Beta Cell Hubs Dictate Pancreatic Islet Responses to Glucose

Abstract

SummaryThe arrangement of β cells within islets of Langerhans is critical for insulin release through the generation of rhythmic activity. A privileged role for individual β cells in orchestrating these responses has long been suspected, but not directly demonstrated. We show here that the β cell population in situ is operationally heterogeneous. Mapping of islet functional architecture revealed the presence of hub cells with pacemaker properties, which remain stable over recording periods of 2 to 3 hr. Using a dual optogenetic/photopharmacological strategy, silencing of hubs abolished coordinated islet responses to glucose, whereas specific stimulation restored communication patterns. Hubs were metabolically adapted and targeted by both pro-inflammatory and glucolipotoxic insults to induce widespread β cell dysfunction. Thus, the islet is wired by hubs, whose failure may contribute to type 2 diabetes mellitus.

Beta-cell hubs maintain Ca2+ oscillations in human and mouse islet simulations

“…The findings of Johnston et al 33 are impressive and convincing, but, like all studies, their work was not without limitations. Their imaging methodology consisted of recording Ca 2+ oscillations in all β-cells in a 20 µm confocal plane.…”

“…Full details of the functional forms and parameters for each of these currents can be found in Cha et al 43 Here, we have added two currents. is the halorhodopsin (NpHR) current; this was employed by Johnston et al 33 to inhibit hub cells. is the current due to GJ coupling of the β-cell with a spatially-contacting β-cell.…”

“…30-32 Recently, Johnston et al . 33 demonstrated, by using functional cell mapping and optogenetics, that certain β-cells (termed ‘hubs’) are indispensable for the maintenance of Ca 2+ activity in the islet. Silencing of these cells revealed that inhibition of a single hub cell could reduce Ca 2+ activity in the islet network.…”

“…In particular, it is not clear if hub inhibition influences Ca 2+ activity in the entire islet, or just Ca 2+ activity in the imaged network. Secondly, to allow selective inhibition of identified hubs, Johnston et al 33 used a transgenic mouse line that expressed halorhodopsin in β-cells - an approach that would be difficult to implement in human islets. How, then, do these findings in mice translate to human islets?…”

“…These models displayed detailed morphological features based on 3D confocal reconstructions of islets. 36,41 We then used these models to explore the experimental findings of Johnston et al 33 In particular, we ask the question: can endowing a model of a mouse islet with a few (10%) highly metabolic β-cells recapitulate the findings of Johnston et al 33 ? We explored this question in an impartial and objective manner by considering parameter uncertainty, cell-to-cell variability, repeating simulations for different random seeds and constructed models for a number of mouse and human islet architectures.…”