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The islet of Langerhans is a complex endocrine micro-organ consisting of a multitude of endocrine and non-endocrine cell types. The two most abundant and prominent endocrine cell types, the beta and the alpha cells, are essential for the maintenance of blood glucose homeostasis. While the beta cell produces insulin, the only blood glucose-lowering hormone of the body, the alpha cell releases glucagon, which elevates blood glucose. Under physiological conditions, these two cell types affect each other in a paracrine manner. While the release products of the beta cell inhibit alpha cell function, the alpha cell releases factors that are stimulatory for beta cell function and increase glucose-stimulated insulin secretion. The aim of this review is to provide a comprehensive overview of recent research into the regulation of beta cell function by alpha cells, focusing on the effect of alpha cell-secreted factors, such as glucagon and acetylcholine. The consequences of differences in islet architecture between species on the interplay between alpha and beta cells is also discussed. Finally, we give a perspective on the possibility of using an in vivo imaging approach to study the interactions between human alpha and beta cells under in vivo conditions.

Pancreatic islet microvasculature is essential for optimal islet function and glucose homeostasis. However, islet vessel pathogenesis in obesity and its role in the manifestation of metabolic disorders remain understudied. Here, we depict the time-resolved decline of intra-islet endothelial cell responsiveness to VEGF-A and islet vessel function in a mouse model of diet-induced obesity. Longitudinal imaging of sentinel islets transplanted into mouse eyes revealed substantial vascular remodeling and diminished VEGF-A response in islet endothelial cells after 12 weeks of Western diet (WD) feeding. This led to islet vessel barrier dysfunction and hemodynamic dysregulation, delaying transportation of secreted insulin into the blood. Notably, islet vessels exhibited a metabolic memory of previous WD feeding. Neither VEGF-A sensitivity nor the other vascular alterations was fully restored by control diet refeeding, resulting in modest yet significant impairment in glucose clearance despite normalized insulin sensitivity. Mechanistic analysis implicated hyperactivation of atypical PKC under both WD and recovery conditions, which inhibited VEGFR2 internalization and blunted VEGF-A–triggered signal transduction in endothelial cells. In summary, prolonged WD feeding causes irreversible islet endothelial cell desensitization to VEGF-A and islet vessel dysfunction, directly undermining glucose homeostasis.

By transplanting pancreatic islets onto the dura mater of the mouse brain, we establish a microscopy platform that enables longitudinal intravital imaging of otherwise optically inaccessible tissue. The system combines a cranial window with an air-cushioned floating arena and stable head fixation, providing high mechanical stability for repeated single-cell Ca 2+ imaging sessions of up to 90 min in awake mice. We show that dura mater-engrafted islets integrate with host vascular and neural networks, and that human islet grafts secrete C-peptide in response to glucose stimulation, indicating metabolic integration. With this platform, we monitor anesthesia-induced changes in capillary blood flow and islet Ca 2+ dynamics. In awake mice, following subcutaneous glucose injection, we characterize intracellular Ca 2+ oscillations in insulin-secreting β-cells, revealing changes in amplitude, period, and plateau fraction while network coordination remains stable. The dura mater thus offers long-term optical access to functional endocrine tissue, facilitating stable intravital imaging under anesthesia-free, physiological conditions. Imaging pancreatic islets in living animals is often limited by poor optical access and motion instability. Here, the authors show that transplanting islets onto the brain’s dura mater enables stable, long-term, and functional imaging in awake mice.

The two insulin receptor (IR) isoforms IR‐A and IR‐B are responsible for the pleiotropic actions of insulin and insulin‐like growth factors. Consequently, changes in IR isoform expression and in the bioavailability of their ligands will impact on IR‐mediated functions. Although alteration of IR isoform expression has been linked to insulin resistance, knowledge of IR isoform expression and mechanisms underlying tissue/cell‐type‐specific changes in metabolic disease are lacking. Using mouse models of obesity/diabetes and measuring the mRNA of the IR isoforms and mRNA/protein levels of total IR, we provide a data set of IR isoform expression pattern that documents changes in a tissue‐dependent manner. Combining tissue fractionation and a new in situ mRNA hybridization technology to visualize the IR isoforms at cellular resolution, we explored the mechanism underlying the change in IR isoform expression in perigonadal adipose tissue, which is mainly caused by tissue remodelling, rather than by a shift in IR alternative splicing in a particular cell type, e.g. adipocytes.

Both continuous aerobic training (CAT) and high-intensity interval training (HIIT) are recommended to promote health and prevent diseases. Exercise-induced circulating extracellular vesicles (EX-EVs) have been suggested to play essential roles in mediating organ crosstalk, but corresponding molecular mechanisms remain unclear. To assess and compare the systemic effects of CAT and HIIT, five healthy male volunteers were assigned to HIIT and CAT, with a 7-day interval between sessions. Plasma EVs were collected at rest or immediately after each training section, prior to proteomics and miRNA profile analysis. We found that the differentially expressed (DE) miRNAs in EX-EVs were largely involved in the regulation of transcriptional factors, while most of the DE proteins in EX-EVs were identified as non-secreted proteins. Both CAT and HIIT play common roles in neuronal signal transduction, autophagy, and cell fate regulation. Specifically, CAT showed distinct roles in cognitive function and substrate metabolism, while HIIT was more associated with organ growth, cardiac muscle function, and insulin signaling pathways. Interestingly, the miR-379 cluster within EX-EVs was specifically regulated by HIIT, involving several biological functions, including neuroactive ligand–receptor interaction. Furthermore, EX-EVs likely originate from various tissues, including metabolic tissues, the immune system, and the nervous system. Our study provides molecular insights into the effects of CAT and HIIT, shedding light on the roles of EX-EVs in mediating organ crosstalk and health promotion.

The cytoarchitecture of human islets has been examined, focusing on cellular associations that provide the anatomical framework for paracrine interactions. By using confocal microscopy and multiple immunofluorescence, we found that, contrary to descriptions of prototypical islets in textbooks and in the literature, human islets did not show anatomical subdivisions. Insulin-immunoreactive β cells, glucagon-immunoreactive α cells, and somatostatin-containing δ cells were found scattered throughout the human islet. Human β cells were not clustered, and most (71%) showed associations with other endocrine cells, suggesting unique paracrine interactions in human islets. Human islets contained proportionally fewer β cells and more α cells than did mouse islets. In human islets, most β, α, and δ cells were aligned along blood vessels with no particular order or arrangement, indicating that islet microcirculation likely does not determine the order of paracrine interactions. We further investigated whether the unique human islet cytoarchitecture had functional implications. Applying imaging of cytoplasmic free Ca²⁺ concentration, $[Ca^{2+}]_i$, we found that β cell oscillatory activity was not coordinated throughout the human islet as it was in mouse islets. Furthermore, human islets responded with an increase in $[Ca^{2+}]_i$ when lowering the glucose concentration to 1 mM, which can be attributed to the large contribution of α cells to the islet composition. We conclude that the unique cellular arrangement of human islets has functional implications for islet cell function.

Bycatch is the most significant threat to marine mammals globally. There are increasing requirements for national governments to fulfil their obligations to international agreements and treaties to assess fisheries catch and bycatch of non-target species. Questionnaire surveys represent one low-cost method to collect data to estimate fisheries catch and bycatch of vulnerable species including marine mammals. Questionnaire surveys can be particularly advantageous when bycatch is being investigated on large spatial and temporal scales, or in data-poor areas. This review aims to provide the necessary guidance required to design and conduct questionnaire studies investigating marine mammal bycatch. To do so, a systematic review was conducted of the methods used in 91 peer-reviewed or grey literature questionnaire studies from 1990 to 2023 investigating marine mammal bycatch. Literature was searched, screened, and analysed following the RepOrting standards for Systematic Evidence Syntheses (ROSES) protocols. A narrative synthesis and critical evaluation of the methods used were conducted and best practice recommendations are proposed. The recommendations include suggestions for how to generate representative samples, the steps that should be followed when designing a questionnaire instrument, how to collect reliable data, how to reduce under-reporting and interviewer bias, and how weighting or model-based bycatch estimation techniques can be used to reduce sampling bias. The review’s guidance and best practice recommendations provide much-needed resources to develop and employ questionnaire studies that produce robust bycatch estimates for marine mammal populations where they are currently missing. Recommendations can be used by scientists and decision-makers across the globe. Whilst the focus of this review is on using questionnaires to investigate marine mammal bycatch, the information and recommendations will also be useful for those investigating bycatch of any other non-target species.

Little is known about the role of islet delta cells in regulating blood glucose homeostasis in vivo. Delta cells are important paracrine regulators of beta cell and alpha cell secretory activity, however the structural basis underlying this regulation has yet to be determined. Most delta cells are elongated and have a well-defined cell soma and a filopodia-like structure. Using in vivo optogenetics and high-speed Ca 2+ imaging, we show that these filopodia are dynamic structures that contain a secretory machinery, enabling the delta cell to reach a large number of beta cells within the islet. This provides for efficient regulation of beta cell activity and is modulated by endogenous IGF-1/VEGF-A signaling. In pre-diabetes, delta cells undergo morphological changes that may be a compensation to maintain paracrine regulation of the beta cell. Our data provides an integrated picture of how delta cells can modulate beta cell activity under physiological conditions. Pancreatic islets are composed of alpha-, beta-, as well as delta-cells and appropriate regulation of glucose homeostasis relies on auto- and paracrine cellular communication. Here, the authors study the role of delta-cell filopodia in this context by employing optogenetic and calcium imaging approaches.

It is well known that type-2 diabetes mellitus (T2D) is increasing worldwide, but also the autoimmune form, type-1 diabetes (T1D), is affecting more people. The latest estimation from the International Diabetes Federation (IDF) is that 1.1 million children and adolescents below 20 years of age have T1D. At present, we have no primary, secondary or tertiary prevention or treatment available, although many efforts testing different strategies have been made. This review is based on the findings that apolipoprotein CIII (apoCIII) is increased in T1D and that in vitro studies revealed that healthy β-cells exposed to apoCIII became apoptotic, together with the observation that humans with higher levels of the apolipoprotein, due to mutations in the gene, are more susceptible to developing T1D. We have summarized what is known about apoCIII in relation to inflammation and autoimmunity in in vitro and in vivo studies of T1D. The aim is to highlight the need for exploring this field as we still are only seeing the top of the iceberg.

Longitudinal monitoring of liver function in vivo is hindered by the lack of high-resolution non-invasive imaging techniques. Using the anterior chamber of the mouse eye as a transplantation site, we have established a platform for longitudinal in vivo imaging of liver spheroids at cellular resolution. Transplanted liver spheroids engraft on the iris, become vascularized and innervated, retain hepatocyte-specific and liver-like features and can be studied by in vivo confocal microscopy. Employing fluorescent probes administered intravenously or spheroids formed from reporter mice, we showcase the potential use of this platform for monitoring hepatocyte cell cycle activity, bile secretion and lipoprotein uptake. Moreover, we show that hepatic lipid accumulation during diet-induced hepatosteatosis is mirrored in intraocular in vivo grafts. Here, we show a new technology which provides a crucial and unique tool to study liver physiology and disease progression in pre-clinical and basic research. Longitudinal monitoring of liver function in vivo is hindered by the lack of high-resolution non-invasive imaging techniques. Here, the authors show a crucial and unique tool for longitudinal in vivo imaging of liver spheroids at cellular resolution to study liver physiology and disease.