Small subpopulations of [beta]-cells do not drive islet oscillatory [Ca.sup.2+] dynamics via gap junction communication

The islets of Langerhans exist as multicellular networks that regulate blood glucose levels. The majority of cells in the islet are excitable, insulin-producing [beta]-cells that are electrically coupled via gap junction channels. [beta]-cells are known to display heterogeneous functionality. However, due to gap junction coupling, [beta]-cells show coordinated [Ca.sup.2+ ] oscillations when stimulated with glucose, and global quiescence when unstimulated. Small subpopulations of highly functional [beta]-cells have been suggested to control [Ca.sup.2+ ] dynamics across the islet. When these populations were targeted by optogenetic silencing or photoablation, [Ca.sup.2+ ] 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 [Ca.sup.2+ ] dynamics. Using a multicellular islet model, we generated normal, skewed or bimodal distributions of [beta]-cell heterogeneity. We examined how islet [Ca.sup.2+ ] 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 [Ca.sup.2+ ] oscillation frequency. Islets were susceptible to marked suppression of [Ca.sup.2+ ] 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, [Ca.sup.2+ ] oscillations remained. Similarly, when ~10% of cells with either the highest frequency or earliest elevations in [Ca.sup.2+ ] were removed from the islet, the [Ca.sup.2+ ] oscillation frequency remained largely unchanged. Overall, these results indicate small populations of [beta]-cells with either increased metabolic activity or increased frequency are unable to disproportionately control islet-wide [Ca.sup.2+ ] via gap junction coupling. Therefore, we need to reconsider the physiological basis for such small [beta]-cell populations or the mechanism by which they may be acting to control normal islet function.