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The Lancet. Diabetes & Endocrinology Sep 2018Frailty is a condition characterised by loss of biological reserves, failure of homoeostatic mechanisms, and vulnerability to adverse outcomes. The endocrine system is... (Review)
Review
Frailty is a condition characterised by loss of biological reserves, failure of homoeostatic mechanisms, and vulnerability to adverse outcomes. The endocrine system is considered particularly important in frailty, because of its complex inter-relationships with the brain, immune system, and skeletal muscle. This Review summarises evidence indicating a key role for the hypothalamic-pituitary axis in the pathogenesis of frailty through aberrant regulation of glucocorticoid secretion, insulin-like growth factor signalling, and androgen production. Evidence also indicates a potential role for vitamin D and insulin resistance in the pathogenesis of frailty. The role of thyroid hormones in the pathogenesis of frailty remains uncertain. Key convergent pathological effects of frailty include loss of muscle mass and strength, with consequent impact on mobility and activities of daily living. Future translational research should focus on the understanding of endocrine mechanisms, to identify potential biomarkers of the condition, modifiable targets for treatment, and novel pharmacological drugs targeted at the endocrine components of frailty.
Topics: Aged; Aging; Androgens; Endocrine System; Frailty; Glucocorticoids; Humans; Insulin Resistance; Sarcopenia; Signal Transduction; Somatomedins; Vitamin D
PubMed: 30017798
DOI: 10.1016/S2213-8587(18)30110-4 -
Frontiers in Endocrinology 2020Hormones are largely responsible for the integrated communication of several physiological systems responsible for modulating cellular growth and development. Although... (Review)
Review
Hormones are largely responsible for the integrated communication of several physiological systems responsible for modulating cellular growth and development. Although the specific hormonal influence must be considered within the context of the entire endocrine system and its relationship with other physiological systems, three key hormones are considered the "anabolic giants" in cellular growth and repair: testosterone, the growth hormone superfamily, and the insulin-like growth factor (IGF) superfamily. In addition to these anabolic hormones, glucocorticoids, mainly cortisol must also be considered because of their profound opposing influence on human skeletal muscle anabolism in many instances. This review presents emerging research on: (1) Testosterone signaling pathways, responses, and adaptations to resistance training; (2) Growth hormone: presents new complexity with exercise stress; (3) Current perspectives on IGF-I and physiological adaptations and complexity these hormones as related to training; and (4) Glucocorticoid roles in integrated communication for anabolic/catabolic signaling. Specifically, the review describes (1) Testosterone as the primary anabolic hormone, with an anabolic influence largely dictated primarily by genomic and possible non-genomic signaling, satellite cell activation, interaction with other anabolic signaling pathways, upregulation or downregulation of the androgen receptor, and potential roles in co-activators and transcriptional activity; (2) Differential influences of growth hormones depending on the "type" of the hormone being assayed and the magnitude of the physiological stress; (3) The exquisite regulation of IGF-1 by a family of binding proteins (IGFBPs 1-6), which can either stimulate or inhibit biological action depending on binding; and (4) Circadian patterning and newly discovered variants of glucocorticoid isoforms largely dictating glucocorticoid sensitivity and catabolic, muscle sparing, or pathological influence. The downstream integrated anabolic and catabolic mechanisms of these hormones not only affect the ability of skeletal muscle to generate force; they also have implications for pharmaceutical treatments, aging, and prevalent chronic conditions such as metabolic syndrome, insulin resistance, and hypertension. Thus, advances in our understanding of hormones that impact anabolic: catabolic processes have relevance for athletes and the general population, alike.
Topics: Adaptation, Physiological; Animals; Exercise; Growth Hormone; Growth and Development; Humans; Hydrocortisone; Muscle, Skeletal; Somatomedins; Testosterone
PubMed: 32158429
DOI: 10.3389/fendo.2020.00033 -
Frontiers of Hormone Research 2016Human growth hormone (GH) was first isolated from the human pituitary gland in 1945 and found to promote the growth of children with hypopituitarism. Since the formation... (Review)
Review
Human growth hormone (GH) was first isolated from the human pituitary gland in 1945 and found to promote the growth of children with hypopituitarism. Since the formation of the World Anti-Doping Association, human GH has appeared on the list of forbidden substances. There is a significant amount of anecdotal evidence that human GH is misused by athletes to enhance performance, and there have been a number of high-profile cases of GH use in professional sport. GH secretagogues (GH-Ss), which increase GH secretion, and insulin-like growth factor (IGF-1), which mediates many of the effects of GH, are also misused, although there is less evidence for this. The effectiveness of GH, IGF-1, and GH-Ss as performance-enhancing drugs remains unclear. Evidence from studies of GH use in people with hypopituitarism show several desirable outcomes, including increased lean body mass, increased strength, and increased exercise capacity. These anabolic and metabolic properties, coupled with the difficulty in detecting them, make them attractive as agents of misuse. Studies in healthy young adults have also demonstrated a performance benefit with GH and IGF-1.
Topics: Doping in Sports; Growth Hormone; Humans; Insulin-Like Growth Factor I
PubMed: 27347885
DOI: 10.1159/000445173 -
Molecular and Cellular Endocrinology Dec 2020The insulin-like growth factor (IGF) system comprises two ligands, IGF-I and IGF-II, that regulate multiple physiological processes, including mammalian development,... (Review)
Review
The insulin-like growth factor (IGF) system comprises two ligands, IGF-I and IGF-II, that regulate multiple physiological processes, including mammalian development, metabolism and growth, through the type 1 IGF receptor (IGF-1R). The growth hormone (GH)-IGF-I axis is the major regulator of longitudinal growth. IGF-II is expressed in many tissues, notably the placenta, to regulate human pre- and post-natal growth and development. This review provides a brief introduction to the IGF system and summarizes findings from reports arising from recent larger genomic sequencing studies of human genetic mutations in IGF1 and IGF2 and genes of proteins regulating IGF action, namely the IGF-1R, IGF-1R signaling pathway components and the IGF binding proteins (IGFBPs). A perspective on the effect of homozygous mutations on structure and function of the IGFs and IGF-1R is also given and this is related to the effects on growth.
Topics: Animals; Female; Genetic Diseases, Inborn; Growth Disorders; Humans; Metabolic Diseases; Mutation; Pregnancy; Receptor, IGF Type 1; Receptors, Somatomedin; Signal Transduction; Somatomedins
PubMed: 32941924
DOI: 10.1016/j.mce.2020.111035 -
Nature Reviews. Endocrinology May 2018Growth hormone (GH) research and its clinical application for the treatment of growth disorders span more than a century. During the first half of the 20th century,... (Review)
Review
Growth hormone (GH) research and its clinical application for the treatment of growth disorders span more than a century. During the first half of the 20th century, clinical observations and anatomical and biochemical studies formed the basis of the understanding of the structure of GH and its various metabolic effects in animals. The following period (1958-1985), during which pituitary-derived human GH was used, generated a wealth of information on the regulation and physiological role of GH - in conjunction with insulin-like growth factors (IGFs) - and its use in children with GH deficiency (GHD). The following era (1985 to present) of molecular genetics, recombinant technology and the generation of genetically modified biological systems has expanded our understanding of the regulation and role of the GH-IGF axis. Today, recombinant human GH is used for the treatment of GHD and various conditions of non-GHD short stature and catabolic states; however, safety concerns still accompany this therapeutic approach. In the future, new therapeutics based on various components of the GH-IGF axis might be developed to further improve the treatment of such disorders. In this Review, we describe the history of GH research and clinical use with a particular focus on disorders in childhood.
Topics: Female; Growth Hormone; Human Growth Hormone; Humans; Male; Somatomedins
PubMed: 29546874
DOI: 10.1038/nrendo.2018.22 -
European Heart Journal Dec 2022Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in diverse patient populations, but their mechanism of action requires further study.... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in diverse patient populations, but their mechanism of action requires further study. The aim is to explore the effect of empagliflozin on the circulating levels of intracellular proteins in patients with heart failure, using large-scale proteomics.
METHODS AND RESULTS
Over 1250 circulating proteins were measured at baseline, Week 12, and Week 52 in 1134 patients from EMPEROR-Reduced and EMPEROR-Preserved, using the Olink® Explore 1536 platform. Statistical and bioinformatical analyses identified differentially expressed proteins (empagliflozin vs. placebo), which were then linked to demonstrated biological actions in the heart and kidneys. At Week 12, 32 of 1283 proteins fulfilled our threshold for being differentially expressed, i.e. their levels were changed by ≥10% with a false discovery rate <1% (empagliflozin vs. placebo). Among these, nine proteins demonstrated the largest treatment effect of empagliflozin: insulin-like growth factor-binding protein 1, transferrin receptor protein 1, carbonic anhydrase 2, erythropoietin, protein-glutamine gamma-glutamyltransferase 2, thymosin beta-10, U-type mitochondrial creatine kinase, insulin-like growth factor-binding protein 4, and adipocyte fatty acid-binding protein 4. The changes of the proteins from baseline to Week 52 were generally concordant with the changes from the baseline to Week 12, except empagliflozin reduced levels of kidney injury molecule-1 by ≥10% at Week 52, but not at Week 12. The most common biological action of differentially expressed proteins appeared to be the promotion of autophagic flux in the heart, kidney or endothelium, a feature of 6 proteins. Other effects of differentially expressed proteins on the heart included the reduction of oxidative stress, inhibition of inflammation and fibrosis, and the enhancement of mitochondrial health and energy, repair, and regenerative capacity. The actions of differentially expressed proteins in the kidney involved promotion of autophagy, integrity and regeneration, suppression of renal inflammation and fibrosis, and modulation of renal tubular sodium reabsorption.
CONCLUSIONS
Changes in circulating protein levels in patients with heart failure are consistent with the findings of experimental studies that have shown that the effects of SGLT2 inhibitors are likely related to actions on the heart and kidney to promote autophagic flux, nutrient deprivation signalling and transmembrane sodium transport.
Topics: Humans; Diabetes Mellitus, Type 2; Heart Failure; Inflammation; Proteomics; Sodium; Sodium-Glucose Transporter 2 Inhibitors; Somatomedins
PubMed: 36017745
DOI: 10.1093/eurheartj/ehac495 -
The Journal of Clinical Endocrinology... Jun 2023The pappalysin metalloproteinases, PAPP-A and PAPP-A2, have emerged as highly specific proteolytic enzymes involved in the regulation of insulin-like growth factor (IGF)... (Review)
Review
The pappalysin metalloproteinases, PAPP-A and PAPP-A2, have emerged as highly specific proteolytic enzymes involved in the regulation of insulin-like growth factor (IGF) signaling. The only known pappalysin substrates are a subset of the IGF binding proteins (IGFBPs), which bind IGF-I or IGF-II with high affinity to antagonize receptor binding. Thus, by cleaving IGFBPs, the pappalysins have the potential to increase IGF bioactivity and hence promote IGF signaling. This is relevant both in systemic and local IGF regulation, in normal and several pathophysiological conditions. Stanniocalcin-1 and -2 were recently found to be potent pappalysin inhibitors, thus comprising the missing components of a complete proteolytic system, the stanniocalcin-PAPP-A-IGFBP-IGF axis. Here, we provide the biological context necessary for understanding the properties of this molecular network, and we review biochemical data, animal experiments, clinical data, and genetic data supporting the physiological operation of this branch as an important part of the IGF system. However, although in vivo data clearly illustrate its power, it is a challenge to understand its subtle operation, for example, multiple equilibria and inhibitory kinetics may determine how, where, and when the IGF receptor is stimulated. In addition, literally all of the regulatory proteins have suspected or known activities that are not directly related to IGF signaling. How such activities may integrate with IGF signaling is also important to address in the future.
Topics: Animals; Humans; Pregnancy-Associated Plasma Protein-A; Insulin-Like Growth Factor I; Glycoproteins; Insulin-Like Growth Factor Binding Proteins; Receptors, Somatomedin; Insulin-Like Growth Factor Binding Protein 4
PubMed: 36718521
DOI: 10.1210/clinem/dgad053 -
Aging Aug 2022
Topics: Growth Hormone; Insulin-Like Growth Factor I
PubMed: 36063137
DOI: 10.18632/aging.204257 -
Cells Jan 2022Over the past two decades, interest in the role of the somatotroph growth hormone/insulin-like growth factor (GH/IGF1) axis in multiple aspects of physiology and...
Over the past two decades, interest in the role of the somatotroph growth hormone/insulin-like growth factor (GH/IGF1) axis in multiple aspects of physiology and pathology has grown exponentially [...].
Topics: Aging; Animals; Genomics; Growth Hormone; Humans; Signal Transduction; Somatomedins
PubMed: 35053333
DOI: 10.3390/cells11020217 -
Annual Review of Entomology 2016Immune defense and reproduction are physiologically and energetically demanding processes and have been observed to trade off in a diversity of female insects. Increased... (Review)
Review
Immune defense and reproduction are physiologically and energetically demanding processes and have been observed to trade off in a diversity of female insects. Increased reproductive effort results in reduced immunity, and reciprocally, infection and activation of the immune system reduce reproductive output. This trade-off can manifest at the physiological level (within an individual) and at the evolutionary level (genetic distinction among individuals in a population). The resource allocation model posits that the trade-off arises because of competition for one or more limiting resources, and we hypothesize that pleiotropic signaling mechanisms regulate allocation of that resource between reproductive and immune processes. We examine the role of juvenile hormone, 20-hydroxyecdysone, and insulin/insulin-like growth factor-like signaling in regulating both oogenesis and immune system activity, and propose a signaling network that may mechanistically regulate the trade-off. Finally, we discuss implications of the trade-off in an ecological and evolutionary context.
Topics: Animals; Immune System; Insect Hormones; Insecta; Insulin; Oogenesis; Signal Transduction; Somatomedins
PubMed: 26667271
DOI: 10.1146/annurev-ento-010715-023924