Year in Review

Metabolic diseases emerged as important risk factors for severe COVID-19, but the mechanisms responsible remained unclear for some time. The severity of metabolic diseases was also associated with worse outcomes in patients with COVID-19, forcing clinicians to adjust their thinking on which patients with metabolic disease, but without COVID-19, to prioritize for treatment during and immediately after the pandemic.

Personalized, or precision, medicine in type 2 diabetes mellitus is becoming a reality with new insights into the contributions of subgroup analyses. The roadmap to future implementation must take into account individual and subgroup variability in genetic architecture, environment, clinical measures, lifestyle, cost-effectiveness and treatment burden.

Multikinase inhibitors are effective treatments for thyroid cancers, acting primarily as antiangiogenic agents. This year, advances have been made in selective targeting of RET and BRAF in patients with medullary and anaplastic thyroid cancers, respectively. However, Hürthle cell carcinomas have a unique genomic landscape with no dominant truncal drivers, precluding simplistic approaches to therapeutic targeting.

Feeding is regulated by defined neuronal pathways and circulating factors that ensure homeostatic balance is maintained. However, many emotion-affective pathways are also involved in communicating positive and negative valence on feeding behaviour. In 2019, several seminal discoveries were made that illuminate the complex interaction between homeostatic and hedonic feeding control mechanisms.

Pancreatic islets, which are critical for glucose homeostasis, are endocrine microorgans embedded in the exocrine pancreas; their location has often limited studying their function. In 2019, advances in islet biology were achieved with new technologies extending findings from several decades ago and with conceptual advances built on findings from other fields.

Exercise is a potent modulator of intestinal microbiota composition and function. In 2019, several studies uncovered biologically important links between skeletal muscle and the gut microbiota, revealing how the gut bacteria respond to an exercise challenge and have reciprocal roles in fuel availability, muscle function and endurance performance.

A key component in the development from fatty liver to hepatocellular carcinoma (HCC) is the appearance of nonalcoholic steatohepatitis (NASH). The precise cellular processes that trigger the advancement of NASH towards HCC are not well understood. In 2018, three key papers were published that help us better understand these processes.

In 2018, more than 4,000 publications were dedicated to the study of the gut microbiota, and an important proportion investigated cardiometabolic disorders associated with overweight and obesity. Novel mechanisms and strategies have emerged, some of which were focused not only on specific bacteria or nutrients, but also on new metabolites.

Circadian rhythm research is beginning to show how rhythms sustain health. Genome-wide transcriptome, metabolome and proteome studies have improved our understanding of circadian regulation. This knowledge is leveraged for behavioural interventions that optimize daily rhythms, the timing of drug delivery and the targeting of clock components to prevent or treat chronic diseases.

Cancer cells consume and utilize glucose at a higher rate than normal cells. However, some microenvironments limit the availability of nutrients and glucose. In 2018, researchers found that tumours depend on a variety of different nutrient sources, both locally and systemically, to overcome metabolic limitations and promote tumour progression and metastasis.

The risk of death from cardiovascular causes in people with type 2 diabetes mellitus remains around twice that in the general population, with heart failure a common event. In 2017, results from cardiovascular outcome trials in people with diabetes mellitus showed that some drugs have dual utility — reducing cardiovascular risk and improving glycaemic control.

Extracellular danger-associated molecular patterns signal to NOD-like receptors, but the exact signalling pathways remain unclear. The inflammasomes, a subgroup of these receptors, translate danger signals into inflammatory responses by maturing IL-1 and IL-18. In 2017, researchers reported novel functions of the mutual interaction between metabolism and the inflammasomes in health and disease.

Studies of rare growth disorders taken together with large-scale genetic studies of adult height variability have uncovered a large genetic network regulating childhood growth. Advances in technology and experimental model systems will help decipher the molecular mechanisms of this complex network and lead to novel treatment approaches for growth disorders.

Nutraceuticals are gaining legitimacy and their potential clinical role is expanding. Data from 2017 provides evidence for their possible use in type 2 diabetes mellitus, the metabolic syndrome, obesity, dyslipidaemia and osteoporosis. Ongoing high-quality research in this area might justify future selective implementation of nutraceuticals into general health practice.

The artificial pancreas — the automated closed-loop control of diabetes mellitus — made its first outpatient strides in 2011. In 2017, the results of long-term clinical trials on the artificial pancreas were published, the first hybrid commercial artificial pancreas system was approved and the artificial pancreas was tested under increasingly demanding conditions. Thus, artificial pancreas technology is here to stay.

Obesity and ageing are major worldwide health challenges associated with lifestyle changes and an increase in age-related diseases, characterized by chronic inflammation dubbed metaflammation and inflammaging. However, the mechanistic link between these inflammatory processes is still unknown. New findings in 2016 shed light on these issues and indicate common targets for intervention.

Neuroendocrine networks were previously perceived mainly as transcriptionally controlled, neural regulatory pathways that are centred at the hypothalamus. However, multisystemic circuits encompassing the brain and peripheral tissues have now been uncovered that involve nonneuronal cells and nontranscriptional regulatory mechanisms, with previously unidentified functions, such as reward and behaviour. Several developments in 2016 have helped to consolidate these new advances.

Adipose tissues have a central role in energy homeostasis, as they secrete adipokines and regulate energy storage and dissipation. Novel adipokines from white, brown and beige adipocytes have been identified in 2016. Identifying the specific receptors for each adipokine is pivotal for developing greater insights into the fat-derived signalling pathways that regulate energy homeostasis.

Type 2 diabetes mellitus (T2DM) is a major global health challenge. Development of more effective strategies for prevention and therapy depends on an improved understanding of its pathogenetic mechanisms. 2016 ends a period during which large-scale discovery of risk alleles for T2DM became routine and heralds a shift in research focus towards their exploitation to fuel mechanistic insights.

Although regular physical activity can prevent or reduce the risk of many age-related diseases, the molecular mechanisms underpinning the protective effects of exercise are largely unknown. In 2016, a series of studies demonstrated that crosstalk between tissues during exercise can protect against metabolic disease, cancer, retinal degeneration and memory loss. These studies provide a molecular basis for the concept of 'exercise as medicine'.