Historic and emerging studies provide evidence for the deterioration of pancreatic α cell function and identity in diabetes mellitus. Increased access to human tissue and the availability of more sophisticated molecular technologies have identified key insights into how α cell function and identity are preserved in healthy conditions and how they become dysfunctional in response to stress. These studies have revealed evidence of impaired glucagon secretion, shifts in α cell electrophysiology, changes in α cell mass, dysregulation of α cell transcription, and α-to-β cell conversion prior to and during diabetes. In this review, we outline the current state of research on α cell identity in health and disease. Evidence in model organisms and humans suggests that in addition to β cell dysfunction, diabetes is associated with a fundamental dysregulation of α cell identity. Importantly, epigenetic studies have revealed that α cells retain more poised and open chromatin at key cell-specific and diabetes-dysregulated genes, supporting the model that the inherent epigenetic plasticity of α cells makes them susceptible to the transcriptional changes that potentiate the loss of identity and function seen in diabetes. Thus, additional research into the maintenance of α cell identity and function is critical to fully understanding diabetes. Furthermore, these studies suggest α cells could represent an alternative source of new β cells for diabetes treatment.

The gastrointestinal system is now considered the largest endocrine organ, highlighting the importance of gut-derived peptides and metabolites in metabolic homeostasis. Gut peptides are secreted from intestinal enteroendocrine cells in response to nutrients, microbial metabolites, and neural and hormonal factors, and they regulate systemic metabolism via multiple mechanisms. While extensive research is focused on the neuroendocrine effects of gut peptides, evidence suggests that several of these hormones act as endocrine signaling molecules with direct effects on the target organ, especially in a therapeutic setting. Additionally, the gut microbiota metabolizes ingested nutrients and fiber to produce compounds that impact host metabolism indirectly, through gut peptide secretion, and directly, acting as endocrine factors. This review will provide an overview of the role of endogenous gut peptides in metabolic homeostasis and disease, as well as the potential endocrine impact of microbial metabolites on host metabolic tissue function.

Glucagon is the principal glucose-elevating hormone that forms the first-line defence against hypoglycaemia. Along with insulin, glucagon also plays a key role in maintaining systemic glucose homeostasis. The cells that secrete glucagon, pancreatic α-cells, are electrically excitable cells and use electrical activity to couple its hormone secretion to changes in ambient glucose levels. Exactly how glucose regulates α-cells has been a topic of debate for decades but it is clear that electrical signals generated by the cells play an important role in glucagon secretory response. Decades of studies have already revealed the key players involved in the generation of these electrical signals and possible mechanisms controlling them to tune glucagon release. This has offered the opportunity to fully understand the enigmatic α-cell physiology. In this review, we describe the current knowledge on cellular electrophysiology and factors regulating excitability, glucose sensing, and glucagon secretion. We also discuss α-cell pathophysiology and the perspective of addressing glucagon secretory defects in diabetes for developing better diabetes treatment, which bears the hope of eliminating hypoglycaemia as a clinical problem in diabetes care.

In biomedicine and many other fields, there are growing concerns around the reproducibility of research findings, with many researchers being unable to replicate their own or others’ results. This raises important questions as to the validity and usefulness of much published research. In this review, we aim to engage researchers in the issue of research reproducibility and equip them with the necessary tools to increase the reproducibility of their research. We first highlight the causes and potential impact of non-reproducible research and emphasise the benefits of working reproducibly for the researcher and broader research community. We address specific targets for improvement and steps that individual researchers can take to increase the reproducibility of their work. We next provide recommendations for improving the design and conduct of experiments, focusing on in vivo animal experiments. We describe common sources of poor internal validity of experiments and offer practical guidance for limiting these potential sources of bias at different experimental stages, as well as discussing other important considerations during experimental design. We provide a list of key resources available to researchers to improve experimental design, conduct, and reporting. We then discuss the importance of open research practices such as study preregistration and the use of preprints and describe recommendations around data management and sharing. Our review emphasises the importance of reproducible work and aims to empower every individual researcher to contribute to the reproducibility of research in their field.

In commemoration of 100 years since the discovery of glucagon, we review current knowledge about the human α cell. Alpha cells make up 30–40% of human islet endocrine cells and play a major role in regulating whole-body glucose homeostasis, largely through the direct actions of their main secretory product – glucagon – on peripheral organs. Additionally, glucagon and other secretory products of α cells, namely acetylcholine, glutamate, and glucagon-like peptide-1, have been shown to play an indirect role in the modulation of glucose homeostasis through autocrine and paracrine interactions within the islet. Studies of glucagon’s role as a counterregulatory hormone have revealed additional important functions of the α cell, including the regulation of multiple aspects of energy metabolism outside that of glucose. At the molecular level, human α cells are defined by the expression of conserved islet-enriched transcription factors and various enriched signature genes, many of which have currently unknown cellular functions. Despite these common threads, notable heterogeneity exists amongst human α cell gene expression and function. Even greater differences are noted at the inter-species level, underscoring the importance of further study of α cell physiology in the human context. Finally, studies on α cell morphology and function in type 1 and type 2 diabetes, as well as other forms of metabolic stress, reveal a key contribution of α cell dysfunction to dysregulated glucose homeostasis in disease pathogenesis, making targeting the α cell an important focus for improving treatment.

Modeling preeclampsia remains difficult due to the nature of the disease and the unique characteristics of the human placenta. Members of the Hominidae superfamily have a villous hemochorial placenta that is different in structure from those of other therian mammals, including the mouse hemochorial placenta, making this common animal model less ideal for studying this disease. Human placental tissues delivered from pregnancies complicated by preeclampsia are excellent for assessing the damage the disease causes but cannot answer how or when the disease begins. Symptoms of preeclampsia manifest halfway through pregnancy or later, making it currently impossible to identify preeclampsia in human tissues obtained from an early stage of pregnancy. Many animal and cell culture models recapitulate various aspects of preeclampsia, though none can on its own completely capture the complexity of human preeclampsia. It is particularly difficult to uncover the cause of the disease using models in which the disease is induced in the lab. However, the many ways by which preeclampsia-like features can be induced in a variety of laboratory animals are consistent with the idea that preeclampsia is a two-stage disease, in which a variety of initial insults may lead to placental ischemia, and ultimately systemic symptoms. The recent development of stem cell-based models, organoids, and various coculture systems have brought in vitro systems with human cells ever closer to recapitulating in vivo events that lead to placental ischemia.

Based on biological sex, the consequential health outcomes from exposures to environmental chemicals or toxicants can differ in disease pathophysiology, progression, and severity. Due to basal differences in cellular and molecular processes resulting from sexual dimorphism of organs including the liver and additional factors influencing ‘gene–environment’ interactions, males and females can exhibit different responses to toxicant exposures. Associations between environmental/occupational chemical exposures and fatty liver disease (FLD) have been well-acknowledged in human epidemiologic studies and their causal relationships demonstrated in experimental models. However, studies related to sex differences in liver toxicology are still limited to draw any inferences on sex-dependent chemical toxicity. The purpose of this review is to highlight the present state of knowledge on the existence of sex differences in toxicant-associated FLD (TAFLD), discuss potential underlying mechanisms driving these differences, implications of said differences on disease susceptibility, and emerging concepts. Chemicals of interest include various categories of pollutants that have been investigated in TAFLD, namely persistent organic pollutants, volatile organic compounds, and metals. Insight into research areas requiring further development is also discussed, with the objective of narrowing the knowledge gap on sex differences in environmental liver diseases. Major conclusions from this review exercise are that biological sex influences TAFLD risks, in part due to (i) toxicant disruption of growth hormone and estrogen receptor signaling, (ii) basal sex differences in energy mobilization and storage, and (iii) differences in chemical metabolism and subsequent body burden. Finally, further sex-dependent toxicological assessments are warranted for the development of sex-specific intervention strategies.

Although originally characterised as proteins involved in the control of reproductive function, activins, and to a lesser degree inhibins, are also important regulators of homeostasis in extragonadal tissues. Accordingly, disrupted inhibin/activin expression can have detrimental effects not only on fertility and fecundity but also on the regulation of muscle, fat and bone mass. Indeed, only recently, two complementary mouse models of inhibin designed to lack bioactivity/responsiveness revealed that inhibin A/B deficiency during pregnancy restricts embryo and fetal survival. Conversely, hyper-elevated levels of activin A/B, as are frequently observed in patients with advanced cancers, can not only promote gonadal tumour growth but also cancer cachexia. As such, it is not surprising that inhibin/activin genetic variations or altered circulating levels have been linked to reproductive disorders and cancer. Whilst some of the detrimental health effects associated with disrupted inhibin/activin levels can be attributed to accompanied changes in circulating follicle-stimulating hormone (FSH) levels, there is now abundant evidence that activins, in particular, have fundamental FSH-independent tissue homeostatic roles. Increased understanding of inhibin/activin activity, garnered over several decades, has enabled the development of targeted therapies with applications for both reproductive and extra-gonadal tissues. Inhibin- or activin-targeted technologies have been shown not just to enhance fertility and fecundity but also to reduce disease severity in models of cancer cachexia. Excitingly, these technologies are likely to benefit human medicine and be highly valuable to animal breeding and veterinary programmes.

Diabetes-related foot disease (DFD), defined as ulceration, infection or destruction of tissues of the foot in a person with current or previously diagnosed diabetes mellitus, is associated with a heavy burden for both patients and the healthcare system with high morbidity, mortality and costs. Improved outcomes for people with DFD are achieved with an interdisciplinary approach and adherence to best practice clinical guidelines; however, in the Australian context, the vastness of the country presents unique challenges in achieving optimal outcomes for all people with DFD, with variation in service delivery, availability and accessibility between metropolitan, rural and remote areas. Aboriginal and Torres Strait Islander Australians and people with diabetes living in rural and remote areas experience higher rates of lower-extremity amputation, and further efforts and resources are required to improve outcomes for these high-risk groups. In recent years, there have been advances in knowledge, including the understanding of the pathogenesis of diabetes-related peripheral neuropathy, genetic polymorphisms and mechanisms of disease associated with acute Charcot neuroarthropathy, biomarkers and potential mediators of diabetes-related foot ulcer (DFU) healing, the microbiology and microbiome profile of DFUs, pressure assessment and management as well as an expanded understanding of DFU sequelae and comorbidities. In this review, we describe new insights into pathophysiology, sequelae and comorbidities of DFD with a focus on basic and translational aspects and contributions to the field from Australian and New Zealand DFD researchers.

‘Pituitary tumours’ is an umbrella term for various tumours originating from different regions of the hypothalamic–pituitary system. The vast majority of pituitary tumours are pituitary adenomas, also recently referred to as pituitary neuroendocrine tumours. The prevalence of clinically relevant pituitary adenomas is approximately 1 in 1000; other pituitary tumours such as craniopharyngioma and pituicytoma are comparatively very rare. This review addresses the molecular and genetic aspects of pituitary adenomas. We first discuss the germline genetic variants underlying familial pituitary tumours, which account for approximately 5% of all pituitary adenoma cases. This includes variants in established pituitary adenoma/hyperplasia predisposition genes (MEN1, PRKAR1A, AIP, CDKN1B, GPR101, SDHA, SDHB, SDHC, SDHD, SDHAF2) as well as emerging genetic associations. In addition, we discuss McCune–Albright syndrome which lies between the germline and somatic pituitary tumour genes as the causative GNAS mutations are postzygotic rather than being inherited, and the condition is associated with multiglandular features due to the involvement of different cell lines rather than being limited to the pituitary. By contrast, somatic GNAS mutations contribute to sporadic acromegaly. USP8 is the only other gene where somatic driver mutations have been established in sporadic pituitary tumorigenesis. However, there are now known to be a variety of other somatic genetic and molecular changes underpinning sporadic pituitary adenomas which we review here, namely: copy number variation, molecular changes in signalling and hypoxia pathways, epithelial–mesenchymal transition, DNA repair, senescence, the immune microenvironment and epigenetics.