Key Advances in Endocrinology

The metabolic dysfunction that characterizes obesity and type 2 diabetes mellitus affects not only the heart and kidneys, but also the liver. Although lifestyle modification remains the cornerstone in the management of metabolic liver diseases, the field has progressed this year, with a new definition, validation of non-invasive biomarkers and numerous clinical trials.

The year 2023 brought reports of highly effective glucagon-like peptide 1 (GLP1) mono-agonists or combinations with amylin receptor agonists. Results for monomolecular co-agonists that added glucagon receptor and/or glucose-dependent insulinotropic polypeptide (GIP) receptor agonism to GLP1 receptor activation were also published in 2023. Interestingly, antagonistic GIP receptor antibodies conjugated with a GLP1 agonist were also shown to be effective.

The pathophysiology of endometriosis is underpinned by a complex interplay of inflammatory processes that are responsible for the local and systemic effects of the condition. Recent studies delve further into this inflammatory interplay; using animal models, they identify potential therapeutic tools and remind us to look beyond the endometriotic lesions.

One hundred years after the Nobel prize was bestowed on Banting and McLeod for the ‘discovery’ of insulin, we are again seeing major evolutions in the management of type 1 diabetes mellitus, with the prospect of achieving disease control beyond mere management now becoming real. Here, we discuss the latest, most notable developments.

Over the past decade, technological advances have enabled cost-efficient, high-throughput analysis of different types of omics data in large human cohorts. Here, we explore insights into the pathophysiology of metabolic disorders revealed through multi-omics studies, discuss novel computational analysis techniques and look at the field’s future directions.

Glucagon-like peptide 1 (GLP1) analogues are licensed options for obesity, but new treatments are required to obtain better weight loss and to directly address other co-morbidities, such as non-alcoholic fatty liver disease. Research published in 2022 shows that co-agonist combinations of GLP1 with other hormones provide clinically important advances.

The year 2022 has been notable for game-changing early progress in clinical trials with stem cell islets; durable and promising 20-year data with long-term outcomes in clinical islet transplantation; and the development of locally protective or gene-editing-based approaches to avoid long-term immunosuppression.

Calorie restriction and timed dietary intake are two approaches known to increase lifespan or delay age-associated diseases. New studies reveal the importance of the ‘how much’ and ‘when’ of dietary intake in ageing modulation and collectively demonstrate how protection of the internal clock by diet can delay the ageing process.

Adipose tissue is highly versatile, dynamic and essential for metabolic health. In 2022, several exciting discoveries provided a high-resolution view of cellular composition and cell–cell communication within the adipose niche, and revealed how adipose tissue communicates with other organs and modulates metabolism during normal and pathophysiological states.

In 2022, the activation mechanism of TSH receptor (TSHR) by TSH and autoantibodies was demonstrated, monocarboxylate transporter 8 (MCT8) deficiency was corrected with gene therapy in mice and mutant thyroid hormone receptor α (TRα) was activated with a synthetic ligand. These results offer translational perspectives for patients with common and rare diseases affecting these proteins.

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.

This Review outlines the occurrence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH) in patients who have undergone liver transplantation for prior NASH-related cirrhosis (recurrent) or other liver indications (de novo).

The carbohydrate-responsive element binding protein (ChREBP) senses intracellular carbohydrates and activates many target genes, including those crucial for de novo lipogenesis in hepatocytes. This Review discusses mechanisms that regulate ChREBP activity, the role of ChREBP in nonalcoholic liver disease (NAFLD) and emerging NAFLD drug targets.

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.

This Review highlights the extrapancreatic actions of the incretin hormones gastric inhibitory polypeptide and glucagon-like peptide 1. These peptides are active on tissues with cardiometabolic relevance, such as liver, adipose tissue, muscle, the immune, kidney, heart, blood vessels and the central nervous system.

Endometrial diseases affect many women yet often have unclear pathogenesis and no definitive treatment. This Review assesses the current systems for modelling endometrial diseases in vitro and outlines future directions for these model systems.

This Perspective discusses potential approaches to managing patients in the early stages of developing type 1 diabetes mellitus, which could enable the initiation of insulin therapy to be delayed in some patients.

There is a growing awareness that type 1 diabetes mellitus (T1DM) is a heterogeneous disease that can be characterized into distinct endotypes. This Review discusses the evidence for endotypes in T1DM and explores the implications for clinical practice.

More genetic variants associated with type 2 diabetes mellitus are being identified. This Perspective article outlines various tools and platforms that can be applied to prioritize candidate genes associated with an increased risk of disease for functional validation.