Issue 43 – Spring 2019

t’s time to submit your abstracts for the 58th ESPE Annual Meeting, which takes place in Vienna, Austria, on 19−21 September 2019, with the theme ‘Variety and variation in paediatric endocrinology’. The abstract deadline is 15 April (23.59 Western European Summer Time), and ESPE Meeting Grants are awarded for the best submissions. Registration is also open now: early bird rates are available until 20 June. ESPE 2019 will bring together the global community of paediatric endocrine specialists to learn about the latest developments in treatment, clinical best practice and cutting edge research. The Meeting’s theme relates to the diversity we encounter in our discipline and the care that we have to exercise when using the term ‘normality’. Join us as we explore this theme through an exciting mix of plenary lectures, symposia, meet the expert sessions, debates on controversies and sessions on novel advances. You will also enjoy oral communications and posters submitted by scientists and clinicians from around the world. Submitting an abstract to ESPE 2019 is a fantastic way to disseminate your research and get the attention of potential collaborators. Whether you are a clinician, a researcher, a nurse or an allied health professional, ESPE 2019 has something for you. ‘Variety and variation’ at ESPE 2019 1

Daniela Nasteska and David Hodson examine the important role of β-cell heterogeneity in
achieving insulin self-sufficiency.

Nearly a century ago, a 14-year-old boy from Toronto, Canada, became the first patient with type 1 diabetes to be successfully treated by insulin injection. Although insulin therapy remains essential for patients with type 1 diabetes and, eventually, for those with type 2, the search to bypass exogenous insulin sources continues. Engineering islets de novo from induced pluripotent stem cells (iPSC) represents a promising avenue in achieving insulin self-sufficiency. However, reconstructing complex 3D structures is not without its challenges. Understanding how different β-cells come together and maintain normal islet function is crucial in achieving successful islet reconstruction ex vivo. Single cells versus populations A single β-cell is not an average representative of the population as a whole. Although β-cells are the sole source of circulating insulin in the body, they show architectural and functional diversity, while maintaining glucose homeostasis. The many differences include variations in individual β-cell maturity, glucose responsiveness, membrane activity and Ca2+ fluxes, intracellular and secreted insulin and cell-to-cell connectivity. Understanding β-cell heterogeneity Evidence for functional and some morphological β-cell heterogeneity has been present for decades. However, recent technological advances have revolutionised the field, allowing scientists to probe deeper into the ways in which heterogeneity is manifested, and the mechanisms behind it. Mouse and human functional, transcriptional and marker-based single cell screening studies have provided high resolution data on an array of newly detected β-cell subpopulations or states. Alongside this, optogenetic tools, which allow control of cell activity by light, have paved the way for functional studies of β-cells within the islet context. In 2016, Johnston et al. described a novel subgroup of immature β-cells termed ‘hubs’ that act as pacemakers.1 Their susceptibility to glucolipotoxic Nearly a century ago, a 14-year-old boy from Toronto, Canada, became the first patient with type 1 diabetes to be successfully treated by insulin injection. Although insulin therapy remains essential for patients with type 1 diabetes and, eventually, for those with type 2, the search to bypass exogenous insulin sources continues. Engineering islets de novo from induced pluripotent stem cells (iPSC) represents a promising avenue in achieving insulin self-sufficiency. However, reconstructing complex 3D structures is not without its challenges. Understanding how different β-cells come together and maintain normal islet function is crucial in achieving successful islet reconstruction ex vivo. Single cells versus populations A single β-cell is not an average representative of the population as a whole. Although β-cells are the sole source of circulating insulin in the body, they show architectural and functional diversity, while maintaining glucose homeostasis. The many differences include variations in individual β-cell maturity, glucose responsiveness, membrane activity and Ca2+ fluxes, intracellular and secreted insulin and cell-to-cell connectivity. Understanding β-cell heterogeneity Evidence for functional and some morphological β-cell heterogeneity has been present for decades. However, recent technological advances have revolutionised the field, allowing scientists to probe deeper into the ways in which heterogeneity is manifested, and the mechanisms behind it. Mouse and human functional, transcriptional and marker-based single cell screening studies have provided high resolution data on an array of newly detected β-cell subpopulations or states. Alongside this, optogenetic tools, which allow control of cell activity by light, have paved the way for functional studies of β-cells within the islet context. In 2016, Johnston et al. described a novel subgroup of immature β-cells termed ‘hubs’ that act as pacemakers.1 Their susceptibility to glucolipotoxic Nearly a century ago, a 14-year-old boy from Toronto, Canada, became the first patient with type 1 diabetes to be successfully treated by insulin injection. Although insulin therapy remains essential for patients with type 1 diabetes and, eventually, for those with type 2, the search to bypass exogenous insulin sources continues. Engineering islets de novo from induced pluripotent stem cells (iPSC) represents a promising avenue in achieving insulin self-sufficiency. However, reconstructing complex 3D structures is not without its challenges. Understanding how different β-cells come together and maintain normal islet function is crucial in achieving successful islet reconstruction ex vivo. Single cells versus populations A single β-cell is not an average representative of the population as a whole. Although β-cells are the sole source of circulating insulin in the body, they show architectural and functional diversity, while maintaining glucose homeostasis. The many differences include variations in individual β-cell maturity, glucose responsiveness, membrane activity and Ca2+ fluxes, intracellular and secreted insulin and cell-to-cell connectivity. Understanding β-cell heterogeneity Evidence for functional and some morphological β-cell heterogeneity has been present for decades. However, recent technological advances have revolutionised the field, allowing scientists to probe deeper into the ways in which heterogeneity is manifested, and the mechanisms behind it. Mouse and human functional, transcriptional and marker-based single cell screening studies have provided high resolution data on an array of newly detected β-cell subpopulations or states. Alongside this, optogenetic tools, which allow control of cell activity by light, have paved the way for functional studies of β-cells within the islet context. In 2016, Johnston et al. described a novel subgroup of immature β-cells termed ‘hubs’ that act as pacemakers.1 Their susceptibility to glucolipotoxic attacks destabilises the functionality of the entire β-cell network, showcasing the potential importance of ‘hubs’ in the development of type 2 diabetes. Similarly, Westacott et al. contributed to mapping the islet circuitry by showing that the β-cell complement is regulated disproportionately by discrete β-cell subpopulations.2 Optimisation of smFISH (single molecule fluorescent in situ hybridisation) has recently revealed the existence of yet another β-cell subpopulation called ‘extreme’ β-cells. Using specific mRNA-tailored probes within a single cell in the intact pancreas, Farack et al. defined the ‘extreme’ population as β-cells specialised in basal insulin secretion, exhibiting high insulin mRNA and proinsulin, but low insulin protein.3 Their proportion rises together with the development of insulin resistance, indicating an involvement of ‘extreme’ cells in either islet failure or insulin secretory compensation. Cell marker approaches described β-cell subgroups based on the presence of cell-specific markers such as Flattop4 or urocortin 3.5 Impact of metabolic stress Common traits in these studies include differences in subpopulation maturity and proliferative capacity that become more prominent under metabolic stress. In line with this, transcriptome-based scRNA-seq (single-cell RNA sequencing) and protein-selective CyTOF (time-of-flight mass cytometry) identified β-cell clusters with different gene and protein signatures which change in proportion depending on islet health.6,7 The balance between the immature and mature β-cell populations, as well as proliferative capacity, appears to be a defining factor in the islet response to challenges, such as development, increased metabolic demand and ageing. Next-generation challenges Although trail-blazing, current studies have not yet answered the question ‘how can we replicate β-cell heterogeneity ex vivo?’ The subpopulations identified to date offer significant clues, but are insufficient to decipher the code of cellular diversity. Future technologies should be able to integrate existing knowledge of subpopulations and reconcile discrepancies between different approaches, leading to construction of robust and functional iPSC-derived islets