Karel Pacak

    A new molecular biology based taxonomy has been proposed for pheochromocytoma and paraganglioma (PPGL). Data from the Cancer Genome Atlas revealed clinically relevant prognostic and predictive biomarkers and stratified PPGLs into three main clusters. Each subgroup has a distinct molecular-biochemical-imaging signature. Concurrently, new methods for biochemical analysis, functional imaging, and medical therapies have also become available. The research community now strives to match the cluster biomarkers with the most superior intervention. The concept of precision medicine has been long awaited, and holds great promise for improved care. Here, we review the current and future PPGL classifications with a focus on hereditary syndromes. We discuss the current strengths and shortcomings of precision medicine, and suggest a condensed manual for diagnosis and treatment of both adult and pediatric PPGL patients. Finally, we consider the future direction of this field, with a particular focus on how advanced molecular characterization of PPGL can improve a patient’s outcome, including cures, and ultimately, disease prevention.

  • Genetic causes of functional adrenocortical adenomas
    Endocr. Rev. (IF 15.745) Pub Date : 2017-08-02
    Maria-Christina Zennaro, Sheerazed Boulkroun, Fabio Fernandes-Rosa

    Aldosterone and cortisol, the main mineralocorticoid and glucocorticoid hormones in humans, are produced in the adrenal cortex, which is composed of three concentric zone with specific functional characteristics. Adrenocortical adenomas (ACA) may lead to the autonomous secretion of aldosterone responsible for primary aldosteronism, the most frequent form of secondary arterial hypertension. In the case of cortisol production, ACA lead to overt or subclinical Cushing syndrome. Genetic analysis driven by next generation sequencing technology has enabled the discovery, during the last seven years, of the genetic causes of a large subset of ACA. In particular, somatic mutations in genes regulating intracellular ionic homeostasis and membrane potential have been identified in aldosterone producing adenoma. These mutations all promote increased intracellular calcium concentrations, with activation of calcium signaling, the main trigger for aldosterone production. In cortisol producing adenomas, recurrent somatic mutations in PRKACA (coding for the cAMP-dependent protein kinase catalytic subunit alpha) affect cyclic AMP-dependent protein kinase A signaling, leading to activation of cortisol biosynthesis. In addition to these specific pathways, the Wnt/β-catenin pathway appears to play an important role in adrenal tumorigenesis, as β-catenin mutations have been identified in both aldosterone as well as cortisol producing adenomas. This, together with different intermediate states of aldosterone and cortisol co-secretion, raises the possibility that the two conditions share a certain degree of genetic susceptibility. Alternatively, different hits may be responsible for the diseases, with one hit leading to adrenocortical cell proliferation and nodule formation, with the second one specifying the hormonal secretory pattern.

  • Fibroblast Growth Factor 21 - Metabolic Role in Mice and Men
    Endocr. Rev. (IF 15.745) Pub Date : 2017-07-28
    Harald Staiger, Michaela Keuper, Lucia Berti, Martin Hrabě de Angelis, Hans-Ulrich Häring

    Since its identification in 2000, the interest of scientists in the hepatokine fibroblast growth factor (FGF) 21 has tremendously grown, and still remains high, due to a wealth of very robust data documenting this factor’s favorable effects on glucose and lipid metabolism in mice. For more than ten years now, intense in vivo and ex vivo experimentation addressed the physiological functions of FGF21 in humans as well as its pathophysiological role and pharmacological effects in human metabolic disease. This work produced a comprehensive collection of data revealing overlaps in FGF21 expression and function but also significant differences between mice and men that have to be considered before translation from bench to bedside can be successful. This review summarizes what is known about FGF21 in mice and humans with a special focus on this factor’s role in glucose and lipid metabolism and in metabolic diseases, such as obesity and type-2 diabetes mellitus. We highlight the discrepancies between mice and men and try to decipher their underlying reasons.

  • Linking stress and infertility: a novel role for ghrelin
    Endocr. Rev. (IF 15.745) Pub Date : 2017-07-27
    Luba Sominsky, Deborah M Hodgson, Eileen A McLaughlin, Roger Smith, Hannah M Wall, Sarah J Spencer

    Infertility affects a remarkable one in four couples in developing countries. Psychological stress is a ubiquitous facet of life, and while stress affects us all at some point, prolonged or unmanageable stress may become harmful for some individuals, negatively impacting on their health, including fertility. For instance, women who struggle to conceive are twice as likely to suffer from emotional distress than fertile women. Assisted reproductive technology treatments place an additional physical, emotional and financial burden of stress, particularly on women, who are often exposed to invasive techniques associated with treatment. Stress-reduction interventions can reduce negative affect and in some cases to improve in vitro fertilisation outcomes. Although it has been well-established that stress negatively affects fertility in animal models, human research remains inconsistent due to individual differences and methodological flaws. Attempts to isolate single causal links between stress and infertility have not yet been successful due to their multi-faceted aetiologies. In this review we will discuss the current literature in the field of stress-induced reproductive dysfunction based on animal and human models, and introduce a novel, and until recently unexplored, link between stress and infertility, the gut-derived hormone, ghrelin. We also present evidence from recent seminal studies demonstrating that ghrelin has a principal role in the stress response and reward processing, as well as in regulating reproductive function, and that these roles are tightly interlinked. Collectively, these data support the hypothesis that stress may negatively impact upon fertility at least in part by stimulating a dysregulation in ghrelin signalling.

  • Insulin Receptor Isoforms in Physiology and Disease: An Updated View
    Endocr. Rev. (IF 15.745) Pub Date : 2017-06-19
    Antonino Belfiore, Roberta Malaguarnera, Veronica Vella, Michael C. Lawrence, Laura Sciacca, Francesco Frasca, Andrea Morrione, Riccardo Vigneri

    The insulin receptor (IR) gene undergoes differential splicing that generates two IR isoforms, IR-A and IR-B. The physiological roles of IR isoforms are incompletely understood and appear to be determined by their different binding affinities for insulin-like growth factors, particularly for IGF-2. Predominant roles of IR-A in prenatal growth and development and of IR-B in metabolic regulation are well established. However, emerging evidence indicates that the differential expression of IR isoforms may also help explain the diversification of insulin and IGF signaling and actions in various organs and tissues, by involving not only different ligand binding affinities but also different membrane partitioning and trafficking and possibly different abilities to interact with a variety of molecular partners. Noteworthy, dysregulation of the IR-A:IR-B ratio is associated with insulin resistance, aging and increased proliferative activity of normal and neoplastic tissues, and appears to sustain detrimental effects.

  • Obesity Pathogenesis: An Endocrine Society Scientific Statement
    Endocr. Rev. (IF 15.745) Pub Date : 2017-06-26
    Michael W Schwartz, Randy J Seeley, Lori M Zeltser, Adam Drewnowski, Eric Ravussin, Leanne M Redman, Rudolph L Leibel

    Obesity is among the most common and costly chronic disorders worldwide. Estimates suggest that in the United States obesity affects one-third of adults, accounts for up to one-third of total mortality, is concentrated among lower income groups, and increasingly affects children as well as adults. A lack of effective options for long-term weight reduction magnifies the enormity of this problem; individuals who successfully complete behavioral and dietary weight-loss programs eventually regain most of the lost weight. We included evidence from basic science, clinical, and epidemiological literature to assess current knowledge regarding mechanisms underlying excess body-fat accumulation, the biological defense of excess fat mass, and the tendency for lost weight to be regained. A major area of emphasis is the science of energy homeostasis, the biological process that maintains weight stability by actively matching energy intake to energy expenditure over time. Growing evidence suggests that obesity is a disorder of the energy homeostasis system, rather than simply arising from the passive accumulation of excess weight. We need to elucidate the mechanisms underlying this “upward setting” or “resetting” of the defended level of body-fat mass, whether inherited or acquired. The ongoing study of how genetic, developmental, and environmental forces affect the energy homeostasis system will help us better understand these mechanisms and are therefore a major focus of this statement. The scientific goal is to elucidate obesity pathogenesis so as to better inform treatment, public policy, advocacy, and awareness of obesity in ways that ultimately diminish its public health and economic consequences.

  • Free Testosterone: Pumping up the Tires or Ending the Free Ride?
    Endocr. Rev. (IF 15.745) Pub Date : 2017-08-07
    David J Handelsman

    The review by Goldman et al. (1) is a strong restatement of the free hormone hypothesis (FHH) with its contingent focus on measurement of so-called “free” testosterone (FT). The FHH has even been recently described as a “central dogma of endocrinology” (2), reminiscent of the hubris of Crick’s (3) central dogma of molecular biology stated as a unidirectional information transfer from DNA to RNA to protein, which proved neither a dogma (an unassailable proposition) nor universally correct. The review provides an outstandingly clear and encyclopedic summation of what is and is not known of the molecular mechanisms of testosterone binding to circulating binding proteins. On the other hand, its coverage of FT measurement and its interpretation are both more selective and tendentious. Above all the review’s overall focus on means rather than ends, on how to do it rather than why, the review belies why the application of FT measurements remain contentious so that less expert readers may wonder what controversy there is that the authors hint at fleetingly.

  • A Reappraisal of Testosterone’s Binding in Circulation: Physiological and Clinical Implications
    Endocr. Rev. (IF 15.745) Pub Date : 2017-06-29
    Anna L Goldman, Shalender Bhasin, Frederick C W Wu, Meenakshi Krishna, Alvin M Matsumoto, Ravi Jasuja

    In the circulation, testosterone and other sex hormones are bound to binding proteins, which play an important role in regulating their transport, distribution, metabolism, and biological activity. According to the free hormone hypothesis, which has been debated extensively, only the unbound or free fraction is biologically active in target tissues. Consequently, accurate determination of the partitioning of testosterone between bound and free fractions is central to our understanding of how its delivery to the target tissues and biological activity are regulated and consequently to the diagnosis and treatment of androgen disorders in men and women. Here, we present a historical perspective on the evolution of our understanding of the binding of testosterone to circulating binding proteins. On the basis of an appraisal of the literature as well as experimental data, we show that the assumptions of stoichiometry, binding dynamics, and the affinity of the prevailing models of testosterone binding to sex hormone-binding globulin and human serum albumin are not supported by published experimental data and are most likely inaccurate. This review offers some guiding principles for the application of free testosterone measurements in the diagnosis and treatment of patients with androgen disorders. The growing number of testosterone prescriptions and widely recognized problems with the direct measurement as well as the computation of free testosterone concentrations render this critical review timely and clinically relevant.

  • Cathepsin K Inhibitors for Osteoporosis: Biology, Potential Clinical Utility, and Lessons Learned
    Endocr. Rev. (IF 15.745) Pub Date : 2017-06-23
    Matthew T Drake, Bart L Clarke, Merry Jo Oursler, Sundeep Khosla

    Cathepsin K is a cysteine protease member of the cathepsin lysosomal protease family. Although cathepsin K is highly expressed in osteoclasts, lower levels of cathepsin K are also found in a variety of other tissues. Secretion of cathepsin K from the osteoclast into the sealed osteoclast–bone cell interface results in efficient degradation of type I collagen. The absence of cathepsin K activity in humans results in pycnodysostosis, characterized by increased bone mineral density and fractures. Pharmacologic cathepsin K inhibition leads to continuous increases in bone mineral density for ≤5 years of treatment and improves bone strength at the spine and hip. Compared with other antiresorptive agents, cathepsin K inhibition is nearly equally efficacious for reducing biochemical markers of bone resorption but comparatively less active for reducing bone formation markers. Despite multiple efforts to develop cathepsin K inhibitors, potential concerns related to off-target effects of the inhibitors against other cathepsins and cathepsin K inhibition at nonbone sites, including skin and perhaps cardiovascular and cerebrovascular sites, prolonged the regulatory approval process. A large multinational randomized, double-blind phase III study of odanacatib in postmenopausal women with osteoporosis was recently completed. Although that study demonstrated clinically relevant reductions in fractures at multiple sites, odanacatib was ultimately withdrawn from the regulatory approval process after it was found to be associated with an increased risk of cerebrovascular accidents. Nonetheless, the underlying biology and clinical effects of cathepsin K inhibition remain of considerable interest and could guide future therapeutic approaches for osteoporosis.

  • Controversies in the Management of Low-Risk Differentiated Thyroid Cancer
    Endocr. Rev. (IF 15.745) Pub Date : 2017-06-19
    Megan R Haymart, Nazanene H Esfandiari, Michael T Stang, Julia Ann Sosa

    Controversy exists over optimal management of low-risk differentiated thyroid cancer. This controversy occurs in all aspects of management, including surgery, use of radioactive iodine for remnant ablation, thyroid hormone supplementation, and long-term surveillance. Limited and conflicting data, treatment paradigm shifts, and differences in physician perceptions contribute to the controversy. This lack of physician consensus results in wide variation in patient care, with some patients at risk for over- or undertreatment. To reduce patient harm and unnecessary worry, there is a need to design and implement studies to address current knowledge gaps.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.