Key Advances in Endocrinology

Metabolites have emerged as central regulators of biological function, but understanding mechanisms of metabolite regulation has proven challenging. In 2021 we have seen discoveries in the field of metabolite signalling motivated by a combination of scientific intuition and the elegant deployment of new technologies.

In 2021, clinical trials reported the promising effects of incretins and a new class of dual glucagon-like peptide 1–glucose-dependent insulinotropic peptide receptor agonists in preventing and treating type 2 diabetes mellitus and obesity. These ‘twincretins’ will transform the prevention of obesity and type 2 diabetes mellitus and the care of people with these conditions.

Obesity and impaired metabolic health are important risk factors for severe COVID-19. Novel data indicate that these risk factors might also promote vaccine-breakthrough SARS-CoV-2 infections in fully vaccinated people. Here, these relationships are discussed and post-acute sequelae of COVID-19 that are related to obesity and impaired metabolic health are addressed.

Physical activity stimulates tissue crosstalk and provides powerful protection against cardiometabolic disease. This past year, several studies have expanded our knowledge of the secreted molecules regulated by physical activity, uncovered new circuits of cell and tissue crosstalk and provided fundamental insights into the mechanisms that underlie the cardiometabolic benefits of exercise.

In 2021, several discoveries shed light on the pathomechanisms of β-cell failure during the initiation and progression of diabetes mellitus, and validated novel molecular targets for intervention. Moreover, the field of stem-cell-derived replacements for β-cells is rapidly advancing. These advances bring us closer to therapies to protect and/or regenerate β-cell mass.

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.

The development and application of effective immunotherapies for type 1 diabetes mellitus has lagged behind our ability to identify and stage individuals in pre-clinical stages of disease. This Year in Review addresses advances in immunotherapy aimed towards prevention and our readiness to roll out screening in the broader population.

Owing to the strong association of non-alcoholic fatty liver disease with obesity and cardiometabolic disease, in 2020 experts controversially proposed to rename this condition as ‘metabolic associated fatty liver disease’. Additional studies have elucidated new genetic and dietary modifiers of this disease. This knowledge is essential to improve diagnosis, risk-stratification and treatment.

Heart failure and chronic kidney disease are frequent causes of morbidity and mortality in people with type 2 diabetes mellitus. Cardiovascular outcome trials have confirmed benefits of sodium–glucose co-transporter 2 inhibitors on cardiovascular events, cardiovascular deaths, hospitalization for heart failure and renal outcomes. These benefits now extend to people with and without type 2 diabetes mellitus.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder characterized by reproductive and metabolic disturbances. Androgen excess is a hallmark of PCOS, driving many of the phenotypic features. In 2020, several findings highlight altered metabolic pathways as an underlying biological mechanism in PCOS. These findings add to our understanding of the complex interaction between metabolic homeostasis and reproduction.

Neuroendocrine neoplasms are derived from the diffuse endocrine system and represent a spectrum of tumours with a diverse range of molecular abnormalities, functionality and anatomical locations. Here, some key advances in molecular diagnosis, functional imaging and therapeutic strategies that have been published in 2020 are discussed.

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.

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.

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.

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.

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.

More than 7,000 clinical trials are currently ongoing involving new drugs for type 2 diabetes mellitus (T2DM). This Review summarizes the novel drugs in development for T2DM that improve insulin sensitivity, stimulate insulin secretion or the incretin axis, or suppress hepatic glucose production.

The pathophysiology of coronavirus disease 19 (COVID-19) and diabetes mellitus are interlinked, and diabetes mellitus is associated with severe COVID-19 outcomes. This Review highlights new advances in diabetes mellitus and COVID-19, considering disease mechanisms and clinical management of patients with diabetes mellitus in the ongoing pandemic.

This Review highlights how obesity and impaired metabolic health increase complications and mortality in coronavirus disease 2019 (COVID-19) and summarizes the consequences of infection with severe acute respiratory syndrome coronavirus 2 for organ function. In addition, there is a discussion on the implications of the COVID-19 pandemic for the obesity pandemic.

This Review summarizes the adaptations to lipid metabolism that occur in skeletal muscle in response to either a high-fat diet or exercise training. In addition, obesity-associated impairments in fatty acid oxidation capacity and the importance of exercise for overcoming lipid metabolic inflexibility in obesity are discussed.

This Review highlights the beneficial adaptive responses to exercise in skeletal muscle and other tissues as well as their molecular mechanisms. In addition, the possibility of exercise-like therapeutic interventions is discussed, providing relevant examples that have used this approach.

Understanding the mechanisms behind β-cell failure in diabetes mellitus is critical to prevent or revert disease. This Review highlights new findings from studies performed on human β-cells or on samples obtained from patients with type 1 or type 2 diabetes mellitus.

This Review highlights the research advances, advantages and challenges in several different strategies for generating functional β-cells for therapeutic use in diabetes mellitus. In addition, scalable bioengineering processes are also discussed for the realization of the therapeutic potential of derived β-cells.