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Showing papers in "Nature Reviews Endocrinology in 2010"


Journal ArticleDOI
TL;DR: The effects observed in animal models after exposure during organogenesis correlate positively with an increased incidence of malformations of the male genital tract and of neoplasms and with the decreased sperm quality observed in European and US populations.
Abstract: Environmental endocrine disrupting chemicals (EDCs), including pesticides and industrial chemicals, have been and are released into the environment producing deleterious effects on wildlife and humans. The effects observed in animal models after exposure during organogenesis correlate positively with an increased incidence of malformations of the male genital tract and of neoplasms and with the decreased sperm quality observed in European and US populations. Exposure to EDCs generates additional effects, such as alterations in male and female reproduction and changes in neuroendocrinology, behavior, metabolism and obesity, prostate cancer and thyroid and cardiovascular endocrinology. This Review highlights the carcinogenic properties of EDCs, with a special focus on bisphenol A. However, humans and wildlife are exposed to a mixture of EDCs that act contextually. To explain this mindboggling complexity will require the design of novel experimental approaches that integrate the effects of different doses of structurally different chemicals that act at different ages on different target tissues. The key to this complex problem lies in the adoption of mathematical modeling and computer simulations afforded by system biology approaches. Regardless, the data already amassed highlight the need for a public policy to reduce exposure to EDCs.

490 citations


Journal ArticleDOI
TL;DR: The ability of glucagon to stimulate energy expenditure, along with its hypolipidemic and satiating effects, make this hormone an attractive pharmaceutical agent for the treatment of dyslipidemia and obesity.
Abstract: The initial identification of glucagon as a counter-regulatory hormone to insulin revealed this hormone to be of largely singular physiological and pharmacological purpose. Glucagon agonism, however, has also been shown to exert effects on lipid metabolism, energy balance, body adipose tissue mass and food intake. The ability of glucagon to stimulate energy expenditure, along with its hypolipidemic and satiating effects, in particular, make this hormone an attractive pharmaceutical agent for the treatment of dyslipidemia and obesity. Studies that describe novel preclinical applications of glucagon, alone and in concert with glucagon-like peptide 1 agonism, have revealed potential benefits of glucagon agonism in the treatment of the metabolic syndrome. Collectively, these observations challenge us to thoroughly investigate the physiology and therapeutic potential of insulin's long-known opponent.

320 citations


Journal ArticleDOI
TL;DR: A model in which the growth hormone receptor exists as a constitutive dimer is discussed in the light of salient information from closely related class 1 cytokine receptors, such as the erythropoietin, prolactin and thrombopOietin receptors.
Abstract: Growth hormone is widely used clinically to promote growth and anabolism and for other purposes. Its actions are mediated via the growth hormone receptor, both directly by tyrosine kinase activation and indirectly by induction of insulin-like growth factor 1 (IGF-1). Insensitivity to growth hormone (Laron syndrome) can result from mutations in the growth hormone receptor and can be treated with IGF-1. This treatment is, however, not fully effective owing to the loss of the direct actions of growth hormone and altered availability of exogenous IGF-1. Excessive activation of the growth hormone receptor by circulating growth hormone results in gigantism and acromegaly, whereas cell transformation and cancer can occur in response to autocrine activation of the receptor. Advances in understanding the mechanism of receptor activation have led to a model in which the growth hormone receptor exists as a constitutive dimer. Binding of the hormone realigns the subunits by rotation and closer apposition, resulting in juxtaposition of the catalytic domains of the associated tyrosine-protein kinase JAK2 below the cell membrane. This change results in activation of JAK2 by transphosphorylation, then phosphorylation of receptor tyrosines in the cytoplasmic domain, which enables binding of adaptor proteins, as well as direct phosphorylation of target proteins. This model is discussed in the light of salient information from closely related class 1 cytokine receptors, such as the erythropoietin, prolactin and thrombopoietin receptors.

304 citations


Journal ArticleDOI
TL;DR: The clinical applicability of adipose tissue transplantation for the treatment of obesity and metabolic disorders will reside in the achievable level of safety, reliability and efficacy compared with other treatments.
Abstract: Humans and other mammals have three main adipose tissue depots: visceral white adipose tissue, subcutaneous white adipose tissue and brown adipose tissue, each of which possesses unique cell-autonomous properties. In contrast to visceral adipose tissue, which can induce detrimental metabolic effects, subcutaneous white adipose tissue and brown adipose tissue have the potential to benefit metabolism by improving glucose homeostasis and increasing energy consumption. In addition, adipose tissue contains adipose-derived stem cells, which possess the ability to differentiate into multiple lineages, a property that might be of value for the repair or replacement of various damaged cell types. Adipose tissue transplantation has primarily been used as a tool to study physiology and for human reconstructive surgery. Transplantation of adipose tissue is, however, now being explored as a possible tool to promote the beneficial metabolic effects of subcutaneous white adipose tissue and brown adipose tissue, as well as adipose-derived stem cells. Ultimately, the clinical applicability of adipose tissue transplantation for the treatment of obesity and metabolic disorders will reside in the achievable level of safety, reliability and efficacy compared with other treatments.

303 citations


Journal ArticleDOI
TL;DR: Mice deficient in nocturnin are protected from diet-induced obesity, exhibit impaired circadian expression of PPARγ and have increased bone mass, and the emerging role ofPPARγ is summarized as an integral part of a complex circadian regulatory system that modulates food storage, energy consumption and skeletal metabolism.
Abstract: Peroxisome proliferator-activated receptor γ (PPARγ) is a critical factor for adipogenesis and glucose metabolism, but accumulating evidence demonstrates the involvement of PPARγ in skeletal metabolism as well. PPARγ agonists, the thiazolidinediones, have been widely used for the treatment of type 2 diabetes mellitus owing to their effectiveness in lowering blood glucose levels. However, the use of thiazolidinediones has been associated with bone loss and fractures. Thiazolidinedione-induced alterations in the bone marrow milieu-that is, increased bone marrow adiposity with suppression of osteogenesis-could partially explain the pathogenesis of drug-induced bone loss. Furthermore, several lines of evidence place PPARγ at the center of a regulatory loop between circadian networks and metabolic output. PPARγ exhibits a circadian expression pattern that is magnified by consumption of a high-fat diet. One gene with circadian regulation in peripheral tissues, nocturnin, has been shown to enhance PPARγ activity. Importantly, mice deficient in nocturnin are protected from diet-induced obesity, exhibit impaired circadian expression of PPARγ and have increased bone mass. This Review focuses on new findings regarding the role of PPARγ in adipose tissue and skeletal metabolism and summarizes the emerging role of PPARγ as an integral part of a complex circadian regulatory system that modulates food storage, energy consumption and skeletal metabolism.

287 citations


Journal ArticleDOI
TL;DR: It is speculated that lipid mediators act on important immune receptors to induce low-grade tissue inflammation, which leads to adipocyte and metabolic dysfunction.
Abstract: Survival of multicellular organisms depends on their ability to fight infection, metabolize nutrients, and store energy for times of need. Unsurprisingly, therefore, immunoregulatory and metabolic mechanisms interact in human conditions such as obesity. Both infiltrating immunoinflammatory cells and adipocytes play critical roles in the modulation of metabolic homeostasis, so it is important to understand factors that regulate both adipocyte and immune cell function. A currently favored paradigm for obesity-associated metabolic dysfunction is that chronic macronutrient and/or lipid overload (associated with adiposity) induces cellular stress that initiates and perpetuates an inflammatory cycle and pathophysiological signaling of immunoinflammatory cells and adipocytes. Many lipid mediators exert their biological effects by binding to cognate receptors, such as G-protein-coupled receptors and Toll-like receptors. This process is tightly regulated under normal physiological conditions, and any disruption can initiate disease processes. Observations that cellular lipid loading (associated with adiposity) initiates inflammatory events has encouraged studies on the role of lipid mediators. In this review, we speculate that lipid mediators act on important immune receptors to induce low-grade tissue inflammation, which leads to adipocyte and metabolic dysfunction.

279 citations


Journal ArticleDOI
TL;DR: Clinical trials to assess the effect of vitamin D supplementation on classical and nonclassical clinical outcomes in developing countries are needed.
Abstract: Hypovitaminosis D is a prevalent disorder in developing countries. Clinical manifestations of hypovitaminosis D include musculoskeletal disorders, such as nonspecific muscle pain, poor muscle strength and low BMD, as well as nonmusculoskeletal disorders, such as an increased risk of respiratory infections, diabetes mellitus and possibly cardiovascular diseases. In developing countries, the prevalence of hypovitaminosis D varies widely by and within regions; prevalence ranges between 30-90%, according to the cut-off value used within specific regions, and is independent of latitude. A high prevalence of the disorder exists in China and Mongolia, especially in children, of whom up to 50% are reported to have serum 25-hydroxyvitamin D levels <12.5 nmol/l. Despite ample sunshine throughout the year, one-third to one-half of individuals living in Sub-Saharan Africa and the Middle East have serum 25-hydroxyvitamin D levels <25 nmol/l, according to studies published in the past decade. Hypovitaminosis D is also prevalent in children and the elderly living in Latin America. Risk factors for hypovitaminosis D in developing countries are similar to those reported in Western countries and include extremes of age, female sex, winter season, dark skin pigmentation, malnutrition, lack of sun exposure, a covered clothing style and obesity. Clinical trials to assess the effect of vitamin D supplementation on classical and nonclassical clinical outcomes in developing countries are needed.

266 citations


Journal ArticleDOI
TL;DR: The interplay between infection with enteroviruses, the immune system and host genes is discussed, and an improved knowledge of the pathogenic mechanisms of enterovirus infections should help to uncover preventive strategies for T1DM.
Abstract: Enteroviruses are believed to contribute to the pathogenesis of type 1 diabetes mellitus (T1DM). In this Review, the interplay between infection with enteroviruses, the immune system and host genes is discussed. Data from retrospective and prospective epidemiological studies strongly suggest the involvement of enteroviruses, such as coxsackievirus B, in the development of T1DM. Enteroviral RNA and/or proteins can be detected in tissues of patients with T1DM. Isolation of coxsackievirus B4 from the pancreas of patients with T1DM or the presence of enteroviral components in their islets strengthens the hypothesis of a relationship between the virus and the disease. Enteroviruses can play a part in the early phase of T1DM through the infection of beta cells and the activation of innate immunity and inflammation. In contrast with its antiviral role, virus-induced interferon alpha can be deleterious, acting as an initiator of the autoimmunity directed against beta cells. Enteroviruses, through persistent and/or successive infections, can interact with the adaptive immune system. Host genes, such as IFIH1, that influence susceptibility to T1DM are associated with antiviral activities. An increased activity of the IFIH1 protein may promote the development of T1DM. An improved knowledge of the pathogenic mechanisms of enterovirus infections should help to uncover preventive strategies for T1DM.

255 citations


Journal ArticleDOI
TL;DR: This important autocrine-based cellular axis that parallels the hormonal-based hypothalamic–pituitary–testicular axis that regulates spermatogenesis is discussed, which is the emerging target for male contraception.
Abstract: Spermiation--the release of mature spermatozoa from Sertoli cells into the seminiferous tubule lumen--occurs by the disruption of an anchoring device known as the apical ectoplasmic specialization (apical ES). At the same time, the blood-testis barrier (BTB) undergoes extensive restructuring to facilitate the transit of preleptotene spermatocytes. While these two cellular events take place at opposite ends of the Sertoli cell epithelium, the events are in fact tightly coordinated, as any disruption in either process will lead to infertility. A local regulatory axis exists between the apical ES and the BTB in which biologically active laminin fragments produced at the apical ES by the action of matrix metalloproteinase 2 can regulate BTB restructuring directly or indirectly via the hemidesmosome. Equally important, polarity proteins play a crucial part in coordinating cellular events within this apical ES-BTB-hemidesmosome axis. Additionally, testosterone and cytokines work in concert to facilitate BTB restructuring, which enables the transit of spermatocytes while maintaining immunological barrier function. Herein, we will discuss this important autocrine-based cellular axis that parallels the hormonal-based hypothalamic-pituitary-testicular axis that regulates spermatogenesis. This local regulatory axis is the emerging target for male contraception.

242 citations


Journal ArticleDOI
TL;DR: The modulating effect of IL-1 on the interaction between the innate and adaptive immune systems and the effects ofIL- 1 on the β-cell point to this molecule being a potential interventional target in autoimmune diabetes mellitus.
Abstract: Interleukin 1 (IL-1) is a 17 kDa protein highly conserved through evolution and is a key mediator of inflammation, fever and the acute-phase response. IL-1 has important functions in the innate immune defense against microbes, trauma and stress, and is also an effector molecule involved in tissue destruction and fibrosis. The inhibition of IL-1 action has clinical efficacy in many inflammatory diseases, such as hereditary autoinflammatory disorders, familial hereditary fever, gout, rheumatoid arthritis and type 2 diabetes mellitus (T2DM). The latter is a common metabolic condition caused by insulin resistance and pancreatic beta-cell failure, the causes of both of which have inflammatory components. IL-1 signaling has roles in beta-cell dysfunction and destruction via the NFkappaB and mitogen-activated-protein-kinase pathways, leading to endoplasmic reticulum and mitochondrial stress and eventually activating the apoptotic machinery. In addition, IL-1 acts on T-lymphocyte regulation. The modulating effect of IL-1 on the interaction between the innate and adaptive immune systems and the effects of IL-1 on the beta-cell point to this molecule being a potential interventional target in autoimmune diabetes mellitus. Genetic or pharmacological abrogation of IL-1 action reduces disease incidence in animal models of type 1 diabetes mellitus (T1DM) and clinical trials have been started to study the feasibility, safety and efficacy of IL-1 therapy in patients with T1DM. Here, we review the rationale for blocking IL-1 in patients with T1DM.

225 citations


Journal ArticleDOI
TL;DR: The findings of the DCCT–EDIC and UKPDS epidemiological studies suggest that early exposure to hyperglycemia predisposes individuals to the development of diabetic complications, a phenomenon referred to as metabolic memory or the legacy effect.
Abstract: Diabetes mellitus (type 1 and type 2) and the complications associated with this condition are an urgent public health problem, as the incidence of diabetes mellitus is steadily increasing. Environmental factors, such as diet and exposure to hyperglycemia, contribute to the etiology of diabetes mellitus and its associated microvascular and macrovascular complications. These vascular complications are the main cause of the morbidity and mortality burden of diabetes mellitus. The DCCT-EDIC and UKPDS epidemiological studies correlated poor glycemic control with the development of vascular complications in patients with type 1 or type 2 diabetes mellitus. The findings of these studies suggest that early exposure to hyperglycemia predisposes individuals to the development of diabetic complications, a phenomenon referred to as metabolic memory or the legacy effect. The first experimental evidence for metabolic memory was reported >20 years ago and the underlying molecular mechanisms are currently being characterized. Interestingly, transient exposure to hyperglycemia results in long-lasting epigenetic modifications that lead to changes in chromatin structure and gene expression, which mediate these persistent metabolic characteristics.

Journal ArticleDOI
TL;DR: Postpartum exacerbation of autoimmunity may reflect an imbalance in TREG cells, which is caused by the rapid fall in the numbers of these cells after delivery, which may explain why thyroid autoantibody levels decline during pregnancy, which leads to remission of Graves disease.
Abstract: Pregnancy and the postpartum period have a profound effect on autoimmune thyroid disease. Graves disease ameliorates during pregnancy, only to relapse postpartum, whereas postpartum thyroiditis is caused by destructive thyroiditis during the first few months after delivery. The immunology of pregnancy underlies these changes: the mother must maintain tolerance of the fetal semi-allograft while not suppressing her own immune system and exposing herself and the fetus to infection. Nonspecific factors, including hormonal changes, trophoblast expression of key immunomodulatory molecules and a switch to a predominantly T-helper-2-type pattern of cytokines, play some part in the maintenance of transient tolerance to paternal antigens in pregnancy; however, the generation of specific regulatory T (T(REG)) cells is key to this maintenance. T(REG) cells preferentially accumulate in the decidua but may also be present in the mother's circulation and are thus capable of regulating coincidental autoimmune responses through the phenomenon of linked suppression. In turn, this suppression may explain why thyroid autoantibody levels decline during pregnancy, which leads to remission of Graves disease. Postpartum exacerbation of autoimmunity may reflect an imbalance in T(REG) cells, which is caused by the rapid fall in the numbers of these cells after delivery.

Journal ArticleDOI
TL;DR: It is speculated that the gastrointestinal tract might have a role in the pathophysiology of T2DM and obesity.
Abstract: Several conventional methods of bariatric surgery can induce long-term remission of type 2 diabetes mellitus (T2DM); novel gastrointestinal surgical procedures are reported to have similar effects. These procedures also dramatically improve other metabolic conditions, including hyperlipidemia and hypertension, in both obese and nonobese patients. Several studies have provided evidence that these metabolic effects are not simply the results of drastic weight loss and decreased caloric intake but might be attributable, in part, to endocrine changes resulting from surgical manipulation of the gastrointestinal tract. In this Review, we provide an overview of the clinical evidence that demonstrates the effects of such interventions-termed metabolic surgery-on T2DM and discuss the implications for future research. In light of the evidence presented here, we speculate that the gastrointestinal tract might have a role in the pathophysiology of T2DM and obesity.

Journal ArticleDOI
TL;DR: The physiological roles of peptide YY, pancreatic polypeptide, islet amyloid polypePTide, glucagon-like peptide 1,glucagon, oxyntomodulin, cholecystokinin and ghrelin are addressed and their potential as targets for the development of novel treatments for obesity is discussed.
Abstract: The gastrointestinal tract is an important source of endocrine signals. Gut hormones such as glucagon-like peptide 1, peptide YY, and islet amyloid polypeptide act in an integrated fashion to modulate appetite and energy expenditure. This Review addresses the physiological roles of gut hormones and discusses their potential as targets for the development of novel treatments for obesity, on the basis of pharmacological mimicry of the hormonal milieu after bariatric surgery.

Journal ArticleDOI
TL;DR: Current strategies to obtain cells which express insulin from different progenitor sources are focused on and the main pathways and genes involved are highlighted, as well as the different approaches for the modulation of the immune response in patients with T1DM.
Abstract: The use of stem cells in regenerative medicine holds great promise for the cure of many diseases, including type 1 diabetes mellitus (T1DM). Any potential stem-cell-based cure for T1DM should address the need for beta-cell replacement, as well as control of the autoimmune response to cells which express insulin. The ex vivo generation of beta cells suitable for transplantation to reconstitute a functional beta-cell mass has used pluripotent cells from diverse sources, as well as organ-specific facultative progenitor cells from the liver and the pancreas. The most effective protocols to date have produced cells that express insulin and have molecular characteristics that closely resemble bona fide insulin-secreting cells; however, these cells are often unresponsive to glucose, a characteristic that should be addressed in future protocols. The use of mesenchymal stromal cells or umbilical cord blood to modulate the immune response is already in clinical trials; however, definitive results are still pending. This Review focuses on current strategies to obtain cells which express insulin from different progenitor sources and highlights the main pathways and genes involved, as well as the different approaches for the modulation of the immune response in patients with T1DM.

Journal ArticleDOI
TL;DR: The genetic basis of APS-1, APs-2 and IPEX syndrome is discussed, with an emphasis on the mechanisms of autoimmunity and currently available therapies to treat their underlying autoimmune disorders.
Abstract: The autoimmune polyglandular syndromes-a group of syndromes comprising a combination of endocrine and nonendocrine autoimmune diseases-differ in their component diseases and in the immunologic features of their pathogenesis. One of the three main syndromes, type 1 autoimmune polyglandular syndrome (APS-1), has a unique pathogenic mechanism owing to mutations in the autoimmune regulator (AIRE) gene, which results in the loss of central tolerance-a process by which developing T cells with potential reactivity for self-antigens are eliminated during early differentiation in the thymus. Patients with IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) syndrome harbor mutations in the forkhead box P3 (FOXP3) gene in regulatory T cells, which leads to severe autoimmunity and immune deficiency. Although both of these disorders are rare, their well-defined mechanisms of disease provide a basis for the understanding of the more common condition, APS-2. In this syndrome, alleles of human leukocyte antigens (HLAs) determine the targeting of specific tissues by autoreactive T cells, which leads to organ-specific autoimmunity as a result of this loss of tolerance. Non-HLA genes also contribute to autoimmunity in APS-2 and, depending on the polymorphism, potentially predispose to a loss of tolerance or influence which organ is specifically targeted. This Review discusses the genetic basis of APS-1, APS-2 and IPEX syndrome, with an emphasis on the mechanisms of autoimmunity and presents currently available therapies to treat their underlying autoimmune disorders.

Journal ArticleDOI
TL;DR: The etiology of G SD-Ia, GSD-Ib and G6Pase-β deficiency is addressed and advances in diagnosis and new treatment approaches, including gene therapy are highlighted.
Abstract: Glycogen storage disease type I (GSD-I) consists of two subtypes: GSD-Ia, a deficiency in glucose-6-phosphatase-α (G6Pase-α) and GSD-Ib, which is characterized by an absence of a glucose-6-phosphate (G6P) transporter (G6PT). A third disorder, G6Pase-β deficiency, shares similarities with this group of diseases. G6Pase-α and G6Pase-β are G6P hydrolases in the membrane of the endoplasmic reticulum, which depend on G6PT to transport G6P from the cytoplasm into the lumen. A functional complex of G6PT and G6Pase-α maintains interprandial glucose homeostasis, whereas G6PT and G6Pase-β act in conjunction to maintain neutrophil function and homeostasis. Patients with GSD-Ia and those with GSD-Ib exhibit a common metabolic phenotype of disturbed glucose homeostasis that is not evident in patients with G6Pase-β deficiency. Patients with a deficiency in G6PT and those lacking G6Pase-β display a common myeloid phenotype that is not shared by patients with GSD-Ia. Previous studies have shown that neutrophils express the complex of G6PT and G6Pase-β to produce endogenous glucose. Inactivation of either G6PT or G6Pase-β increases neutrophil apoptosis, which underlies, at least in part, neutrophil loss (neutropenia) and dysfunction in GSD-Ib and G6Pase-β deficiency. Dietary and/or granulocyte colony-stimulating factor therapies are available; however, many aspects of the diseases are still poorly understood. This Review will address the etiology of GSD-Ia, GSD-Ib and G6Pase-β deficiency and highlight advances in diagnosis and new treatment approaches, including gene therapy.

Journal ArticleDOI
TL;DR: Patients with toxic multinodular goiter have a higher cardiovascular risk than do patients with Graves disease, although cardiovascular complications in both groups are differentially influenced by the patient's age and the cause of hyperthyroidism.
Abstract: Various clinical disorders can cause hyperthyroidism, the effects of which vary according to the patient's age, severity of clinical presentation and association with other comorbidities. Hyperthyroidism is associated with increased morbidity and mortality from cardiovascular disease, although whether the risk of specific cardiovascular complications is related to the etiology of hyperthyroidism is unknown. This article will focus on patients with Graves disease, toxic adenoma and toxic multinodular goiter, and will compare the cardiovascular risks associated with these diseases. Patients with toxic multinodular goiter have a higher cardiovascular risk than do patients with Graves disease, although cardiovascular complications in both groups are differentially influenced by the patient's age and the cause of hyperthyroidism. Atrial fibrillation, atrial enlargement and congestive heart failure are important cardiac complications of hyperthyroidism and are prevalent in patients aged > or = 60 years with toxic multinodular goiter, particularly in those with underlying cardiac disease. An increased risk of stroke is common in patients > 65 years of age with atrial fibrillation. Graves disease is linked with autoimmune complications, such as cardiac valve involvement, pulmonary arterial hypertension and specific cardiomyopathy. Consequently, the etiology of hyperthyroidism must be established to enable correct treatment of the disease and the cardiovascular complications.

Journal ArticleDOI
TL;DR: This Review focuses on evidence-based physical therapy approaches, including exercise, vibration training and improvements of safety at home and during periods of mobility, which include risk factor assessment, dietary supplements, elements of physical therapy and exercise.
Abstract: Falls and fall-related injuries, such as fractures, are a growing problem among older adults, often causing longstanding pain, functional impairments, reduced quality of life and excess health-care costs and mortality. These problems have led to a variety of single component or multicomponent intervention strategies to prevent falls and subsequent injuries. The most effective physical therapy approach for the prevention of falls and fractures in community-dwelling older adults is regular multicomponent exercise; a combination of balance and strength training has shown the most success. Home-hazard assessment and modification, as well as assistive devices, such as canes and walkers, might be useful for older people at a high risk of falls. Hip protectors are effective in nursing home residents and potentially among other high-risk individuals. In addition, use of anti-slip shoe devices in icy conditions seems beneficial for older people walking outdoors. To be effective, multifactorial preventive programs should include an exercise component accompanied by individually tailored measures focused on high-risk populations. In this Review, we focus on evidence-based physical therapy approaches, including exercise, vibration training and improvements of safety at home and during periods of mobility. Additionally, the benefits of multifaceted interventions, which include risk factor assessment, dietary supplements, elements of physical therapy and exercise, are addressed.

Journal ArticleDOI
TL;DR: Craniopharyngiomas have an overall incidence of 0.5–2.0 new cases per million of the population per year, and ∼30–50% of all cases represent childhood craniopharyNGioma, and the appropriate time point of irradiation after incomplete resection is currently under investigation in a randomized trial.
Abstract: Craniopharyngiomas have an overall incidence of 0.5-2.0 new cases per million of the population per year, and ∼30-50% of all cases represent childhood craniopharyngioma. These partly cystic embryogenic malformations of the sellar region are presumably derived from Rathke cleft epithelium. Many of the typical manifestations at primary diagnosis are nonspecific and include headache, visual impairment, polyuria and/or polydypsia, growth retardation and weight gain. Total resection is the treatment of choice in patients with favorable tumor localization, with the intention to maintain hypothalamic-pituitary and optical nerve functions. When the tumor localization is unfavorable, a limited resection followed by local irradiation is recommended. The overall survival rates are high (91-98%). High recurrence rates after complete resection and high progression rates after incomplete resection have been observed, although the risk of recurrence or progression is less after complete resection than partial resection. Irradiation of the tumor is protective and the appropriate time point of irradiation after incomplete resection is currently under investigation in a randomized trial. Long-term sequelae substantially reduce the quality of life of ∼50% of long-term survivors, notably extreme obesity owing to hypothalamic involvement.

Journal ArticleDOI
TL;DR: Whether SPARC could be a key player in the pathology of obesity and its related metabolic complications and a novel and important link between obesity and diabetes mellitus is examined.
Abstract: SPARC (secreted protein acidic and rich in cysteine, also known as osteonectin or BM-40) is a widely expressed profibrotic protein with pleiotropic roles, which have been studied in a variety of conditions. Notably, SPARC is linked to human obesity; SPARC derived from adipose tissue is associated with insulin resistance and secretion of SPARC by adipose tissue is increased by insulin and the adipokine leptin. Furthermore, SPARC is associated with diabetes complications such as diabetic retinopathy and nephropathy, conditions that are ameliorated in the Sparc-knockout mouse model. As a regulator of the extracellular matrix, SPARC also contributes to adipose-tissue fibrosis. Evidence suggests that adipose tissue becomes increasingly fibrotic in obesity. Fibrosis of subcutaneous adipose tissue may restrict accumulation of triglycerides in this type of tissue. These triglycerides are, therefore, diverted and deposited as ectopic lipids in other tissues such as the liver or as intramyocellular lipids in skeletal muscle, which predisposes to insulin resistance. Hence, SPARC may represent a novel and important link between obesity and diabetes mellitus. This Review is focused on whether SPARC could be a key player in the pathology of obesity and its related metabolic complications.

Journal ArticleDOI
TL;DR: In studies reported before FDA approval, dronedarone proved to be associated with significantly fewer adverse effects than amiodarone, making it a more attractive choice for patients with atrial fibrillation or flutter, who are at risk of developing amioarone-induced thyroid dysfunction.
Abstract: Amiodarone is a benzofuran derivative approved for the treatment of cardiac arrhythmias. Traditionally classified as a class III antiarrhythmic agent, amiodarone possesses electrophysiologic properties of all four Vaughan-Williams classes. This drug, however, has high iodine content, and this feature plus the intrinsic effects on the body make amiodarone especially toxic to the thyroid gland. Treatment can result in a range of effects from mild derangements in thyroid function to overt hypothyroidism or thyrotoxicosis. The diagnosis and treatment of amiodarone-induced hypothyroidism is usually straightforward, whereas that of amiodarone-induced thyrotoxicosis and the ability to distinguish between the type 1 and type 2 forms of the disease are much more challenging. Dronedarone was approved in 2009 for the treatment of patients with atrial fibrillation. As amiodarone, dronedarone is a benzofuran derivative with similar electrophysiologic properties. In contrast to amiodarone, however, dronedarone is structurally devoid of iodine and has a notably shorter half-life. In studies reported before FDA approval, dronedarone proved to be associated with significantly fewer adverse effects than amiodarone, making it a more attractive choice for patients with atrial fibrillation or flutter, who are at risk of developing amiodarone-induced thyroid dysfunction.

Journal ArticleDOI
TL;DR: Several independent studies have now confirmed the presence of functional brown adipose tissue in adult humans, for whom this tissue is probably metabolically beneficial given its association with both low BMI and low total adipose tissues content.
Abstract: New targets for pharmacological interventions are of great importance to combat the epidemic of obesity. Brown adipose tissue could potentially represent one such target. Unlike white adipose tissue, brown adipose tissue has the ability to dissipate energy by producing heat rather than storing it as triglycerides. In small mammals, the presence of active brown adipose tissue is pivotal for the maintenance of body temperature and possibly to protect against the detrimental effects of surplus energy intake. Animal studies have shown that expansion and/or activation of brown adipose tissue counteracts diet-induced weight gain and related disorders such as type 2 diabetes mellitus. Several independent studies have now confirmed the presence of functional brown adipose tissue in adult humans, for whom this tissue is probably metabolically beneficial given its association with both low BMI and low total adipose tissue content. Over the past few years, knowledge of the transcriptional control and development of brown adipose tissue has increased substantially. Thus, several possible targets that may be useful for the expansion and/or activation of this tissue by pharmacological means have been identified. Whether or not brown adipose tissue will be useful in the battle against obesity remains to be seen. However, this possibility is certainly well worth exploring.

Journal ArticleDOI
TL;DR: Behavioral analysis can identify drugs that selectively affect desire to eat, enjoyment of eating, satiation or postmeal satiety, and rational interventions designed specifically to modulate these processes could limit the normally aversive consequences of caloric restriction and maximize an individual's capacity to successfully gain control over their appetite.
Abstract: For obese individuals, successful weight loss and maintenance are notoriously difficult. Traditional drug development fails to exploit knowledge of the psychological factors that crucially influence appetite, concentrating instead on restrictive criteria of intake and weight reduction, allied to a mechanistic view of energy regulation. Drugs are under development that may produce beneficial changes in appetite expression in the obese. These currently include glucagon-like peptide-1 analogs such as liraglutide, an amylin analog davalintide, the 5-HT(2C) receptor agonist lorcaserin, the monoamine re-uptake inhibitor tesofensine, and a number of combination therapies such as pramlintide and metreleptin, bupropion and naltrexone, phentermine and topiramate, and bupropion and zonisamide. However, the effects of these treatments on eating behavior remain poorly characterized. Obesity is typically a consequence of overconsumption driven by an individual's natural sensitivity to food stimuli and the pleasure derived from eating. Intuitively, these processes should be effective targets for pharmacotherapy, and behavioral analysis can identify drugs that selectively affect desire to eat, enjoyment of eating, satiation or postmeal satiety. Rational interventions designed specifically to modulate these processes could limit the normally aversive consequences of caloric restriction and maximize an individual's capacity to successfully gain control over their appetite.

Journal ArticleDOI
TL;DR: This Perspective focuses on two elements of the authors' food supply and eating environment that facilitate high energy intake: a high eating rate and distraction of attention from eating, which are believed to undermine the body's capacity to regulate its energy intake at healthy levels.
Abstract: This Perspective focuses on two elements of our food supply and eating environment that facilitate high energy intake: a high eating rate and distraction of attention from eating. These two elements are believed to undermine our body's capacity to regulate its energy intake at healthy levels because they impair the congruent association between sensory signals and metabolic consequences. The findings of a number of studies show that foods that can be eaten quickly lead to high food intake and low satiating effects-the reason being that these foods only provide brief periods of sensory exposure, which give the human body insufficient cues for satiation. Future research should focus on the underlying physiological, neurological and molecular mechanisms through which our current eating environment affects our control of food intake.

Journal ArticleDOI
TL;DR: The antihypertensive efficacy of mineralocorticoid-receptor blockers, even in patients with aldosterone values in the normal range, supports the evidence that ald testosterone plays a part in blood pressure elevation in the absence of primary aldosteronism.
Abstract: In the setting of primary aldosteronism, elevated aldosterone levels are associated with increased blood pressure. Aldosterone concentrations within the normal range, however, can also alter blood pressure. Furthermore, the aldosterone-to-renin ratio, an indicator of aldosterone excess, is associated with hypertension, even in patients without excessive absolute aldosterone levels. In this Review we assess the data on the role of aldosterone in the development and maintenance of hypertension. We provide an overview of the complex crosstalk between genetic and environmental factors, and about aldosterone-mediated arterial hypertension and target organ damage. The discussion is organized according to major targets of aldosterone action: the collecting duct in the kidney, the vasculature and the central nervous system. The antihypertensive efficacy of mineralocorticoid-receptor blockers, even in patients with aldosterone values in the normal range, supports the evidence that aldosterone plays a part in blood pressure elevation in the absence of primary aldosteronism.

Journal ArticleDOI
TL;DR: The systematic study of estrogen activation pathways suggests that the enzymes steroid sulfatase and 17β-hydroxysteroid dehydrogenase type 1, which both have pivotal roles in estrogen biosynthesis, are promising targets; the results of a phase I trial of steroid sulf atase inhibitors are encouraging.
Abstract: Breast cancer is a major cause of death in Western women, with a 10% lifetime risk of the disease. Most breast cancers are estrogen-dependent. Molecular therapies for breast cancer have developed rapidly in the past few decades and future treatment strategies are being investigated. The selective estrogen receptor (ER) modulator tamoxifen, which until now has served as a standard therapy, functions not only as an estrogen antagonist but also as an estrogen agonist in terms of bone maintenance. Aromatase inhibitors have performed well in international trials and have become a new standard therapy for estrogen-dependent breast cancer. The systematic study of estrogen activation pathways suggests that the enzymes steroid sulfatase and 17beta-hydroxysteroid dehydrogenase type 1, which both have pivotal roles in estrogen biosynthesis, are promising targets; the results of a phase I trial of steroid sulfatase inhibitors are encouraging. The activity of the human epidermal growth factor receptor (HER) pathway correlates negatively with that of the ER. HER2 is overexpressed in 22% of all breast cancers. In the decade since HER2 began being targeted, the monoclonal antibody trastuzumab has been used as well as pertuzumab and HER2 vaccines. Among the estrogen-independent breast cancers, the basal-like subtype has low survival, and therapeutic improvement is a priority. Crosstalk between ER and HER2 signaling pathways means that combinatory therapies may hold the key to enhancement of treatment responses. Other molecular therapies involving functional genomics and RNA interference studies also hold promise.

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TL;DR: The purpose of a diagnostic test is to identify individuals who have a disorder and reassure those who do not, and the use of HbA1c levels for diagnosing diabetes mellitus or prediabetes is ill-advised.
Abstract: The purpose of a diagnostic test is to identify individuals who have a disorder and reassure those who do not. An HbA₁(c)-based diagnosis of diabetes mellitus or prediabetes fails to meet that purpose. Diabetes mellitus is a disorder of glucose, not HbA₁(c), metabolism. Microvascular complications in diabetes mellitus are driven by chronic hyperglycemia. The correlation of these complications with HbA₁(c) levels is convenient; however, unlike the direct information provided by glucose, HbA₁(c) values reflect glycemic and nonglycemic factors. The latter include modulators of glucose transport across the erythrocyte membrane, intracellular protein glycation and deglycation, erythrocyte turnover, systemic illness and hematological and medical disorders, among others. Genetic rather than glycemic factors explain most of the variance in HbA₁(c) levels. Finally, HbA₁(c) values are misleading as a measure of average blood glucose among persons of African, Asian, Hispanic and other non-European ancestry. Given the numerous pitfalls, the use of HbA₁(c) levels for diagnosing diabetes mellitus or prediabetes is ill-advised.

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TL;DR: This Review discusses current understanding of the mechanisms of autoimmune-mediated bone loss in view of new insight from two new fields of research: osteoimmunology, which analyzes the direct effect of immune cells on bone, and the integrative metabolism approach, which established the existence of neuroendocrine loops that regulate bone remodeling.
Abstract: Although decreased bone mass and osteopenia are common complications of autoimmune diseases, the mechanisms that explain the bone loss are diverse. This Review discusses the multiple faces of autoimmune-induced bone loss—from the direct destruction of bone by inflammation, as observed in rheumatoid arthritis, to the less-characterized potential perturbation of metabolic pathways that systematically control bone mass in type 1 diabetes mellitus or autoimmune thyroid diseases.

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TL;DR: The aim of this article is to present relevant information on analytical and clinical aspects regarding serum TSH determination and its usefulness to detect subtle thyroid function abnormalities associated with the pregnant state, namely overt and subclinical hypothyroidism and hyperthyroidism.
Abstract: Improvements in the sensitivity of the serum TSH assay have revolutionized our strategies for investigating thyroid function and firmly established TSH as the first-line thyroid function test for most clinical situations, including pregnancy. As a single hormone determination, serum TSH provides the most sensitive index to reliably detect thyroid function abnormalities. Normal thyroid function is important to ensure the best possible pregnancy outcome; in addition, disorders of the thyroid gland are relatively frequent in women of childbearing age. The aim of this article is, therefore, to present relevant information on analytical, as well as clinical, aspects regarding serum TSH determination and its usefulness to detect subtle thyroid function abnormalities associated with the pregnant state, namely overt and subclinical hypothyroidism and hyperthyroidism. As these disorders are associated with poor pregnancy outcome, the authors of the present article are in favor of serum TSH measurement for all pregnant women.