The ability to generate stem cell-derived pancreatic β (SCβ) cells and stem cell-derived islets has opened new opportunities for type 1 diabetes mellitus therapies and disease modelling. Carefully assessing how closely SCβ cells resemble their primary counterparts is crucial to the support of ongoing clinical trials and human-centric studies on diabetes pathophysiology. Observed differences between SCβ cells and primary human β cells are generally attributed to the incomplete maturation of SCβ cells in vitro. However, even cells further matured in vivo can differ considerably from mature primary islet cells. In this Review, we examine key features of human β cells and islets, and summarize our current knowledge of these features in stem cell-derived products. We highlight knowledge gaps and discuss the requirements for comparative studies, emphasizing the importance of tissue quality, harmonizing approaches, integrating datasets and data sharing.
CheckCausesObesity.com (CCO) is a science-based screening and monitoring tool, developed by multidisciplinary experts and consistent with international guidelines. CCO systematically screens for potential obesity causes and contributing factors across seven categories, including lifestyle and medical factors, alongside selected comorbidities as well as anthropometric, demographic and socioeconomic characteristics. CCO supports individualized assessment, treatment and population-level monitoring.
Hypochondroplasia is a skeletal dysplasia caused by pathogenic variants in FGFR3 and characterized by disproportionate short stature and relative macrocephaly. Diagnostic uncertainty remains common, particularly in early childhood and in individuals with mild or atypical presentations, leading to delayed diagnosis, inconsistent management, and challenges in counselling and care planning. Individuals can be affected by medical complications and psychosocial consequences and have unmet needs for multidisciplinary care. To address these unmet needs, an international, multidisciplinary panel of experts and patient representatives convened to develop consensus-based diagnostic recommendations using a modified two-stage Delphi approach, with a predefined consensus threshold of 70% of respondents rating statements ≥70 (on a scale of 0 to 100). The panel integrated clinical, anthropometric, radiographic, neuroimaging and genetic criteria to define diagnostic categories that can be applied across diverse health-care settings globally. Major and minor diagnostic criteria are proposed, alongside guidance on the appropriate use of molecular testing, radiographic evaluation and brain magnetic resonance imaging. These recommendations provide a practical framework to help standardize timely and accurate diagnosis of hypochondroplasia in clinical practice and research.
Obesity involves dysfunction in metabolic tissues that is not always fully corrected by weight loss. An mRNA-lipid nanoparticle platform might offer a programmable approach for in situ production of therapeutic proteins directly in target tissues, enabling endocrine signalling, adipose remodelling and multi-pathway metabolic regulation.
The transition from postdoctoral researcher to independent investigator is marked by complex decision-making and uncertainty. At the Danish Diabetes and Endocrine Academy Postdoc Summit 2025, we discussed these challenges, as well as strategies to support this transition.
Obesity is a chronic, adiposity-based disease with increasing global prevalence and multiple, competing definitions. Traditionally, body mass index (BMI) has been the primary tool for diagnosis, although it does not completely reflect adipose tissue mass, distribution or associated organ dysfunction. In the past 2 years, major professional societies (including the European Association for the Study of Obesity (EASO), the Lancet Diabetes & Endocrinology Commission, the American College of Cardiology (ACC) and the American Association of Clinical Endocrinologists (AACE)) have advanced new diagnostic frameworks that move beyond BMI to incorporate multimodal assessment of adiposity and its clinical consequences. By integrating anthropometric precision with standardized complication assessment, these frameworks support earlier identification of risk, improved prognostication and more equitable, patient-centred obesity care. However, the way in which the new guidelines should be integrated into routine clinical care remains unclear. Here we synthesize current evidence across anthropometric measures of obesity and body composition imaging. We clarify the diagnostic performance, limitations and relevance of these measures across diverse populations. We compare areas of convergence and divergence among the new guidelines, particularly the shift towards defining clinical obesity on the basis of both excess adiposity and evidence of organ dysfunction or functional impairment. Obesity is a chronic, adiposity-based disease with multiple, competing definitions. In the past 2 years, major professional societies have advanced new diagnostic frameworks that incorporate multimodal assessment of adiposity and its clinical consequences. In this Review, Tandar et al. evaluate contemporary anthropometric and body composition measurements, synthesize new frameworks and guidelines for the diagnosis and staging of obesity, and discuss their implications for clinical practice.
Regulation of insulin secretion by pancreatic β-cells is central to maintaining glucose homeostasis and overall metabolic health. Glucose is recognized as the major driver of insulin secretion; however, here, we highlight established and emerging evidence of important contributions of other nutrients, including amino acids, fatty acids and alternative fuels, as well as non-nutrient factors, in modulating both basal and postprandial insulin release. We discuss molecular mechanisms underlying insulin release, including roles for reactive oxygen species, and the consequences of β-cell overwork. This Review also addresses the physiological and pathophysiological significance of insulin secretion dynamics, including changes in β-cell mass and function across the lifespan, circadian and pulsatile patterns of secretion, and adaptive responses to metabolic stress. We reflect on how genetic predisposition, environmental exposures, pharmaceuticals, food additives and lifestyle factors can influence insulin secretion and contribute to hyperinsulinaemia, insulin resistance and metabolic disease. We identify knowledge gaps that would benefit from additional study, especially in human models. By integrating evidence from both human in vitro studies and preclinical models, we summarize the multifactorial regulation of insulin secretion and underscore its relevance for developing strategies to prevent and manage diabetes mellitus and related metabolic disorders.
Although oxytocin is widely known as the ‘love hormone’, it is also released during social conflict, promoting acute social defence and facilitating neural circuit plasticity that heightens future social avoidance, vigilance and sensitivity to non-social stressors.
Cancer cachexia is a wasting syndrome that is associated with advanced cancer and causes high morbidity and mortality. Now, preclinical and clinical findings define cachexia as a systemic metabolic disorder beyond anorexia. Reframing cachexia as a treatable disease could contribute to increasing the quality of life and survival of patients.
The body possesses critical nutrient sensors that rapidly coordinate feeding behaviour and systemic metabolism through hormones and neural pathways. In this Review, we highlight the mechanisms by which lipid sensing triggers the release of small intestinal-derived cholecystokinin, peptide YY, glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide, as well as kidney-derived growth differentiation factor 15, to regulate satiety and glucose homeostasis through the brain. We discuss how dysregulation of lipid sensing pathways contributes to obesity and type 2 diabetes mellitus, and how interventions including bariatric surgery, modulation of the gut microbiota and pharmacological agonists restore polyhormonal secretion and action on metabolism. We propose that lipid sensing in the small intestine and the kidney orchestrates an endocrine and neural axis that governs energy balance, providing a lipid-sensing-dependent framework for the development of next-generation therapies in obesity and metabolic disease to remotely and concurrently target multiple brain hormone receptors to lower food intake and body weight.
Nutrient-stimulated hormone-based therapies are redefining obesity care, yet weight loss that compromises skeletal muscle can undermine functional and metabolic benefit. We argue for high-quality weight loss, positioning exercise as a required co-therapy to preserve muscle, improve function and sustain cardiometabolic gains.
Nutrition shapes development, health and risk of disease over the life course and across generations. The predominant approaches to understanding these relationships have either been to consider the effects of single nutrients, one at a time, or to consider associations with food types and dietary patterns. Although, to date, the single-nutrient approach has defined much of the scientific enquiry and public debate on the macronutrients - carbohydrate, fat and protein - there is an emerging appreciation that their proportions and quality matter more than their individual effects. Growing evidence demonstrates that macronutrient interactions operate at multiple biological levels, and research on dietary protein has proven a particularly productive entry point for characterizing these mixture effects. In this narrative Review, we begin by analysing key issues and introducing a framework for navigating the complexity of macronutrient mixtures (nutritional geometry), then consider the role of macronutrient proportions on food intake, systemic physiology, health and the risk of disease across the life course. Finally, we discuss how human nutritional biology has been subverted within the modern, industrialized food environment, contributing to the global burden of obesity and related diseases of unhealthy ageing.
Hepatic nerves have an underexplored role in liver function. The global prevalence of liver disease has reached unprecedented levels, with over 1.6 billion individuals affected by metabolic dysfunction-associated steatotic liver disease (MASLD). A comprehensive understanding of these liver disease mechanisms is essential for identifying the aetiologies of such conditions. Studies from the past 5 years suggest that hepatic nerves might influence the progression of MASLD to metabolic dysfunction-associated steatohepatitis and hepatocellular carcinoma. As MASLD advances, hepatic sympathetic activity increases while hepatic sympathetic innervation diminishes. Conversely, both parasympathetic and sympathetic innervation might contribute to hepatic fibrosis and liver dysfunction. This Review examines the function of hepatic neurons, their modulation by metabolic disease and the potential to target these mechanisms to develop novel treatments for liver diseases.
Epstein–Barr virus is suspected to have a role in autoimmune disorders such as multiple sclerosis and systemic lupus erythematosus. In type 1 diabetes mellitus, however, clinical and experimental studies suggest that the virus might protect against islet cell autoimmunity.
