What's new in Endocrinology? (Vol II)

Jeff M P Holly ^1* Marc R Blackman ² Sally Radovick ³ Hubert Vaudry ⁴

• ¹ University of Bristol, Bristol, United Kingdom
• ² Washington DC VA Medical Center, United States Department of Veterans Affairs, Washington D.C., District of Columbia, United States
• ³ University of Arizona, Tucson, Arizona, United States
• ⁴ Université de Rouen, Mont-Saint-Aignan, Upper Normandy, France

The prevalence of obesity and type 2 diabetes mellitus (T2DM) have grown alarmingly across the world during the last few decades and have become major challenges for public health. Both conditions present due to hormonal disturbances, and it has become increasingly clear that these result from dietary changes caused by a transformation in our food environment. Anjom-Shoae et al. review recent evidence examining the acute and long-term effects of high protein diets and comparing the effects of diets high in either animal or plant proteins (2). It is well established that high protein diets can have beneficial effects on body weight and glycaemic control, at least over a short timeframe, related to their effects on satiety, gastric emptying times and gut hormone release. Diets high in either animal or plant proteins had these beneficial effects on body weight and glycaemic control over shorter periods; in comparison, longer-term studies, greater than 12 months, indicated that diets high in plant proteins had either neutral or beneficial effects, whereas diets high in animal protein exerted adverse effects. The latter observations are consistent with several prospective epidemiological studies of large populations that have all shown that diets high in animal proteins are associated with an increased risk of obesity and T2DM. The reasons for the differential long-term effects of animal and plant proteins are not clear, but could be due to differences in amino acid composition, glycaemic load and/or the higher insulinotropic effects of animal proteins, with the insulin then promoting fat deposition and inhibiting fat oxidation. More studies are needed to understand the effects of different proteins on the gastrointestinal and other mechanisms involved in food intake and glycaemic control.With the prevalence of T2DM continuing to grow, the marked differences in its presentation and progression present challenges for the management of patients. Groups working with the Risk Assessment and Progression of Diabetes (RHAPSODY) consortium have used an unsupervised, "bottom-up", multimodal, multivariate strategy to analyze multi-omic data obtained from two European cohorts of patients with T2DM in order to better characterize the complexity of the molecular interactions that underlie this heterogeneity among patients (3). By measuring 180 circulating lipids and 1195 proteins, they identified two subgroups of patients who differed in terms of insulin sensitivity and secretion, and glycemic deterioration,. and identified various groups of biomarkers, most notably those involved in immune processes, that were associated with these distinct subgroups of patients. These biomarkers will provide valuable targets for future studies examining causal pathways for disease progression.Proinflammatory cytokines have been implicated in the pancreatic -cell failure that underlies both type 1 diabetes mellitus (T1DM) and T2DM. Understanding the molecular mechanisms in this process can lead to the discovery of biomarkers that may assist in monitoring disease progression and to new targets for therapeutic interventions. A novel cytokine mediated effect on -cell RNA turnover is reported by Ghjiasi et al (4). Another very international collaboration used human and rodent -cell models to reveal a novel cytokine mediated effect on -cell RNA turnover. These investigators found that cytokines decreased the activity of nonsense-mediated RNA decay (NMD), which normally functions to eliminate premature termination containing mRNAs, and thus could disturb the balance between anti-and pro-apoptotic transcripts. These findings open up new avenues of research into the various components of the NMD machinery as potential biomarkers or therapeutic targets.The regulation of reproductive function is intimately controlled in relation to metabolic status. Recent advances in our understanding of the pathways involved is reviewed by Rodríguez-Vázquez et al, with a focus on the impact of metabolism on pubertal development and fertility (5). They describe the pivotal role played by the hypothalamus in integrating central neuronal signals with hormonal signals, wherein peripheral metabolic hormones such as leptin, insulin, and ghrelin act on Kiss1 and GnRH neurons to regulate pubertal development according to metabolic status. In addition, it has emerged that many cellular sensors also play a direct role in this integration, including energy sensors such as AMPK, mTOR and SIRT1, as well as several lipid sensing pathways, including fatty acid receptors, fatty acid transport proteins, and nuclear receptors. Nuclear receptors such as peroxisome proliferator-activated receptors are differentially expressed in specific hypothalamic neurons, and when fatty acids are bound, these are then translocated to the nucleus where they can activate or repress gene transcription. In addition, both bile acids (BA), which are synthesised in the liver, and secondary BA, which are formed after transformation by the gut microbiota, interact with the G protein coupled-receptor, TGR5, in the hypothalamus. A complex framework for the integral regulation of whole-body metabolism and reproductive function is described, which should enable further functional connectivity mapping of the hypothalamic neuronal and glial cells involved.Cushing's syndrome (CS) is a classical, but relatively rare, endocrine disease that is due to hypercortisolism and is treated by surgical excision of the causal adrenal or pituitary lesion. Despite successful treatment a large proportion of patients in remission suffer from persistent fatigue, muscle weakness and sarcopenia. Recent evidence has increasingly implicated microRNAs (miRNAs) in skeletal muscle regulation and Seco-Cervera et al. conducted a pilot study screening for circulating miRNAs that could be potential biomarkers of sarcopenia in a group of patients with CS in sustained biochemical remission (6). In a pilot study, confirmed in a second validation cohort, they found that miR-28-5p was upregulated in CS patients with sarcopenia as compared to those without. Prior evidence indicates that miR-28-5p is a muscle-specific miRNA that is involved in myoblast proliferation, differentiation and regeneration suggesting that there may be a functional link to the persistent sarcopenia. These preliminary findings suggest that miR-28-5p may be a promising candidate circulating biomarker to indicate the risk of persistent sarcopenia in treated CS patients despite normalised cortisol levels, who may then benefit from adapted exercise programs to improve their quality of life and prevent future falls. More generally it may also indicate a fertile area of future investigations as a potential therapeutic target for age-related sarcopenia and various pathological, muscle wasting conditions. Two manuscripts in this collection describe updated guidelines for the diagnosis and management of rickets and multiple endocrine neoplasia (MEN), two other classical endocrinopathies, particularly in light of advances in molecular medicine. Rickets is a heterogeneous group of skeletal diseases resulting from impaired mineralisation of growing bones due to nutritional or hereditary disturbances in calcium and phosphate homeostasis. On behalf of the Bone and Mineral Metabolism Group of the Italian Society of Pediatric Endocrinology and Diabetology, Baroncelli et al. present practical guidance on the diagnosis, treatment, and management of patients with rickets (7). Extensive guidelines, including algorithms, are provided to ensure early differential diagnosis of nutritional and genetic forms of rickets according to biochemical findings and clinical and radiological examinations. Specific recommendations for the multidisciplinary treatment programs of each distinct form of rickets are also provided, including for rare, hereditary forms of the disease.Multiple endocrine neoplasia (MEN) is a group of diseases characterised by multiple tumours occurring within endocrine tissues of an individual. Since the first form, MEN1, was reported 70 years ago three further forms, MEN2, MEN3 and MEN4 have subsequently been described. These syndromes were initially characterised according to their clinical phenotype and their underlying genetic causes were subsequently discovered. Romanet et al review recent advances in the genetics, diagnosis and screening for the various forms of MEN (8). MENs are rare hereditary diseases that are transmitted in an autosomal dominant manner and not all cases fit within the classical MEN subgroups. Romanet et al. describe guidelines for MEN diagnosis along with challenges and pitfalls of different sequencing strategies that can be applied. They (1) emphasise the strategy for management of index cases and presymptomatic genetic screening and counselling for relatives; (2) describe advances in strategies for unravelling gene-disease relationships including the value of using induced pluripotent stem cells to generate patient-derived spheroids, tumoroids and organoids for investigating the pathophysiology and potential drug responses; and (3) highlight the need for national or regional large cohort studies to better understand these rare diseases.Melatonin a classical hormone that is produced by the pineal gland, an outgrowth of the posterodorsal thalamus, is secreted predominantly at night, with a primary endocrine role in maintaining the circadian rhythm throughout the body. Less well known is that most melatonin is produced by extrapineal tissues, and Reiter et al (9) give an update on the potential functions of this second source of melatonin. They estimate that less than 5% of the melatonin in the body is produced in the pineal gland, whereas the vast majority of melatonin is produced in multiple tissues throughout the body and is not linked to dark/light cycles or secreted into the circulation, but acts locally, primarily in an autocrine, and possibly also paracrine, manner. This extrapineal melatonin appears to be produced in the mitochondria, where it has roles in scavenging free radicals, re-dox homeostasis and anti-inflammation, and may therefore be important for maintaining general health and countering pathology.The final article in the Research Topic does not relate to advances in endocrine science or practice but describes an emerging challenge regarding how endocrinology is reported. At Frontiers in Endocrinology, we have witnessed an exponential rise in the submission of manuscripts that are derivative, or primarily redundant and otherwise of low-quality. This phenomenon has been exacerbated by manuscripts that do not report novel findings or new data, but report analyses of huge amounts of data that can now be found within large publicly-available databases. Additionally, there has been considerable growth in redundant bibliometric reviews and fraudulent manuscripts, many produced by "papermills". Such manuscripts have been witnessed across most medical specialties and are of limited value to our or other readers. In a commentary, we document how this has affected Frontiers in Endocrinology, and we outline some of the measures that we have taken to reduce their frequency and prevent them from overwhelming the literature (10).Technological advances continue to provide endocrinologists with ever more powerful tools that continue to reveal new understanding and opportunities for novel treatments, even for the most well characterized endocrine conditions. The challenges faced by endocrinologists also continue to evolve as populations increasingly age and modern lifestyles increase the burden of metabolic disorders. This collection of articles reflects a variety of these challenges and the dynamic nature of modern endocrinology.