Reviews & Analysis

Here, Patrice Cani and colleagues discuss interactions between gut microorganisms, the endocannabinoid system and host metabolism, in the context of both physiology and pathophysiology. The authors highlight the importance of gut barrier function by discussing the role of specific factors involved in intestinal permeability and their role in the gut microbiota–endocannabinoid system axis. The therapeutic potential of targeting the endocannabinoid system to treat cardiometabolic disorders and intestinal inflammation is also discussed.

Diabetic cardiomyopathy is a major cause of morbidity and mortality, and its prevalence is increasing. This Review discusses the latest research in diabetic cardiomyopathy, summarizes current understanding of the molecular mechanisms underpinning this condition and explores potential preventive and therapeutic strategies.

Studies published in 2015 have continued to unravel the genomic landscape of thyroid cancer, particularly of its less common forms (such as medullary and anaplastic carcinomas) and of familial forms of thyroid cancer. As a result, new diagnostic and therapeutic markers have been identified and validated for clinical use.

This Review outlines the molecular basis of nongenomic mechanisms of thyroid hormone action. Davis and colleagues also discuss the possible physiological or pathophysiological consequences of these actions, as well as the interactions between nongenomic and genomic effects of thyroid hormone.

Statins are widely used to prevent cardiovascular disease, but have been associated with an increased risk of new-onset diabetes mellitus. This Review discusses the evidence for this association, as well as what is known about the potential mechanisms underpinning this effect. The implications for clinical management of individuals at medium-to-high risk of new-onset diabetes mellitus are also discussed.

A new study shows that low and high maternal levels of free T₄ during pregnancy are associated with reduced IQ and cortex and grey matter volumes in offspring. Do these findings herald change for the clinical management of pregnant women with borderline low or high normal levels of T₄?

Exercise training has positive effects on disease risk and health outcomes through mechanisms that have not been fully characterized. Newly published data reveal that a single bout of exercise regulates the phosphoproteome via activation of a global network of kinases and 5′-AMP-activated protein kinase substrates — targets with therapeutic potential for chronic metabolic diseases.

In 2015, four studies demonstrated that hepatic glucose metabolism is altered by targeting the farnesoid X-activated receptor in the gut, the insulin receptor in extrahepatic tissues such as the brain and an S-nitrosylation–endoplasmic reticulum-stress-dependent pathway in the liver. Targeting nutrient-dependent and hormone-dependent signalling pathways in these organs could help regulate hepatic glucose production in patients with diabetes mellitus and obesity.

Medical therapies for patients with acromegaly are limited by variable efficacy, associated adverse effects and the need for frequent injections. This Review outlines the need for new therapeutic agents for patients with acromegaly, reviews clinical trial data of investigational agents and considers how these therapies might best be integrated into clinical practice in the future.

Finnish women <60 years old have an increased risk of death from cardiac events or stroke within a year of stopping hormone-replacement therapy (HRT), compared with women who have not had HRT and with those on current therapy. The safety of the practice of annual discontinuation of HRT should be questioned.

A recent US study comparing different drugs for ovarian stimulation in women with unexplained infertility demonstrates that letrozole is less effective than gonadotropins or clomiphene; however, the primary end point for the study was not efficacy but, rather, multiple pregnancy rates. This study confirms, yet again, that gonadotropins are associated with unacceptably high rates of multiple births.

Endocrine disruptors are critical environmental exposures that influence health and can promote epigenetic transgenerational inheritance of disease and abnormal physiology. Advances in 2015 included analyses of the effects of endocrine disruptors on human disease, further examples of endocrine disruptors promoting transgenerational behavioural effects, insights into effects of endocrine disruptors on epigenetic programming of primordial germ cells and the finding that endocrine disruptors can transgenerationally promote genetic mutations.

Here, Denise Lackey and Jerrold Olefsky discuss the innate immune cells involved in secreting inflammatory factors during obesity. The role of innate immune cells in maintaining an anti-inflammatory and insulin-sensitive environment in the lean state is also reviewed. This Review also provides an overview of the mechanisms for regulating proinflammatory immune responses that could lead to future therapeutic opportunities to improve insulin sensitivity.

Lysosomal acid lipase deficiency can lead to liver failure and early death. A recently published placebo-controlled trial shows that enzyme-replacement therapy improves plasma levels of lipids and aminotransferases, and reduces liver fat content. However, the effect on clinical end points and an appropriate indication for treatment remain to be established.

Changes in protein or histone acetylation are key integrators of physiological processes such as the circadian clock, cell cycle and gene regulation. In this Review, the authors describe the role of reversible acetylation in metabolic control and how these processes contribute to adaptive cellular and organismal homeostasis. The potential for modulating these pathways as a treatment for various metabolic diseases is also discussed.

The skeleton has a central role in the development and regulation of bone metastasis. Here, Larry Suva and colleagues review the skeletal consequences of bone metastasis from an orthopaedic perspective. The authors discuss the effects of existing cancer treatments on bone and the bone marrow microenvironment, as well as the mechanisms mediating these effects and the current utility of modern orthopaedic interventions.

The past decade has witnessed incredible advances in the field of reproductive endocrinology. The use of new genetic and genomic tools has had a particular impact, leading to advances in our understanding, diagnosis and treatment of reproductive endocrine disorders, particularly those related to the neuroendocrine control of reproduction and ovarian biology.

Genetic studies have identified dozens of mutations that are associated with reproductive disorders, including common variants associated with the timing of puberty and/or menopause. This Review discusses the contribution of such genetic findings to our understanding of the molecular regulation of reproductive timing and the biological basis of the epidemiological links between reproductive ageing and disease risk.

In this Review, Martin Heni and colleagues outline the effects of insulin in the brain in humans and the relevance of the effects for physiology. The metabolic consequences of brain insulin resistance are discussed and possible future approaches to overcome brain insulin resistance and thereby prevent or treat obesity and type 2 diabetes mellitus are outlined.

Here, five of our Advisory Board Members look back at the past decade of endocrinology research, highlighting key advances and identifying roadblocks. They also discuss where effort and money should be invested now and speculate on where progress might be made in the coming decade.