Small subpopulations of β-cells do not drive islet oscillatory [Ca2+] dynamics via gap junction communication

Abstract

The islets of Langerhans exist as multicellular networks that regulate blood glucose levels. The majority of cells in the islet are excitable, insulin-producing β-cells that are electrically coupled via gap junction channels. β-cells are known to display heterogeneous functionality. However, due to gap junction coupling, β-cells show coordinated [Ca2+] oscillations when stimulated with glucose, and global quiescence when unstimulated. Small subpopulations of highly functional β-cells have been suggested to control [Ca2+] dynamics across the islet. When these populations were targeted by optogenetic silencing or photoablation, [Ca2+] dynamics across the islet were largely disrupted. In this study, we investigated the theoretical basis of these experiments and how small populations can disproportionality control islet [Ca2+] dynamics. Using a multicellular islet model, we generated normal, skewed or bimodal distributions of β-cell heterogeneity. We examined how islet [Ca2+] dynamics were disrupted when cells were targeted via hyperpolarization or populations were removed; to mimic optogenetic silencing or photoablation, respectively. Targeted cell populations were chosen based on characteristics linked to functional subpopulation, including metabolic rate of glucose oxidation or [Ca2+] oscillation frequency. Islets were susceptible to marked suppression of [Ca2+] when ~10% of cells with high metabolic activity were hyperpolarized; where hyperpolarizing cells with normal metabolic activity had little effect. However, when highly metabolic cells were removed from the model, [Ca2+] oscillations remained. Similarly, when ~10% of cells with either the highest frequency or earliest elevations in [Ca2+] were removed from the islet, the [Ca2+] oscillation frequency remained largely unchanged. Overall, these results indicate small populations of β-cells with either increased metabolic activity or increased frequency are unable to disproportionately control islet-wide [Ca2+] via gap junction coupling. Therefore, we need to reconsider the physiological basis for such small β-cell populations or the mechanism by which they may be acting to control normal islet function.

Glucose-dependent activation, activity, and deactivation of beta cell networks in acute mouse pancreas tissue slices

“…More specifically, different lines of evidence suggest that the functionally most connected cells are metabolically more active (66,67,101,104,144,145). At the same time, our current and previous experimental and model findings that the parameter value distributions and functional behavior of cells are heterogeneous in a rather continuous manner (28-30, 32, 34, 145, 146), with no clear-cut subpopulations, are compatible with the view that only a few cells with extreme parameter values are not necessary for normal b cell activation, coordinated activity, and deactivation (41,122). Again, we would like to underline that the terms "first-responders" and "hubs," as defined in this study, are not the same as "pacemakers."…”

“…Our data do not imply that the first-responders are in any way necessary for islets to respond to glucose concentrations and that their role is fixed in time. It is reasonable to speculate that the removal or dysfunction of first-responders would make other cells become first-responders (33,41,104,105,122), and recent experimental data corroborated this (54). Even without removal or dysfunction, the metabolic status and physiological features change as b cells mature (123).…”

“…Importantly, we wish to point out that parameter values were rather continuous, with no clear extremes. Also, we do not believe or wish to suggest that removing the cells with the highest parameter values would dramatically alter the collective behavior (122). Moreover, it remains to be investigated whether these roles are relatively constant in time or change dynamically (40).…”

Beta-cell Metabolic Activity Rather than Gap Junction Structure Dictates Subpopulations in the Islet Functional Network

“…A scale-free distribution implies that there exists a subset of highly connected nodes, often called "hubs" (4,30). By studying the distribution of the functional network, Johnston et al and others (30)(31)(32) have suggested that 𝛽-cell hub cells have a greater than average influence on the islet and may be preferentially attacked by diabetic conditions, suggesting a possible mechanism behind the loss of pulsatile insulin secretion in diabetes. These 𝛽-cell hubs were also shown to have unique characteristics including high metabolic activity and depolarizing before and repolarizing after the rest of the islet (30,33).…”

“…These β -cell hubs were also shown to have unique characteristics including high metabolic activity and depolarizing before and repolarizing after the rest of the islet (30, 33) . However, electrophysiological experiments and computational studies suggest that it is not feasible for one cell or a small population of cells to have disproportionate influence over the Islet (31, 34, 35) . These studies have caused debate over the most accurate topological description of the islet network (36, 37) .…”