β-­cell hubs dictate pancreatic islet responses to glucose

The 3D-packaging of β-cells into spheroid micro-organs termed islets of Langerhans leads to a gain-of- function due to heightened intercellular communications. Dissociated β-cells fail to respond coordinately to input, secrete less insulin relative to cell mass and display elevated basal hormone levels suggesting connectivity is imperative for insulin secretion. β-cells are a heterogeneous population in regards to both metabolism and insulin secretion. Recent studies performed by this group and others, have revealed functional differences between hundreds of individual β-cells monitored in situ in the intact islet. A role for specialized β-cells in orchestrating these dynamics has long been postulated, including the presence of putative 'pacemakers'. However, whether particular subsets of functionally different cells drive the behavior of others has so far been difficult to prove empirically. Over the past decade, optogenetics has allowed reversible control of neuronal activity with light. In parallel, photopharmacology has enabled the development of synthetic photoswitches including JB253, a photoswitchable sulfonylurea which has been shown to optically control β-cell activity in vitro. Using this all-optical interrogation of individual β-cells in situ, alongside functional connectivity analysis this study set out to probe the topology that regulates population glucose responsiveness and understand islet heterogeneity in the context of insulin release. Mapping of islet functional architecture revealed the presence of highly-connected hub cells with pacemaker properties. Silencing of hubs via optically-controlled hyperpolarisation, abolished coordinated islet responses to glucose, whereas specific stimulation of hubs using JB253 restored communication patterns. Hubs were metabolically-adapted and their population size was reduced by both pro-inflammatory and glucolipotoxic insults to induce widespread β-cell dysfunction. Therefore, it appears the β-cell population within the pancreatic islet is wired by hubs, whose failure may contribute to T2D. Application of the photoswitchable insulin secretagogue, JB253, in vivo suggests that glycaemia can be optically controlled in vivo.