The effects of beta-cell mass and function, intercellular coupling, and islet synchrony on 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 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 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 K + channels modifies oscillatory activity patterns of β-cell population lacking intercellular coupling, which significantly affect Ca 2 + concentration and insulin secretion.