- Starvation in the Midst of Plenty: Reflections on the History and Biology of Insulin and Leptin. [Journal Article]
- EREndocr Rev 2018 Oct 23
- Insulin and leptin are critical metabolic hormones that play essential but distinct roles in regulating the physiologic switch between the fed and starved states. The discoveries of insulin and lepti...
Insulin and leptin are critical metabolic hormones that play essential but distinct roles in regulating the physiologic switch between the fed and starved states. The discoveries of insulin and leptin, in 1922 and 1994 respectively, arose out of radically different scientific environments. Despite the dearth of scientific tools available in 1922, insulin's discovery rapidly launched a life-saving therapy for what we now know to be Type I diabetes, and continually enhanced insulin therapeutics are now effectively applied to both major forms of this increasingly prevalent disease. In contrast, while the discovery of leptin provided deep insights into the regulation of CNS energy balance circuits, and an effective therapy for an extremely rare form of obesity, its therapeutic impact beyond that has been surprisingly limited. Despite an enormous accumulated body of information, many important questions remain unanswered about the mechanisms of action and role in disease of both hormones. In addition, though many decades apart, both discoveries reveal the complexities inherent to scientific collaboration and the assignment of credit, even when the efforts are spectacularly successful.
- Skeletal and extra-skeletal actions of vitamin D: Current evidence and outstanding questions. [Journal Article]
- EREndocr Rev 2018 Oct 12
- The etiology of endemic rickets was discovered a century ago. Vitamin D is the precursor of 25-hydroxyvitamin D and other metabolites, including 1,25(OH)2D, the ligand for the vitamin D receptor (VDR...
The etiology of endemic rickets was discovered a century ago. Vitamin D is the precursor of 25-hydroxyvitamin D and other metabolites, including 1,25(OH)2D, the ligand for the vitamin D receptor (VDR). The effects of the vitamin D endocrine system on bone and its growth plate is primarily indirect and mediated by its effect on intestinal calcium transport and serum calcium and phosphate homeostasis. Rickets and osteomalacia can be prevented by daily supplements of 400 IU of vitamin D. Vitamin D deficiency (serum 25OHD < 50 nmol/l) accelerates bone turnover, bone loss and osteoporotic fractures. These risks can be reduced by 800 IU of vitamin D together with an appropriate calcium intake, given to institutionalized or vitamin D deficient elderly subjects.The VDR and vitamin D metabolic enzymes are widely expressed. Numerous genetic, molecular, cellular and animal studies strongly suggest that vitamin D signaling has many extra-skeletal effects. These include regulation of cell proliferation, immune and muscle function, skin differentiation, and reproduction, as well as vascular and metabolic properties. From observational studies in human subjects, poor vitamin D status is associated with nearly all diseases predicted by these extraskeletal actions. Results of randomized controlled trials and Mendelian randomization studies are supportive of vitamin D supplementation in reducing incidence of some diseases, but, globally, conclusions are mixed. These findings point to a need of continued ongoing and future basic and clinical studies to better define whether vitamin D status can be optimized to improve many aspects of human health.Vitamin D deficiency enhances the risk of osteoporotic fractures and is associated with many diseases. We review what is established and what is plausible regarding the health effects of vitamin D.
- The Forgotten Lipids: Triglycerides, Remnant Cholesterol, and Atherosclerotic Cardiovascular Disease Risk. [Journal Article]
- EREndocr Rev 2018 Oct 11
- Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide. Low-density lipoprotein cholesterol (LDL-C) is a well-established mediator of atherosclerosis and a key ta...
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide. Low-density lipoprotein cholesterol (LDL-C) is a well-established mediator of atherosclerosis and a key target for intervention for the primary and secondary prevention of ASCVD. However, despite significant reduction in LDL-C, patients continue to have recurrent ASCVD events. Hypertriglyceridemia maybe an important contributor of this residual risk. Observational and genetic epidemiological data strongly support a causal role of triglycerides and the cholesterol content within triglyceride-rich lipoproteins (TGRL) and/or remnant cholesterol (RC) in the development of ASCVD. TGRL are comprised of hepatically derived very low-density lipoprotein (VLDL) and intestinally derived chylomicrons. RC is the cholesterol content of all TGRL and plasma triglycerides serve as a surrogate measure of TGRL and RC. Although lifestyle modification remains the cornerstone for management of hypertriglyceridemia, many novel drugs are in development and have shown impressive TG lowering efficacy. Several ongoing randomized controlled trials are under way to examine the impact of these novel agents on ASCVD outcomes. In this comprehensive review, we provide an overview of the biology, epidemiology and genetics of triglycerides and ASCVD and discuss current and novel triglyceride lowering therapies under development.
- The Krüppel-Like Factors and Control of Energy Homeostasis. [Journal Article]
- EREndocr Rev 2018 Oct 10
- Nutrient handling by higher organisms is a complex process that is regulated in a significant manner at the transcriptional level. Studies over the past 15 years highlight the critical importance of ...
Nutrient handling by higher organisms is a complex process that is regulated in a significant manner at the transcriptional level. Studies over the past 15 years highlight the critical importance of a family of transcriptional regulators termed the Krüppel-like factors (KLFs) in metabolism. Within an organ, distinct KLFs direct networks of metabolic gene targets to achieve specialized functions. This regulation is often orchestrated in concert with recruitment of tissue-specific transcriptional regulators, particularly members of the nuclear receptor family. Upon nutrient entry into the intestine, gut and liver KLFs control a range of functions from bile synthesis to intestinal stem cell maintenance to affect nutrient acquisition. Subsequently, coordinated KLF activity across multiple organs distributes nutrients to sites of storage or liberates them for use, in response to changes in nutrient status. Finally, in energy consuming organs like cardiac and skeletal muscle, KLFs tune local metabolic programs to precisely match substrate uptake, flux and utilization, particularly via mitochondrial function, with energetic demand; this is achieved in part through circulating mediators including glucocorticoids and insulin. In this Review, we summarize current understanding of KLFs in regulation of nutrient absorption, inter-organ circulation, and tissue-specific utilization.
- Endocrinology of Transgender Medicine. [Journal Article]
- EREndocr Rev 2018 Oct 10
- Gender affirming treatment for transgender people requires a multidisciplinary approach in which endocrinologists play a crucial role. The aim of this paper is to review recent data on hormonal treat...
Gender affirming treatment for transgender people requires a multidisciplinary approach in which endocrinologists play a crucial role. The aim of this paper is to review recent data on hormonal treatment of this population and its effect on physical, psychological and mental health. The Endocrine Society guidelines for transgender women include estrogens in combination with androgen lowering medications. Feminizing treatment with estrogens and anti-androgens has desired physical changes, such as enhanced breast growth, reduction of facial and body hair growth and fat redistribution in a female pattern. Possible side effects should be discussed with patients, particularly those at risk of venous thromboembolism. The Endocrine Society guidelines for transgender men include testosterone therapy for virilization with deepening of the voice, cessation of menses plus increase of muscle mass, facial and body hair. Due to the lack of evidence, treatment for gender non-binary people should be individualized. Young people may receive pubertal suspension, consisting of gonadotrophin-releasing hormone analogs, later followed by sex steroids. Options for fertility preservation should be discussed before any hormonal intervention. Morbidity and cardiovascular risk with cross-sex hormones is unchanged among transgender men and unclear among transgender women. Sex steroid-related malignancies can occur, but are rare. Mental health problems such as depression and anxiety have been found to reduce considerably following hormonal treatment. Future studies should aim to explore the long-term outcome of hormonal treatment in transgender people and provide evidence as to effect of gender affirming treatment in the non-binary population.
- Non-classical growth hormone insensitivity (GHI): characterization of mild abnormalities of GH action. [Journal Article]
- EREndocr Rev 2018 Sep 27
- GH insensitivity (GHI) presents in childhood with growth failure and in its severe form is associated with extreme short stature, dysmorphic and metabolic abnormalities. In recent years, the clinical...
GH insensitivity (GHI) presents in childhood with growth failure and in its severe form is associated with extreme short stature, dysmorphic and metabolic abnormalities. In recent years, the clinical, biochemical and genetic characteristics of GHI and other overlapping short stature syndromes have rapidly expanded. This can be attributed to advancing genetic techniques and a greater awareness of this group of disorders. We review this important spectrum of defects, which present with phenotypes at the milder end of the GHI continuum. We discuss their clinical, biochemical and genetic characteristics. The objective of this review is to clarify the definition, identification and investigation of this clinically relevant group of growth defects. We also review the therapeutic challenges of mild GHI.
- Emerging biomarkers, tools, and treatments for diabetic polyneuropathy. [Journal Article]
- EREndocr Rev 2018 Sep 25
- Diabetic neuropathy, with its major clinical sequels notably neuropathic pain, foot ulcers, and autonomic dysfunction, is associated with substantial morbidity, increased risk of mortality, and reduc...
Diabetic neuropathy, with its major clinical sequels notably neuropathic pain, foot ulcers, and autonomic dysfunction, is associated with substantial morbidity, increased risk of mortality, and reduced quality of life. Despite its major clinical impact, diabetic neuropathy remains underdiagnosed and undertreated. Moreover, the evidence supporting a benefit for causal treatment is weak at least in patients with type 2 diabetes, and current pharmacotherapy is largely limited to symptomatic treatment options. Thus, a better understanding of the underlying pathophysiology is mandatory for translation into new diagnostic and treatment approaches. Improved knowledge about pathogenic pathways implicated in the development of diabetic neuropathy could lead to novel diagnostic techniques that have the potential of improving the early detection of neuropathy in diabetes and prediabetes to eventually embark on new treatment strategies. Here we first provide an overview on the current clinical aspects and illustrate the pathogenetic concepts of (pre)diabetic neuropathy. We then describe the biomarkers emerging from these concepts and novel diagnostic tools and appraise their utility in the early detection and prediction of predominantly distal sensorimotor polyneuropathy (DSPN). Finally, we discuss the evidence for and limitations of the current and novel therapy options with particular emphasis on lifestyle modification and pathogenesis-derived treatment approaches. Altogether, recent years have brought forth a multitude of emerging biomarkers reflecting different pathogenic pathways such as oxidative stress and inflammation and diagnostic tools for an early detection and prediction of (pre)diabetic neuropathy. Ultimately, these insights should culminate in improving our therapeutic armamentarium against this common and debilitating or even life-threatening condition.
- Pathophysiology and Individualized Treatment for Hypothalamic Obesity Following Craniopharyngioma and Other Suprasellar Tumors: A Systematic Review. [Journal Article]
- EREndocr Rev 2018 Sep 20
- The development of hypothalamic obesity (HO) following craniopharyngioma (CP) and other suprasellar tumors leads to reduced patient quality of life. No treatment algorithms are currently available fo...
The development of hypothalamic obesity (HO) following craniopharyngioma (CP) and other suprasellar tumors leads to reduced patient quality of life. No treatment algorithms are currently available for management of HO. Depending on which hypothalamic nuclei are destroyed, the pathophysiologic mechanisms and clinical symptoms that contribute to HO differ among patients. Here, we review the contribution of the hypothalamus to the pathophysiologic mechanisms and symptoms underlying CP-associated HO. In addition, we performed a systematic search of MEDLINE and Embase to identify all intervention studies for weight management in patients with CP or other suprasellar tumors published until September 2017. The search yielded 1866 publications, of which 40 were included. Of these 40 studies, we identified four modalities for intervention (i.e., lifestyle, dietary, pharmacotherapeutic, or surgical) within six clinical domains (i.e., psychosocial disorders, hyperphagia, sleep disturbances, decreased energy expenditure, hyperinsulinemia, and hypopituitarism). We used the findings from our systematic review, in addition to current knowledge on the pathophysiology of HO, to develop an evidence-based treatment algorithm for patients with HO caused by CP or other suprasellar tumors. Although the individual effects of the HO interventions were modest, beneficial individual effects may be achieved when the pathophysiologic background and correct clinical domain are considered. These two aspects can be combined in an individualized treatment algorithm with a stepwise approach for each clinical domain. Recently elucidated targets for HO intervention were also explored to improve future management of HO for patients with CP and other suprasellar tumors.
- MELATONIN AS A HORMONE: NEW PHYSIOLOGICAL AND CLINICAL INSIGHTS. [Journal Article]
- EREndocr Rev 2018 Sep 12
- Melatonin is a ubiquitous molecule present in almost every live being from bacteria to humans. In vertebrates, besides being produced in peripheral tissues and acting as an autocrine and paracrine si...
Melatonin is a ubiquitous molecule present in almost every live being from bacteria to humans. In vertebrates, besides being produced in peripheral tissues and acting as an autocrine and paracrine signal, melatonin is centrally synthetized by a neuroendocrine organ, the pineal gland. Independently of the considered specie, pineal hormone melatonin is always produced during the night and its production and secretory episode duration is directly dependent on the length of the night. As its production is tightly linked to the light/dark cycle, melatonin main hormonal systemic integrative action is to coordinate behavioral and physiological adaptations to the environmental geophysical day and season. The circadian signal is dependent on its daily production regularity, on the contrast between day and night concentrations and on specially developed ways of action. During its daily secretory episode, melatonin coordinates the night adaptive physiology through immediate effects and primes the day adaptive responses through prospective effects that will only appear at daytime, when melatonin is absent. Similarly, the annual history of the daily melatonin secretory episode duration primes the central nervous/endocrine system to the seasons to come. Remarkably, maternal melatonin programs the fetuses' behavior and physiology to cope with the environmental light/dark cycle and season after birth. These unique ways of action turn melatonin into a biological time-domain acting molecule. The present review focus on the above considerations, proposes a putative classification of clinical melatonin dysfunctions and discuss general guidelines to the therapeutic use of melatonin.
New Search Next
- Insulin-like growth factor-I receptor and thyroid-associated ophthalmopathy. [Journal Article]
- EREndocr Rev 2018 Sep 11
- Thyroid-associated ophthalmopathy (TAO) is a complex disease process presumed to emerge from autoimmunity occurring in the thyroid gland, most frequently in Graves' disease (GD). It is disfiguring an...
Thyroid-associated ophthalmopathy (TAO) is a complex disease process presumed to emerge from autoimmunity occurring in the thyroid gland, most frequently in Graves' disease (GD). It is disfiguring and potentially blinding, culminating in orbital tissue remodeling and disruption of function of structures adjacent to the eye. There are currently no medical therapies proven capable of altering the clinical outcome of TAO in randomized, placebo-controlled multicenter trials. The orbital fibroblast represents the central target for immune reactivity. Recent identification of fibroblasts that originate in the bone marrow as monocyte progenitors provides a plausible explanation for why antigens, the expressions of which were once considered restricted to the thyroid, are detected in the TAO orbit. These cells, known as fibrocytes, express relatively high levels of functional thyrotropin receptor (TSHR) through which they can be activated by TSH and the GD-specific pathogenic antibodies that underpin thyroid over-activity. Fibrocytes also express insulin-like growth factor-I receptor (IGF-IR) with which TSHR forms a physical and functional signaling complex. Notably, inhibiting IGF-IR activity results in the attenuation of signaling initiated at either receptor. Some studies suggest that IGF-IR-activating antibodies are generated in GD while others refute this concept. These observations served as the rationale for implementing a recently completed therapeutic trial of teprotumumab, a monoclonal inhibitory antibody targeting IGF-IR in TAO. Results of that trial in active, moderate to severe disease revealed dramatic and rapid reductions in disease activity and severity. Targeting IGF-IR with specific biologic agents may represent a paradigm shift in the therapy of TAO.