The effects of beta-cell mass and function, intercellular coupling, and islet synchrony on $\textrm{Ca}^{2+}$ dynamics

Abstract

Type 2 diabetes (T2D) is a challenging metabolic disorder characterized by a substantial loss of $β$-cell mass and alteration of $β$-cell function in the islets of Langerhans, disrupting insulin secretion and glucose homeostasis. The mechanisms for deficiency in $β$-cell mass and function during the hyperglycemia development and T2D pathogenesis are complex. To study the relative contribution of $β$-cell mass to $β$-cell function in T2D, we make use of a comprehensive electrophysiological model of human $β$-cell clusters. We find that defect in $β$-cell mass causes a functional decline in single $β$-cell, impairment in intra-islet synchrony, and changes in the form of oscillatory patterns of membrane potential and intracellular $\textrm{Ca}^{2+}$ concentration, which can lead to changes in insulin secretion dynamics and in insulin levels. The model demonstrates a good correspondence between suppression of synchronizing electrical activity and published experimental measurements. We then compare the role of gap junction-mediated electrical coupling with both $β$-cell synchronization and metabolic coupling in the behavior of $\textrm{Ca}^{2+}$ concentration dynamics within human islets. Our results indicate that inter-$β$-cellular electrical coupling depicts a more important factor in shaping the physiological regulation of islet function and in human T2D. We further predict that varying the whole-cell conductance of delayed rectifier $\textrm{K}^{+}$ channels modifies oscillatory activity patterns of $β$-cell population lacking intercellular coupling, which significantly affect $\textrm{Ca}^{2+}$ concentration and insulin secretion.