Reviews & Analysis

Identification of the cellular and molecular mechanisms that regulate bone remodelling is crucial for the development of effective skeletal therapeutics. A new study in mice shows that erythropoietin increases bone loss by enhancing osteoclast differentiation and bone resorption.

The extracellular calcium-sensing receptor (CaSR) is a G protein-coupled receptor that has a key role in Ca²⁺homeostasis via its role in the parathyroid glands and kidneys. New evidence has shown that CaSR also regulates skeletal homeostasis. In this Review, David Goltzman and Geoffrey Hendy discuss the role of CaSR in chondrocytes and development of the cartilagenous growth plate, in osteoblasts and osteoclasts, and effects of CaSR on skeletal development and bone turnover.

MicroRNAs (miRNAs) regulate the differentiation of adipoctyes, as well as endocrine and inflammatory processes in adipose tissues. In this Review, Arner and Kulyté addressed the characterization and functions of miRNA regulatory networks in human adipose tissue, in particular the networks that contribute to chronic low-level inflammation. The potential for targeting these networks, as well as individual miRNAs, in obesity and other metabolic disorders is also discussed.

Chylomicronaemia is a challenging metabolic disorder that presents in two distinct primary forms: rare monogenic early-onset chylomicronaemia and polygenic late-onset chylomicronaemia. In this Review, Amanda Brahm and Robert Hegele discuss the genetic basis of the disorder and present a framework for the diagnosis and treatment of patients with severe hypertriglyceridaemia that results from chylomicronaemia.

The lack of short-term cardiovascular benefit observed when therapies to improve glycaemic control are used in patients with diabetes mellitus has drawn attention to the need to limit potential risks of treatment, especially those related to hypoglycaemia. A recent report considers HbA_1c levels <7% in older people a sign of overtreatment, but other findings suggest additional ways to identify and control risk.

Resistance to TSH that results from mutations in TSHR causes overt or subclinical congenital hypothyroidism (SCH). Tenenbaum-Rakover et al. now demonstrate that thyroid hormone levels remain stable in patients with heterozygous TSHR mutations who have SCH, but can decline progressively in some patients with homozygous TSHR mutations, which necessitates treatment with levothyroxine.

Exercise training is one of the key interventions for preventing and treating type 2 diabetes mellitus. Although the health-promoting effects of exercise are largely ascribed to improvements in skeletal muscle insulin sensitivity, new data published in Diabetes suggest 'exercise-trained' subcutaneous adipose tissue might also have an important role in enhancing glucose homeostasis.

Several studies have linked maternal iodine deficiency during pregnancy with adverse neurodevelopmental outcomes in offspring. A new study warns that excessive iodine exposure might also be detrimental to maternal thyroid health and recommends a lower limit for maternal iodine intake during pregnancy than that currently advised by the WHO.

In contemporary society, the ready availability of calorie-dense, highly palatable foods has contributed to the global obesity epidemic. Individuals with obesity often consume an excess of food, despite knowledge of the associated adverse consequences. In this Review, Santa-Cruz Calvo and Egan explore the physiology of taste perception with regard to taste receptors, neuronal signalling and hormonal control of food intake.

A prospective randomized controlled trial in patients with papillary thyroid cancer without lymph node metastases demonstrated similar oncologic outcomes in patients who underwent total thyroidectomy with prophylactic central compartment lymph node dissection (pCCND) and in those who underwent total thyroidectomy without pCCND. However, pCCND was associated with an increased rate of complications.

The replacement or regeneration of pancreatic β cells has the potential to reverse the progression of diabetes mellitus. This Review discusses the physiology of normal β-cell replication, the signalling pathways and epigenetic mechanisms that regulate entry to the cell cycle in β cells, and approaches for discovering novel molecules that drive β-cell replication. The potential and challenges of implementing strategies that replace or regenerate β-cells in humans is also discussed.

The adenosine–adenosine receptor system has a key role in regulating glucose homeostasis and in the pathophysiology of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). In this Review, the authors discuss the role of the adenosinergic system in regulating both the onset and progression of T1DM and T2DM, and the potential of manipulating this system as an approach to manage T1DM, T2DM and their associated complications.

Combination immunotherapies for type 1 diabetes mellitus (T1DM) that have shown promise in preclinical studies are often not effective in clinical trials, possibly because of the heterogeneity of the disease. This Review summarizes the available data about combination immunotherapies in T1DM, particularly addressing their clinical importance.

The renin–angiotensin–aldosterone system (RAAS) regulates blood pressure homeostasis via multiple mechanisms that act on a variety of organs. The development of drugs that target RAAS components is an active area of research. The authors of this Review discuss current and future therapeutic manipulation of the RAAS and its promise in improving the care of patients with hypertension.

An innovative strategy that uses a well-balanced monomeric peptide triagonist to target three metabolically related hormone receptors has been developed. This strategy seems to be the most effective pharmacological approach to reverse obesity and its metabolic comorbidities in rodents and could open new ways to tackle the dual burden of obesity and diabetes mellitus in humans.

Successful studies in the nonobese diabetic (NOD) mouse model often do not translate to positive outcomes in human studies. This Perspectives outlines the genetic and immunologic differences that might contribute to these differential outcomes and suggests how the NOD mouse model could be adapted to improve its utility.

Type 1 diabetes mellitus (T1DM) is associated with increased risk of mortality, despite improvements in management of glucose levels and treatment of cardiovascular risk factors. A population-based study of individuals with T1DM and control individuals matched for age and sex has used glycaemic control to characterize the excess risk of overall and cardiovascular mortality.

Thyroid-associated ophthalmopathy (TAO) is an orbital manifestation of Graves disease. The pathogenesis of TAO is still not well understood and effective therapies for TAO are lacking. Here, Terry Smith reviews the processes that underlie autoimmunity and inflammation in the orbit of patients with TAO, with a focus on the role of infiltrating fibrocytes expressing the TSH receptor. Therapeutic implications are also discussed.

Stromal cells and stem cells have been successfully used for bone-tissue-engineering applications in clinical trials; however, the routine use of these cells is far from being adopted into clinical practice. In this Review, Warren Grayson and colleagues discuss the scientific, technical, practical and regulatory obstacles that are preventing the widespread therapeutic use of stromal cells and stem cells to enhance skeletal repair.

Long non-coding RNAs (lncRNAs) have important roles in many physiological and pathological processes. The authors of this Review focus on the endocrine system and discuss the involvement of lncRNAs in the development and function of various endocrine organs, as well as the associations of lncRNAs with endocrine diseases such as diabetes mellitus and endocrine cancers.