How heterogeneity in glucokinase and gap junction coupling determines the islet electrical response

Abstract

Understanding how cell sub-populations in a tissue impact the function of the overall system is often challenging. There is extensive heterogeneity among insulin-secreting {beta}-cells within islets of Langerhans, including their insulin secretory response and gene expression profile; and this heterogeneity can be altered in diabetes. Several studies have identified variations in nutrient sensing between {beta}-cells, including glucokinase (GK) levels, mitochondrial function or expression of genes important for glucose metabolism. Sub-populations of {beta}-cells with defined electrical properties can disproportionately influence islet-wide free-calcium activity ([Ca2+]) and insulin secretion, via gap junction electrical coupling. However, it is poorly understood how sub-populations of {beta}-cells with altered glucose metabolism may impact islet function. To address this, we utilized a multicellular computational model of the islet in which a population of cells deficient in GK activity and glucose metabolism was imposed on the islet, or where {beta}-cells were heterogeneous in glucose metabolism and GK kinetics were altered. This included simulating Glucokinase gene (GCK) mutations that cause monogenic diabetes. We combined these approaches with experimental models in which gck was genetically deleted in a population of cells or GK was pharmacologically inhibited. In each case we modulated gap junction electrical coupling. Both the simulated islet and the experimental system required 30-50% of the cells to have near-normal glucose metabolism. Below this number, the islet lacked any glucose-stimulated [Ca2+] elevations. In the absence of electrical coupling the change in [Ca2+] was more gradual. As such, given heterogeneity in glucose metabolism, electrical coupling allows a large minority of cells with normal glucose metabolism to promote glucose-stimulated [Ca2+]. If insufficient numbers of cells are present, which we predict can be caused by a subset of GCK mutations that cause monogenic diabetes, electrical coupling exacerbates [Ca2+] suppression. This demonstrates precisely how heterogeneous {beta}-cell populations interact to impact islet function.\n\nSIGNIFICANCEBiological tissues contain heterogeneous populations of cells. Insulin-secreting {beta}-cells within the islets of Langerhans are critical for regulating blood glucose homeostasis. {beta}-cells are heterogeneous but it is unclear how the islet response is impacted by different cell populations and their interactions. We use a multicellular computational model and experimental systems to predict and quantify how cellular populations defined by varied glucose metabolism interact via electrical communication to impact islet function. When glucose metabolism is heterogeneous, electrical coupling is critical to promote electrical activity. However, when cells deficient in glucose metabolism are in the majority, electrical activity is completely suppressed. Thus modulating electrical communication can promotes islet electrical activity, following dysfunction caused by gene mutations that impact glucose metabolism.