Current Opinion in Endocrinology, Diabetes, and Obesity

Published by Lippincott, Williams & Wilkins
Online ISSN: 1752-296X
Publications
Article
Regardless of social, cultural and behavioural environments, obesity is usually caused by an energy intake above requirements, which is accommodated by the accumulation of triacylglycerols. The composition of dietary fat impacts tissue fatty acids, which are important modulators of multiple cell functions, including differentiation, lipogenesis, lipolysis and the generation of inflammatory mediators. This review focuses on the possible contribution of fatty acids to the link between obesity and inflammation in young children. Adipose tissue is a complex organ that functions to regulate fatty acid balance, clearing and releasing fatty acids, and synthesizing protein and signaling molecules that act as local and distant inflammatory mediators. Obesity, even in young children, is associated with increased circulating inflammatory mediators. As a result of changes in dietary fat compositions, infants are exposed to high n-6, saturated and trans fatty acids and low n-3 fatty acids. Saturated and trans fatty acids increase and n-3 fatty acids decrease many metabolic and inflammatory changes that accompany diet-induced triacylglycerol storage. High linoleic acid is associated with increased oxidative stress. There is a biological reason to consider that dietary fatty acids may contribute to oxidative stress and heightened inflammatory responses in young children.
 
Article
An adverse prenatal environment may induce long-term metabolic consequences, in particular obesity and insulin resistance. Although the mechanisms are unclear, this 'programming' has generally been considered an irreversible change in developmental trajectory. Recent work has highlighted the importance of the hormone leptin during critical windows of development in the pathogenesis of programming related disorders. Maintaining a critical leptin level during development may allow the normal maturation of tissues and pathways involved in metabolic homeostasis and a period of relative hypo or hyperleptinemia may induce some of the metabolic adaptations which underlie developmental programming. Furthermore, nutritional or therapeutic intervention in postnatal life can ameliorate the consequences of developmental malprogramming and, at least in the rodent, developmental programming is potentially reversible by intervention with leptin late in the phase of developmental plasticity. Inappropriate growth during pregnancy or lactation can result in individuals with an increased risk of later obesity and related metabolic sequelae. Taken together, recent studies highlight the importance of leptin in disorders manifest as a consequence of developmental programming and offer exciting new strategies for therapeutic intervention, whether it be maternal or neonatal intervention or targeted nutritional manipulation in postnatal life.
 
Article
Diabetes mellitus is an exploding epidemic costing billions of dollars yearly. Type 2 diabetes mellitus is characterized by insulin resistance and is closely associated with arterial hypertension. Emerging literature has demonstrated that modulation of the renin-angiotensin-aldosterone system by use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers leads to improved insulin sensitivity, glycemic control and possibly prevention of type 2 diabetes mellitus. Several major studies investigating angiotensin II receptor blocker or angiotensin-converting enzyme inhibitor use in either hypertensive or heart failure patients have found lower incidence of type 2 diabetes mellitus when compared with placebo, beta-blocker, calcium-channel blocker or diuretic. None of these trials, however, studied prevention of diabetes as a primary endpoint. The Dream Trial and upcoming NAVIGATOR, ONTARGET/TRANSCEND trials specifically look at the prevention of diabetes as a primary endpoint. Several studies have evaluated possible mechanisms of how the renin-angiotensin-aldosterone system can alter insulin sensitivity and glycemic control. This review will focus on the recent literature that demonstrates renin-angiotensin-aldosterone system modulation and its effects on diabetes prevention, glycemic control and insulin sensitivity, as well as possible mechanisms for achieving this goal.
 
Article
As the incidence of type 2 diabetes continues to rise worldwide at epidemic proportions, endeavors to find more effective therapies increase. Gastrointestinal bypass surgery is now gaining awareness as a potential effective and long-term treatment. There is now a substantial body of evidence supporting the efficacy of gastrointestinal surgery in controlling type 2 diabetes. This is well documented in several studies of obese diabetic patients undergoing gastrointestinal bypass procedures. Additionally, smaller studies and case reports also demonstrate the efficacy of gastrointestinal bypass surgery in nonobese diabetic patients. The pathophysiologic basis of the improvement in diabetes after gastrointestinal bypass surgery is still unclear; however, the dominant hypotheses involve changes in hormone signaling from the small bowel. The implications of 'diabetes surgery' are vast, and could dramatically change the face of diabetes as we know it today. In clinical practice surgery could represent an alternative for the treatment of diabetes. On a broader perspective, surgery may facilitate research aimed at understanding the etiology of the disease.
 
Article
Chronic stress, combined with positive energy balance, may be a contributor to the increased risk for obesity, especially upper body obesity, and other metabolic diseases. This association may be mediated by alterations in the hypothalamic-pituitary-adrenal (HPA) axis. In this review, we summarize the major research that has been conducted on the role of the HPA axis in obesity and metabolic disease. Dysregulation in the HPA axis has been associated with upper body obesity, but data are inconsistent, possibly due to methodological differences across studies. In addition to systemic effects, changes in local cortisol metabolism in adipose tissue may also influence the risk for obesity. HPA axis dysregulation may be the causal link between conditions such as maternal malnutrition and sleep deprivation with metabolic disease. The present review provides evidence for the relationship between chronic stress, alterations in HPA activity, and obesity. Understanding these associations and its interactions with other factors will be important in developing effective treatments for obesity and related metabolic diseases.
 
Article
Although studies of pancreata from type 1 diabetes (T1D) patients largely fell dormant for a period of decades, research efforts have recently been 'rekindled' in this area to address, using modern techniques, many unanswered questions related to the pathogenesis of this disease. As historically noted, a pancreatic infiltrate commonly referred to as 'insulitis' is present at the symptomatic onset of T1D. Recent studies have further characterized this infiltrate both in terms of its cellular composition as well as the mechanisms that likely underlie beta cell death in T1D. In addition, the notion that the pancreas from T1D patients is completely devoid of insulin producing cells years after the onset of disease has been challenged, whereas the concepts of whether beta cell regeneration or replication are present have also been subject to much debate. Novel concepts regarding the rate and degree of beta cell loss throughout the natural history of the disease have also been put forward to aid in explaining the disorder's pathogenesis. Although answers to many long-standing questions in T1D have recently been addressed, perhaps the main finding has been one supporting a disease of remarkable heterogeneity. However, additional lessons remain to be learned from the pancreas in T1D. Hence, attempts aimed at organizing the scientific community to address these issues are ongoing, particularly those from collaborative efforts, including the Belgium Organ Donor Consortium and the Network for Pancreatic Organ Donors with Diabetes (nPOD).
 
Article
Metabolic syndrome and cardiovascular diseases are important causes of morbidity and mortality among patients with severe mental illnesses. Atypical or second-generation antipsychotics (SGAs) are associated with obesity and other components of metabolic syndrome, particularly abnormal glucose and lipid metabolism. This review aims to provide a summary of recent evidence on metabolic risks associated with SGAs, current recommendations for metabolic monitoring, and efficacy of treatment options currently available. Studies have identified younger, antipsychotic-naive patients with first-episode psychosis as a population vulnerable to adverse metabolic effects from SGAs. These patients gained more weight and developed evident lipid and glucose abnormalities as soon as 8-12 weeks after treatment initiation. Findings are more striking among children and adolescents. The differential effects of various SGAs are well described, with clozapine and olanzapine associated with the highest metabolic risk. In addition to behavioral therapy, emerging data suggest that pharmacological therapy, most notably metformin, is efficacious in the treatment and possibly prevention of SGA-associated metabolic derangements. More data have become available on the burden from metabolic complications associated with SGAs. New and effective treatment options are required in the near future to improve cardiovascular health in this susceptible population.
 
Article
Glucagon-like peptide 1 receptor (GLP-1R) agonists provide good glycemic control combined with low hypoglycemia risk and weight loss. Here, we summarize the recently published data for this therapy class, focusing on sustainability of action, use in combination with basal insulin, and the efficacy of longer acting agents currently in development. The safety profile of GLP-1R agonists is also examined. GLP-1R agonists provide sustained efficacy and their combination with basal insulin is well tolerated, providing additional glycemic control and weight benefits compared with basal insulin alone. Data suggest that the convenience of longer acting agents may be at the expense of efficacy. Despite the initial concerns, most evidence indicates that GLP-1R agonists do not increase the risk of pancreatitis or thyroid cancer. However, the extremely low incidence of these events means further investigations are required before a causal link can be eliminated. Large-scale clinical trials investigating the long-term cardiovascular safety of this therapy class are ongoing and may also provide important insights into pancreatic and thyroid safety. GLP-1R agonists offer sustained glycemic efficacy, weight loss benefits, and a low risk of hypoglycemia. The results of ongoing trials should help to clarify the safety of this therapy class.
 
Article
To understand the role of inflammation as the fundamental cause of type 2 diabetes and specifically to examine the contribution of IL-1beta. Recent studies from animals, in-vitro cultures and clinical trials provide evidence that support a causative role for IL-1beta as the primary agonist in the loss of beta-cell mass in type 2 diabetes. In vitro, IL-1beta-mediated autoinflammatory process results in beta-cell death. The autoinflammation is driven by glucose, free fatty acids, leptin, and IL-1beta itself. Caspase-1 is required for IL-1beta activity and the release of free fatty acids from the adipocyte. An emerging hypothesis gains support from patients with type 2 diabetes in which an imbalance in the amount of IL-1beta agonist activity versus the specific countering by the naturally occurring IL-1 receptor antagonist (IL-1Ra) determines the outcome of islet inflammation. An important confirmation comes from clinical trials. Blockade of IL-1 receptor with anakinra, the recombinant form of IL-1Ra, or neutralizing anti-IL-1beta antibodies, provides proof-of-principle data that reducing IL-1beta activity is sufficient for correcting dysfunctional beta-cell production of insulin in type 2 diabetes, including a possibility that suppression of IL-1beta-mediated inflammation in the microenvironment of the islet allows for regeneration. Monotherapy or add-on therapy targeting IL-1beta in type 2 diabetes holds promise for long-term benefits in glycemic control and possibly reducing cardiovascular events.
 
Article
Type 1 diabetes (T1D) is characterized by autoimmune-mediated destruction of pancreatic beta cells culminating in absolute insulin deficiency. Despite enhanced knowledge of the natural history of type 1 diabetes we have yet to develop an intervention to consistently and safely prevent or reverse type 1 diabetes. This review explores the lessons learned from recent type 1 diabetes interventional studies, sets out controversial issues and seeks to provide a roadmap for future interventions. The type 1 diabetes intervention studies of the 1980s demonstrated potential for preserving c-peptide, but were abandoned due to unacceptable side-effect profiles of the agents being used. Pilot studies of new immunosuppressive and immunomodulatory agents with improved side-effect profiles have recently demonstrated promise in preserving c-peptide in new-onset type 1 diabetes patients. Several of these agents, including insulin, anti-CD3, mycophenolate mofetil, daclizumab and anti-CD20, are currently being tested in multicenter intervention trials. The inability to cure type 1 diabetes underscores the complex pathophysiology of the disease, and our poor knowledge of the precise etiological triggers and immunological mechanisms which culminate in the disease. While ongoing efforts to test individual agents with potential to ameliorate diabetes are needed, combination therapies employing multiple safe agents are likely to be the future of type 1 diabetes intervention studies.
 
Article
To update on the clinical trials using antigen-specific therapies in autoimmune diabetes. Type 1 diabetes is now a predictable disease with the measurement of islet autoantibodies, and the incidence is increasing dramatically. Well tolerated and effective interventions are needed to stop the underlying autoimmune destruction of insulin-producing beta cells. Beta-cell antigens, insulin and glutamic acid decarboxylase, are being used to preserve endogenous insulin production in individuals with new-onset diabetes and to prevent diabetes. The results of antigen-specific immune intervention trials are reviewed and consideration is given to future directions for inducing tolerance in type 1 diabetes. Antigen-specific immune therapies act by enhancing regulatory T cell function, in animal models often locally and selectively in islets or pancreatic lymph nodes while inhibiting effector T cells. This therapeutic pathway provides a safe treatment to preserve beta cell function in new-onset diabetic individuals with the GAD-Alum vaccine being the most extensively studied therapy. Insulin is being used in many forms to prevent diabetes and stop the underlying autoimmune process. For the future, combination immune therapies targeting different pathways in the immune system will be needed to effectively induce sustained tolerance in type 1 diabetes.
 
Article
The purpose of this review is to summarize why and how liquid chromatography tandem mass spectrometry (LC-MS/MS) is increasingly replacing other methodologies for the measurement of sex steroids. Measurement of sex steroids, particularly testosterone and estradiol, is important for diagnosis or management of a host of conditions (e.g. disorders of puberty, hypogonadism, polycystic ovary syndrome, amenorrhea, and tumors of ovary, testes, breast and prostate). Historically, metabolites of testosterone and estradiol were measured as ketosteroids in urine using colorimetric assays that lacked sensitivity and specificity due to endogenous and exogenous interferences. Extracted competitive manual radio-immunoassays provided improved, but still imperfect, specificity, and offered increased sensitivity. As testing demand increased, they were displaced by automated immunoassays. These offered better throughput and precision, but suffered worse specificity problems. Moreover, agreement between different immunoassays has often been poor and they are all compromised by a limited dynamic measurement range. To overcome these problems, LC-MS/MS methods have been developed and validated for quantitation of sex steroids. These methods reduce interferences, provide better specificity, improve dynamic range, and reduce between-method bias. Endocrine Society and Urology Society guidelines have highlighted the limitations of the immunoassays for sex steroids and have provided convincing evidence that mass spectrometric methods are preferable for measurement of sex steroid hormones. In this review, we describe LC-MS/MS methods for measurement of testosterone and estradiol.
 
Article
The purpose of this study is to review the regulation of phosphate and recent progress in fibroblast growth factor-23 (FGF-23), a key phosphate regulatory hormone. Phosphate is required for mineralization of bone, muscle strength and a host of biologic functions. Phosphate is sensed by bone that responds with secretion of FGF-23. The major action of FGF-23 is to stimulate phosphaturia. Feedback loops between FGF-23, 1,25-dihydroxyvitamin D3 and parathyroid hormone maintain phosphate homeostasis. Information about FGF-23 has accumulated from studies in patients with oncogenic osteomalacia and inherited disorders of phosphate wasting rickets that explains the pathophysiology. Exciting new discoveries have highlighted FGF-23 as an independent risk factor for cardiovascular disease in patients with chronic kidney disease. The phosphate sensor triggering FGF-23 production remains to be identified. Derangements in FGF-23 production, half-life or downstream response are responsible for several disorders of phosphate wasting, rickets and oncogenic osteomalacia. Very high levels of FGF-23 in renal failure are an independent risk for cardiovascular disease.
 
Article
Cholecystokinin, a regulatory peptide found in multiple molecular forms in brain and small intestine, is responsible for integration of functions associated with the intake, digestion and absorption of food. Whether the different molecular forms have identical biological activities is controversial. New information suggests that CCK58, the largest form of cholecystokinin detected in blood and tissue, has unique functions compared with other forms, and may be the predominant, perhaps only, circulating form in mammals. CCK58 has highly distinctive actions compared with shorter forms, most notably the strong stimulation of water secretion from the pancreas, and the lack of induction of pancreatitis by supramaximal doses of the peptide. Because CCK58 may be the main endogenous form of cholecystokinin, these recent findings have far reaching implications because almost all studies carried out with cholecystokinin have been done with shorter forms, predominately CCK8. Conclusions of studies using CCK8 or other shorter forms of cholecystokinin, therefore, may need to be reevaluated. There is a compelling reason to reevaluate the role of cholecystokinin in health and disease because the predominant form of cholecystokinin, CCK58, has unique biological activities compared with forms of cholecystokinin used in previous basic and clinical studies.
 
Article
To examine the clinical and basic studies regarding persistent adverse effects associated with 5α reductase inhibitor treatment for androgenetic alopecia. Recent postmarketing reports and a US Food and Drug Administration analysis have documented uncommon persistent sexual and nonsexual side-effects in a subset of younger men who have taken finasteride 1 mg for androgenic alopecia. While the mechanisms of the sexual side-effects in humans is incompletely understood, one study found lower cerebrospinal fluid concentrations of dihydrotestosterone, progesterone, dihydroprogesterone and allopregnanolone, and higher levels of testosterone, 5α-androstane-3α,17β-diol and pregnenolone. Another study found up-regulation of the androgen receptor in the human foreskin with a mean of 5 years after finasteride discontinuation. Studies of erectile dysfunction in finasteride-treated rats showed fewer autophagosomes in smooth muscle on transmission electron microscopy, increased apoptosis, decreased smooth muscle, increased collagen deposition and decreased endothelial nitric oxide synthase. Finally, 5α reductase inhibitors have also been found to alter semen parameters in healthy men. Multiple animal studies provide a biological basis for many of the persistent effects seen in humans such as erectile dysfunction, depression and decreased alcohol consumption. Prescribers of 5α reductase inhibitors should discuss the potential risks with their patients seeking treatment for androgenetic alopecia.
 
Article
This review summarizes recent developments in the activity, regulation, and physiology of the ABCG5 ABCG8 (G5G8) transporter and the use of its xenobiotic substrates, phytosterols, as cholesterol lowering agents in the treatment of cardiovascular disease. Recent progress has significant implications for the role of G5G8 and its substrates in complications associated with features of the metabolic syndrome. Recent reports expand the clinical presentation of sitosterolemia to include platelet and adrenal dysfunction. The G5G8 sterol transporter is critical to hepatobiliary excretion of cholesterol under nonpathological conditions and has been linked to the cholesterol gallstone susceptibility. Finally, the cardiovascular benefits of cholesterol lowering through the use of phytosterol supplements were offset by vascular dysfunction, suggesting that alternative strategies to reduced cholesterol absorption offer greater benefit. Insulin resistance elevates G5G8 and increases susceptibility to cholesterol gallstones. However, this transporter is critical for the exclusion of phytosterols from the absorptive pathways in the intestine. Challenging the limits of this protective mechanism through phytosterol supplementation diminishes the cardioprotective benefits of cholesterol lowering in mouse models of cardiovascular disease.
 
Article
Percutaneous image-guided procedures, largely based on thermal ablation, are at present under investigation for achieving a nonsurgical targeted cytoreduction in benign and malignant thyroid lesions. In several uncontrolled clinical trials and in two randomized clinical trials, laser ablation has demonstrated a good efficacy and safety for the shrinkage of benign cold thyroid nodules. In hyperfunctioning nodules, laser ablation induced a nearly 50% volume reduction with a variable frequency of normalization of thyroid-stimulating hormone levels. Laser ablation has been tested for the palliative treatment of poorly differentiated thyroid carcinomas, local recurrences or distant metastases. Laser ablation therapy is indicated for the shrinkage of benign cold nodules in patients with local pressure symptoms who are at high surgical risk. The treatment should be performed only by well trained operators and after a careful cytological evaluation. Laser ablation does not seem to be consistently effective in the long-term control of hyperfunctioning thyroid nodules and is not an alternative treatment to 131I therapy. Laser ablation may be considered for the cytoreduction of tumor tissue prior to external radiation therapy or chemotherapy of local or distant recurrences of thyroid malignancy that are not amenable to surgical or radioiodine treatment.
 
Article
The use of radiofrequency ablation has increased rapidly in recent years and is receiving increased attention as a minimally invasive method to treat benign and malignant thyroid nodules. Radiofrequency ablation has been shown to be an alternative to surgery in the treatment of benign thyroid nodules. Radiofrequency ablation of benign cold nodules showed volume reductions of 32.7-58.2% at 1 month and 50.7-84.8% at 6 months, while reducing symptoms and cosmetic problems. Radiofrequency ablation of autonomously functioning thyroid nodules effectively improves thyroid function and reduces nodule volume. Recently, radiofrequency ablation of recurrent thyroid cancers showed good short-term results for locoregional control of well differentiated thyroid carcinoma in patients at high risk for surgery. Various complications of radiofrequency ablation have been reported, including pain, voice change, hematoma, skin burn at the puncture site, thyrotoxicosis, hypothyroidism, edema, and fever, but most patients recovered spontaneously without sequelae. Radiofrequency ablation is an effective and well tolerated treatment option for benign thyroid nodules. Radiofrequency ablation of recurrent thyroid cancers may be an alternative to surgery in patients at high surgical risk.
 
Article
To provide information of the current prevalence of illicit use of androgens by individuals of the community. Prevalence of abuse of androgens in individuals of the general population has reached alarming dimensions. Use of androgens is no longer limited to competitive sports, but has spread to leisure and fitness sports, bodybuilding, and nonathletes motivated to increase muscular mass and physical attractiveness. Alarming studies from Germany demonstrated that members of the healthcare systems provide illegal androgens to 48.1% of abusers visiting fitness centers. The new trend to combine androgens with growth hormone, insulin, and insulinotropic milk protein-fortified drinks may potentiate health risks of androgen abuse. The use of androgens has changed from being a problem restricted to sports to one of public health concern. The potential health hazards of androgen abuse are underestimated in the medical community, which unfortunately contributes to illegal distribution of androgens. Both the adverse effects of current androgen abuse especially in young men as well as the chronic toxicity from past long-term abuse of now middle-aged men has to be considered as a growing public health problem. In the future, an increasing prevalence of androgen misuse in combination with other growth-promoting hormones and insulinotropic milk protein products has to be expected, which may have further promoting effects on the prevalence of chronic western diseases.
 
Article
To summarize the relevance of the 'accelerator hypothesis' to type 1 diabetes pathogenesis and examine if recent evidence supports the hypothesis. The 'accelerator hypothesis' proposes 'three processes in type 1 diabetes which variably accelerate the loss of beta cells through apoptosis: constitution, insulin resistance and autoimmunity'. Insulin resistance is an independent risk factor for progression to clinical type 1 diabetes in people with islet autoimmunity. Higher bodyweight is also associated with type 1 diabetes development although no longitudinal studies have simultaneously assessed bodyweight and insulin resistance in preclinical diabetes. Currently, there is no evidence for the view that accelerated beta-cell apoptosis is due to insulin resistance in the pathogenesis of type 1 diabetes. Insulin resistance accelerates development of type 1 diabetes in people with islet autoimmunity and insulin deficiency. The increasingly 'obesogenic' environment which promotes insulin resistance could account for the rising incidence of type 1 diabetes.
 
Article
To update the reader's knowledge about the factors that influence bone mineral accrual and to review the advances in the assessment of bone health and treatment of bone disorders. Maternal vitamin D status influences neonatal calcium levels, bone mineral density (BMD) and bone size. In turn, BMD z-score tends to track in childhood. These factors highlight the importance of bone health as early as fetal life. Dual-energy x-ray absorptiometry is the mainstay of clinical bone health assessment in this population because of the availability of appropriate reference data. Recently, more information has become available about the assessment and treatment of bone disease in chronically ill pediatric patients. Bone health must become a health focus starting prenatally in order to maximize peak bone mass and to prevent osteoporosis-related bone disease in adulthood. Vitamin D, calcium and weight-bearing activity are the factors of key importance throughout childhood in achieving optimal bone health as BMD z-score tracks through childhood and into adulthood. Recent updates of the International Society for Clinical Densitometry focus on the appropriate use of dual-energy x-ray absorptiometry in children of all ages, including children with chronic disease, and on the treatment of pediatric bone disease.
 
Article
To assess factors that influence the tempo of bone mass accrual with emphasis on obesity, exercise, and nutritional factors. The prevalence of childhood obesity has increased dramatically throughout the world. Recent studies suggest that adiposity may be detrimental to development of bone strength parameters, and bone mass accrual during growth. Weight-bearing exercise during prepubertal and peripubertal period appears to enhance bone strength parameters. Maternal ultraviolet B radiation exposure and vitamin D status has been shown to have a positive effect on neonatal bone status, which appears to track up to the prepubertal period. Administration of vitamin D with or without calcium, but not calcium alone, during the prepubertal period might be an important 'window' for improving skeletal mineralization. Obesity in children appears to be detrimental to development of bone strength parameters and bone mass accrual. Weight-bearing exercise during prepubertal and peripubertal period and vitamin D supplementation during pregnancy, infancy, and peripubertal period might be important for bone mass accrual. However, adequately powered randomized controlled trials with follow-up into adulthood are needed to determine if these interventions improve the tempo of bone mass accrual.
 
Article
To describe the role of free fatty acid (FFA) as a cause for insulin resistance in obese people. Elevated plasma FFA levels can account for a large part of insulin resistance in obese patients with type 2 diabetes. Insulin resistance is clinically important because it is closely associated with several diseases including type 2 diabetes, hypertension, dyslipidemia and abnormalities in blood coagulation and fibrinolysis. These disorders are all independent risk factors for cardiovascular disease (heart attacks, strokes and peripheral arterial disease). The mechanisms by which FFA can cause insulin resistance, although not completely known, include generation of lipid metabolites (diacylglycerol), proinflammatory cytokines (TNF-α, IL-1β, IL-6, MCP1) and cellular stress including oxidative and endoplasmic reticulum stress. Increased plasma FFA levels are an important cause of obesity-associated insulin resistance and cardiovascular disease. Therapeutic application of this knowledge is hampered by the lack of readily accessible methods to measure FFA and by the lack of medications to lower plasma FFA levels.
 
Article
The incidence of obesity and its related metabolic disorders has increased significantly over the past 3 decades, culminating in the current global epidemic of metabolic disease and leading to the search for contributing factors. Exposure of the developing foetus/neonate to a typical Western diet increases their risk of obesity and metabolic disorders throughout the life-course, creating an intergenerational cycle of metabolic disease. In Western countries, this epidemic of metabolic disease has coincided with a marked increase in the intake of omega-6 polyunsaturated fatty acids (omega-6 PUFA), leading to suggestions that the two may be causally related. Recent studies have emphasized the proadipogenic properties of the omega-6 PUFA, and provided evidence that rodents fed on diets with omega-6 PUFA contents similar to the typical US diet (6-8% energy) have an increased fat mass. Importantly, recent studies have shown that perinatal exposure to a high omega-6 PUFA diet results in a progressive accumulation of body fat across generations. This review highlights the recent evidence supporting the role of the omega-6 PUFA in the early life origins of obesity and metabolic disease, the need for more clinical studies and the potential need for health agencies to re-evaluate current recommendations to further increase omega-6 PUFA intakes.
 
Article
Although the concept that acromegaly is associated with heightened cardiovascular risk is not new, it has become apparent that there are a number of risk factors associated with this disease and that specific therapeutic modalities may have variable effects on these risk factors. In addition, it is important to understand the medical therapies available for acromegaly and their role in acromegaly management. Acromegaly is associated with heightened cardiovascular risk, including derangements in glucose homeostasis and lipids, but also in markers of vascular function. Recent studies have demonstrated treatment-specific effects on these markers. In addition, recent studies have detailed further the efficacy and safety of various therapeutic options, in particular that of pegvisomant, the growth hormone receptor antagonist. A role for medical therapy as primary, de-novo therapy has been considered and recent studies support such use. The goals of acromegaly therapy are to control excess growth hormone secretion and limit, if not reverse, the long-term medical consequences and risk of premature mortality associated with acromegaly. It is critical to control both the growth hormone hypersecretion and associated cardiovascular risk factors to prevent the associated risks of cardiovascular disease and enhanced mortality. Medical therapy has an important adjuvant role in the management of acromegaly and use of somatostatin analogs as first-line therapy for specific groups of patients should be considered.
 
Article
This review focuses on combination drug treatment for acromegaly patients, including novel concepts and experimental therapies, with an emphasis on the author's personal experience. A review of published clinical studies demonstrates that combination therapy; somatostatin receptor ligands and dopamine agonists, somatostatin receptor ligands and pegvisomant, or cabergoline and pegvisomant could provide significant additive biochemical control of acromegaly in patients inadequately controlled with conventional somatostatin receptor ligand therapy. Advances in combination medical therapy have opened up new perspectives for acromegaly patients who are poorly, or nonresponsive to, presently available single drug therapies.
 
Article
To discuss the role of medical therapy of acromegaly as a first-line treatment, focusing on recent data on the use of somatostatin analogs (SSAs), the first-choice pharmacotherapy for treating acromegaly. Despite pituitary surgery and radiotherapy, a significant number of patients with acromegaly needed adjuvant medical therapy, and primary medical therapy nowadays is increasingly considered. According to a recent consensus statement on the management of acromegaly, primary pharmacological therapy with SSAs may be indicated in patients who are otherwise poor surgical candidates or refuse surgery, and in those in whom there is a low probability of a surgical cure. The long-acting SSAs have been found to be effective in improving symptoms and signs of acromegaly in a high percentage of patients and induce normalization of growth hormone and insulin-like growth factor-I levels approximately in 60-80% of patients, respectively. Evidence has suggested that SSAs induce a clinically significant tumor shrinkage when given as first-line, when this reduction of tumor volume could be helpful in improving the outcome of subsequent surgery or improving the clinical syndrome in patients with unacceptable surgical risk, whereas the tumor shrinkage was seen less frequently when the drug was used after surgical resection and/or radiotherapy. Pharmacological management plays a pivotal role in the treatment of acromegaly, and first-line medical therapy with SSAs is being widely used in clinical practice, either prior to surgery or in patients who are otherwise poor surgical candidates and in those in whom there is a low probability of a surgical cure.
 
Article
Purpose of review: To provide an update on current understanding of osteoporosis associated with acromegaly. Recent findings: Patients with acromegaly have an increased risk of morphometric vertebral fractures. This seems to correlate with acromegaly activity and its duration, but it persists after biochemical control is achieved. Coexistent hypogonadism, diabetes mellitus and over-replacement with glucocorticoids have additional detrimental effects. Bone mineral density can be normal, increased or decreased, and is usually discordant with occurrence of fractures. However, a decrease in the hip bone mineral density during follow-up has been associated with development of new vertebral fractures. Bone turnover markers are increased and tend to normalize after biochemical control of acromegaly. Hypercalcemia rarely occurs in acromegaly and may be parathyroid hormone-dependent or 1,25 dihydroxy-vitamin D dependent. The latter improves with biochemical control of acromegaly. Summary: Screening with thoracic and lumbar vertebral radiographs is indicated in patients with acromegaly. We recommend biochemical control of acromegaly, treatment of hypogonadism and other risk factors of osteoporosis and avoiding supraphysiologic doses of glucocorticoids. Further studies are needed to understand mechanisms of skeletal fragility in acromegaly and clinical impact of vertebral fractures. Further studies of tailored therapy for patients with acromegaly and osteoporosis are also needed.
 
Article
To discuss novel drug formulations being developed for the medical treatment of acromegaly and to highlight recent data from studies reporting more effective therapeutic strategies using existing drugs. Despite advances in the management of acromegaly a significant number of patients remain uncontrolled. Primary medical treatment is being increasingly considered, but use of somatostatin analogues, the current mainstay of medical therapy, achieves control in only around 60% of patients, whilst 10-20% may be controlled with dopamine agonists. Consequently, improvements in drug efficacy and convenience are needed. Newer longer-acting somatostatin analogues are in development and combination regimes with the growth hormone receptor antagonist, pegvisomant, given at more cost-effective weekly doses show promising results. Somatostatin analogue-resistant tumours may respond to ligands with higher affinities to other receptors, such as pasireotide (SOM 230). Further, the combined dopamine/somatostatin receptor analogue BIM-23A760 has increased affinity to somatostatin receptors 2 and 5 and to the dopamine 2 receptor, and phase 2 clinical studies are underway. These novel drugs, formulations and treatment regimes should potentially add to the armamentarium of treatment options for patients with acromegaly.
 
Article
Description of recent outcomes and approaches to the treatment of patients with de-novo and recurrent acromegaly. Radiosurgery for acromegaly results in a higher likelihood of remission and an earlier time to remission than does conventional radiotherapy. Somatostatin analogs results in control of acromegaly and one half of patients. Combining treatment with pegvisomant and somatostatin analogs results in overall improved quality of life. Existing treatments offer patients and their treating physicians opportunities to restore life expectancy to normal and reverse many of the symptoms and signs of acromegaly.
 
Article
We review recent understanding of the pathophysiology, molecular biology, and management of Turner syndrome. Sophisticated genetic techniques are able to detect mosaicism in one-third of individuals previously thought to have monosomy X. Prenatal detection using maternal blood should permit noninvasive detection of most fetuses with an X chromosome abnormality. Disproportionate growth with short limbs has been documented in this condition, and a target gene of short stature homeobox, connective tissue growth factor (Ctgf), has been described. Liver disease is more common in Turner syndrome than previously recognized. Most girls have gonadal failure. Spontaneous puberty and menarche is more commonly seen in girls with XX mosaicism. Low-dose estrogen replacement therapy may be given early to induce a more normal onset and tempo of puberty. Oocyte donation for assisted reproduction carries a substantial risk, particularly if the woman has known cardiac or aortic disease. Neurodevelopmental differences in Turner syndrome are beginning to be correlated with differences in brain anatomy. An increased understanding of the molecular basis for aspects of this disorder is now developing. In addition, a renewed focus on health maintenance through the life span should provide better general and targeted healthcare for these girls and women.
 
Article
The present review examines the role of actin binding proteins (ABPs) on blood-testis barrier (BTB), an androgen-dependent ultrastructure in the testis, in particular their involvement on BTB remodeling during spermatogenesis. The BTB divides the seminiferous epithelium into the basal and the adluminal compartments. The BTB is constituted by coexisting actin-based tight junction, basal ectoplasmic specialization, and gap junction, and also intermediate filament-based desmosome between Sertoli cells near the basement membrane. Junctions at the BTB undergo continuous remodeling to facilitate the transport of preleptotene spermatocytes residing in the basal compartment across the immunological barrier during spermatogenesis. Thus, meiosis I/II and postmeiotic spermatid development take place in the adluminal compartment behind the BTB. BTB remodeling also regulates exchanges of biomolecules between the two compartments. As tight junction, basal ectoplasmic specialization, and gap junction use F-actin for attachment, actin microfilaments rapidly convert between their bundled and unbundled/branched configuration to confer BTB plasticity. The events of actin reorganization are regulated by two major classes of ABPs that convert actin microfilaments between their bundled and branched/unbundled configuration. We provide a model on how ABPs regulate BTB remodeling, shedding new light on unexplained male infertility, such as environmental toxicant-induced reproductive dysfunction since the testis, in particular the BTB, is sensitive to environmental toxicants, such as cadmium, bisphenol A, phthalates, and PFOS (perfluorooctanesulfonic acid or perfluorooctane sulfonate).
 
Article
To review the current knowledge of genetic variants in the two genes affecting the individual responsiveness to follicle-stimulating hormone (FSH) action-the FSH beta-subunit (FSHB) and the FSH receptor (FSHR), as well as the pharmacogenetic ramifications of the findings. Four common variants in the FSHB and the FSHR genes were shown to exhibit significant effect on FSH action: linked FSHR variants Thr307Ala and Asn680Ser determining common receptor isoforms, and gene expression affecting polymorphisms FSHR -29G/A and FSHB -211G/T. In women, the FSHR Thr307Ala/Asn680Ser polymorphisms show consistent predictive value for estimating the most optimal recombinant FSH dosage in controlled ovarian hyperstimulation (COH). The same variants exhibit a potential for the pharmacogenetic assessment of the treatment of polycystic ovarian syndrome. The FSHR -29G/A variant was also shown to contribute to ovarian response to COH. Pilot studies have suggested the FSHB -211 TT homozygous oligozoospermic men with genetically determined low concentration of FSH, as potentially the best responders to FSH treatment; furthermore, modulation of this response by FSHR polymorphisms is possible. Genetic variants in FSHB and FSHR exhibit a potential for pharmacogenetic applications in selecting appropriate treatment options (timing and dosage) in male and female conditions requiring or benefiting from FSH therapy.
 
Article
Hereditary 1,25-dihydroxyvitamin-D [1,25(OH)2D3]-resistant rickets (HVDRR) is a rare genetic disease caused by generalized resistance to 1,25(OH)2D3. Less than 100 cases are reported in the literature. These patients provide an experiment by nature enabling us to understand the role of vitamin D, especially in light of the ongoing debate concerning normal vitamin D levels and the supplement dosage that should be recommended.This article summarizes the role of vitamin D in calcium absorption, rennin-angiotensin system (RAS), and cardiac state in HVDRR patients. The precise spectrum of vitamin D activities can now be better evaluated by critical analysis of mouse models with targeted deletion of the gene encoding the vitamin D receptor (VDR). Of special interest is the unraveling of the role of VDR in calcium absorption and cardiac status in VDR-knockout mice. The facts that VDR-knockout mice up-regulate intestinal calcium absorption and skeletal mineralization independently of the VDR during pregnancy and lactation point to the existence of VDR-independent mechanisms that are involved in calcium absorption. The observation that mice with genetic disruption of the 1α-hydroxylase gene or of the VDR gene have an overstimulated RAS and consequently develop high blood pressure and cardiac hypertrophy raised concern about potential risks to the cardiovascular system in HVDRR patients. The current review summarizes the new understanding of the effects of vitamin D on calcium absorption, the RAS, and heart hypertrophy derived from studying HVDRR patients from infancy to their mid-30s.
 
Article
Purpose of review: This review provides an update on the associations of testosterone, estrogens, sex hormone binding globulin, GH-IGF-I, osteocalcin and mechanical loading with relevance to skeletal health. Recent findings: The simple concept of a dual model of action of androgens, i.e. either directly via the androgen receptor or indirectly by estrogens, is proving more complicated because of novel interactions of these hormones and their receptors with other hormonal as well as mechanical signals. Summary: Testosterone - in contrast with estrogen - is not uniformly associated with fracture risk in men. However, androgen receptor mediated action is clearly important for trabecular bone maintenance in male mice whereas both estrogens and androgens regulate cortical bone growth. The osteoblast and osteocyte appear to be involved in such androgen receptor mediated action on bone in male mice. Studies in mice also showed an unexpected interaction between osteocalcin and testosterone production in males and, vice versa, between ovarian production of follicle-stimulating hormone with testosterone and potentially bone formation.
 
Article
To review the current understanding regarding thyroid hormone action on skin. To provide a historical context for the recent findings. Although direct thyroid hormone actions have been demonstrated on multiple aspects of cutaneous biology, rigorous study remains scant. Still, there is a slowly evolving literature supporting the concept that thyroid hormone can directly stimulate epidermis, dermis, and hair. That action may be accessed to treat cutaneous disease. Here, we review the literature regarding thyroid hormone action on skin along with skin manifestations of thyroid disease. We provide context for more recent findings of direct thyroid hormone stimulation of cutaneous cell proliferation in vitro and in vivo which may portend the use of thyroid hormone to treat cutaneous pathologies.
 
Article
Chronic kidney disease is characterized by multiple abnormalities in the thyroid hormone physiology. In the present review, we will briefly discuss the effects of uremia on thyroid hormone synthesis, metabolism, transport, and action. Uremic toxins have been shown to interfere at various levels of the thyroid hormone action, including thyroid hormone transport across plasma membrane and thyroid hormone receptor activity. These abnormalities could explain the resistance to thyroid hormone action in uremia, at least in some tissues. The pathogenesis of thyroid axis abnormalities in uremia is incompletely understood, and its clinical significance remains unclear. The increasing prevalence of chronic kidney disease underscores the need for further efforts to understand the metabolic consequences of uremia and address questions such as the impact of thyroid hormone therapy.
 
Article
Description of the progress about the vascular effects promoted by thyroid hormones. Over the past few years, a number of studies have shown that in addition to genomic effects on blood vessels, thyroid hormones exert extranuclear nongenomic effects on vascular smooth muscle cells and endothelium. These nongenomic effects occur rapidly and do not involve thyroid hormone response elements-mediated transcriptional events. In this context, the genomic and nongenomic events promoted by thyroid hormones act in concert to control the vascular hemodynamic and regulate the cardiovascular function. Considering the antiatherogenic property of thyroid hormones and the rapid effects produced by this molecule as a vasodilator, including that in the coronary bed, a better understanding of the molecular mechanisms involved in its action may contribute to the development of drugs that can be clinically used to increase the known benefits promoted by thyroid hormones in cardiovascular physiology.
 
Article
Purpose of review: Aldosterone is now recognized as an increasingly important contributor to cardiometabolic pathology via inflammatory and fibrosis-related pathways in addition to its classically described role in sodium and volume regulation. Consequently, much effort has been directed towards characterizing the molecular pathways involved in aldosterone-mediated fibrosis and inflammation. What was once viewed as straightforward steroid hormone biology is now appreciated as a highly complex and tightly regulated series of pathways and interactions. These recognitions have fuelled a multidisciplinary effort to identify precisely how aldosterone mediates intracellular activation of both genomic (latent) and nongenomic (rapid) mechanisms of influence. This review will explore recent novel pathways regulating aldosterone action, focusing on the nongenomic pathways. Recent findings: Several recent discoveries have redefined our understanding of aldosterone interactions at the cellular level. This includes activation of the mineralocorticoid receptor at the plasma membrane instead of via classical nuclear hormone receptor interaction, and identification of novel cofactor scaffolding proteins that modify aldosterone influence at the cellular level. In addition, aldosterone activation of secondary messenger system cascades can occur directly and independent of mineralocorticoid receptor interaction. Summary: Substantial progress in detailing the molecular biology of aldosterone regulation and action should facilitate study of how it exerts detrimental effects in cardiometabolic diseases. However, to date, the clinical impact of these discoveries has not been validated. Translational efforts are now required to determine if novel therapeutic targets can be developed.
 
Article
The purpose of this review is to highlight the importance of pituitary adenylate cyclase-activating polypeptide in physiological processes and to describe how this peptide is becoming increasingly recognized as having a major role in the body. Since its discovery in 1989, investigators have sought to determine the site of biological activity and the function of pituitary adenylate cyclase-activating polypeptide in maintaining homeostasis. Since its discovery, pituitary adenylate cyclase-activating polypeptide appears to play an important role in the regulation of processes within the central nervous system and gastrointestinal tract, as well in reproductive biology. Pituitary adenylate cyclase-activating polypeptide has been shown to regulate tumor cell growth and to regulate immune function through its effects on T lympocytes. These discoveries suggest the importance of pituitary adenylate cyclase-activating polypeptide in neuronal development, neuronal function, gastrointestinal tract function and reproduction. Future studies will examine more closely the role of pituitary adenylate cyclase-activating polypeptide in regulation of malignantly transformed cells, as well as in regulation of immune function.
 
Article
Nongenomic actions of 3,3',5-triiodo-L-thyronine (T3) occur quite rapidly usually via activation of signaling cascades. In this review, we focus on recent advances made in the understanding of activation of the phosphatidylinositol 3-kinase pathway by T3 in alveolar epithelial cells, resulting in upregulation of Na,K-ATPase hydrolytic activity and potential physiological significance of this finding. T3 stimulates the Src family of kinases. Activation of Src-kinase and phosphatidylinositol 3-kinase/protein kinase B is required for the T3-induced stimulation of alveolar epithelial Na,K-ATPase activity in rat alveolar epithelial cells. The stimulation does not require transcription. This T3-sensitive Na,K-ATPase stimulation in rat alveolar epithelial cells is switched on late in gestation. In skin fibroblasts phosphatidylinositol 3-kinase is also involved in the nongenomic T3 stimulation of ZAK1-4alpha protein expression, an endogenous calcineurin inhibitor. T3 plays an important role in cell survival and differentiation. Nongenomic regulation of phosphatidylinositol 3-kinase and downstream molecules by T3 is being recognized in different tissues. Upregulation of alveolar Na,K-ATPase is one such molecule, which plays an important role in removal of edema fluid from the alveolar space. These effects are rapid and do not require direct nuclear gene transcription.
 
Article
Inflammation and the concomitant acute phase response induce marked changes in the lipoprotein profile, particularly the high-density lipoprotein (HDL) fraction. The present review describes the transfer proteins and lipases that remodel HDL and regulate its plasma levels, discusses the changes occurring in their activities during inflammation, and the influence of this altered remodeling on HDL function. The review will also discuss the contribution of the ATP-binding-membrane-cassette transporters to the protective actions of HDL. Studies using different models showed that remodeling of acute phase HDL in vitro generates pre-beta migrating particles capable of cholesterol efflux. Induction of the acute phase response in humans resulted in a reduction of HDL phospholipids without a change in HDL-cholesterol. However, the capacity of HDL to promote cholesterol efflux ex vivo was impaired. Studies with ATP-binding-membrane-cassette transporter A1 and ATP-binding-membrane-cassette transporter G1 knockout mice demonstrated anti-inflammatory roles for these transporters by virtue of reducing cell-membrane-free cholesterol and lipid raft content, thus attenuating proinflammatory signaling pathways. It is well known that HDL has anti-inflammatory properties that are diminished during inflammation. Acute phase HDL contains serum amyloid A that can be liberated during remodeling by cholesteryl ester transfer protein and secretory phospholipase A2, or other inflammatory factors. The ability of serum amyloid A and apolipoprotein A-I to promote cholesterol efflux may confer protective effects during the acute phase response.
 
Article
Ghrelin, an orexigenic hormone secreted from the stomach, exists in the circulation in two isoforms: des-acyl and acyl ghrelin. Acylation by the enzyme ghrelin O-acyl-transferase (GOAT) enables ghrelin to activate the ghrelin receptor. This review discusses recent findings illustrating the role of acyl ghrelin, des-acyl ghrelin and GOAT in regulating glucose homeostasis. Recent publications support a role of ghrelin in modulating glucose homeostasis. Novel cellular mechanisms have been proposed to explain these effects. Controversy on this topic continues to exist owing to inconsistent observations made in both rodents and humans. Many recent studies are uncovering a role of des-acyl ghrelin in glucose metabolism specifically in modulating insulin sensitivity and glucose uptake into adipocytes. A novel role of ghrelin acylation by the enzyme GOAT in regulating glucose metabolism during caloric deprivation has newly been discovered. Ghrelin plays a role in regulating glucose homeostasis through the modulation of insulin secretion and insulin sensitivity. Acyl ghrelin and des-acyl ghrelin appear to have opposing glucoregulatory effects and regulation of acylation by the enzyme GOAT appears to play a role in mediating glucose metabolism. Modulation of GOAT or ghrelin signaling may be a clinically relevant strategy to treat metabolic diseases such as type II diabetes.
 
Diagram of the reverse cholesterol transport pathway
Diagram of the lecithin : cholesterol acyltransferase reaction
Article
We discuss the latest findings on the biochemistry of lecithin : cholesterol acyltransferase (LCAT), the effect of LCAT on atherosclerosis, clinical features of LCAT deficiency, and the impact of LCAT on cardiovascular disease from human studies. Although there has been much recent progress in the biochemistry of LCAT and its effect on high-density lipoprotein metabolism, its role in the pathogenesis of atherosclerosis is still not fully understood. Studies from various animal models have revealed a complex interaction between LCAT and atherosclerosis that may be modified by diet and by other proteins that modify lipoproteins. Furthermore, the ability of LCAT to lower apoB appears to be the best way to predict its effect on atherosclerosis in animal models. Recent studies on patients with LCAT deficiency have shown a modest but significant increase in incidence of cardiovascular disease consistent with a beneficial effect of LCAT on atherosclerosis. The role of LCAT in the general population, however, has not revealed a consistent association with cardiovascular disease. Recent research findings from animal and human studies have revealed a potential beneficial role of LCAT in reducing atherosclerosis but additional studies are necessary to better establish the linkage between LCAT and cardiovascular disease.
 
Article
The purpose of this article is to review the current therapy of Addison's disease and to highlight recent developments in this field. Conventional steroid replacement for Addison's disease consists of twice or three-times daily oral hydrocortisone and once-daily fludrocortisone; however, new treatment modalities such as modified-released hydrocortisone and continuous subcutaneous hydrocortisone infusion have recently been developed. These offer the potential for closer simulation of the physiological serum cortisol rhythm. Two studies have also looked at modifying the natural history of adrenal failure using adrenocorticotropic hormone (ACTH) stimulation and immunomodulatory therapies, leading to the concept of residual adrenal function in some Addison's disease patients. Following more than 60 years with no significant innovation in the management of Addison's disease, these new approaches hold promise for improved patient health and better quality of life in the future.
 
Article
To describe the recent efforts to understand the molecular and genetic mechanisms involved in the tumorigenesis of pituitary adenomas. There is rapidly accumulating evidence for the roles of molecular abnormalities in pituitary adenoma tumorigenesis, including dysregulation of the cell cycle, signal transduction pathways, oncogenes and tumor suppressor genes. MicroRNAs have been identified as important participants in gene regulation and may have a role in therapy. Stem cells have also provided novel concepts for tumorigenesis and potentially treatment. Pituitary adenomas are relatively common neoplasms, whose pathogenesis is still poorly understood. Although considered by many as benign monoclonal proliferations, their clinical spectrum is diverse including hormone hypersecretion, and various degrees of invasiveness, suggesting multiple steps and mechanisms. This review summarizes recent development in the molecular tumorigenesis of pituitary adenomas emphasizing the dysregulation of the cell cycle components, tumor suppressor genes, oncogenes, stem cells and microRNAs.
 
Article
Stereotactic radiosurgery has become the preferred radiation treatment modality for secreting and nonsecreting pituitary adenomas, although randomized studies comparing delivery systems, fractionation and dose have not been performed. The technical achievement of radiosurgery delivery systems has minimized the radiation dose to surrounding normal tissue compared with external beam radiotherapy. With a reduction in acute and chronic side effects, the total dose to abnormal tissue can be increased allowing for greater tumor control. The radiobiology, control rates and normal tissue tolerances of stereotactic radiosurgery in the treatment of pituitary adenomas is reviewed.
 
Top-cited authors
Michael F Holick
  • Boston University
Jae M Sevelius
  • University of California, San Francisco
Joshua D Safer
  • Icahn School of Medicine at Mount Sinai
Jamie Lynn Feldman
  • University of Minnesota Twin Cities
Robert Garofalo
  • Ann & Robert H. Lurie Children's Hospital of Chicago