How Heterogeneity in Glucokinase and Gap-Junction Coupling Determines the Islet [Ca2+] Response

Abstract

Understanding how cell subpopulations in a tissue impact overall system function is challenging. There is extensive heterogeneity among insulin-secreting b-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 b-cells, including glucokinase (GK) levels, mitochondrial function, or expression of genes important for glucose metabolism. Subpopulations of b-cells with defined electrical properties can disproportionately influence islet-wide free-calcium activity ([Ca 2þ ]) and insulin secretion via gap-junction electrical coupling. However, it is poorly understood how subpopulations of b-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 in which b-cells were heterogeneous in glucose metabolism and GK kinetics were altered. This included simulating GK 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, fewer than cells with normal K ATP conductance. Below this number, the islet lacked any glucose-stimulated [Ca 2þ ] elevations. In the absence of electrical coupling, the change in [Ca 2þ ] was more gradual. As such, electrical coupling allows a large minority of cells with normal glucose metabolism to promote glucose-stimulated [Ca 2þ ]. 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 [Ca 2þ ] suppression. This demonstrates precisely how metabolically heterogeneous b-cell populations interact to impact islet function.

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

“…Experimental evidence indicates that within the intact islet there exists 10-20% variation in metabolic activity [37]. Previous modelling studies have represented beta cell heterogeneity as a continuous distribution with 10-25% variation in GK activity and metabolic activity, which is sufficient to model the impact of electrical coupling and heterogeneity within the islet [29,[34][35][36]. However, recent experimental evidence has suggested that small β -cell subpopulations with elevated metabolic activity or GK expression are present within the islet and may disproportionately drive elevated [Ca 2+ ] [29,30].…”

“…However, recent studies have demonstrated that heterogeneity plays a physiological role in regulating insulin release within the islet [29,30,35]. Previously, using computational models and experimental systems, we demonstrated that a large minority (close to 50%) of metabolically active β -cells were necessary to maintain the activity of the islet [35]. In contrast to this, experimental and theoretical studies have suggested that small (~10%) highly functional subpopulations may be required to maintain whole islet electrical dynamics [30,41].…”

“…-cell heterogeneity has largely been studied in single cells. However, recent studies have demonstrated that heterogeneity plays a physiological role in regulating insulin release within the islet [29,30,35]. Previously, using computational models and experimental systems, we demonstrated that a large minority (close to 50%) of metabolically active β -cells were necessary to maintain the activity of the islet [35].…”

“…β -cell electrical activity model-The coupled β -cell model was described previously [35] and adapted from the published Cha-Noma single cell model [53,54]. All code was written in C++ and run on the SUMMIT supercomputer (University of Colorado Boulder).…”

“…In this study we explore the theoretical basis for whether small β -cell subpopulations can control multicellular islet [Ca 2+ ] dynamics. Towards this, we utilize a computational model of the islet that wehave previously validated against a wide-range of experimental data [29,[34][35][36]. This includes understanding how populations of inexcitable cells suppress islet function and the role for electrical coupling.…”