The effects of beta-cell mass and function, intercellular coupling, and islet synchrony on Ca2+ dynamics

Type 2 diabetes (T2D) is a challenging metabolic disorder characterized by a substantial loss of beta -cell mass and alteration of beta -cell function in the islets of Langerhans, disrupting insulin secretion and glucose homeostasis. The mechanisms for deficiency in beta -cell mass and function during the hyperglycemia development and T2D pathogenesis are complex. To study the relative contribution of beta -cell mass to beta -cell function in T2D, we make use of a comprehensive electrophysiological model of human beta -cell clusters. We find that defect in beta -cell mass causes a functional decline in single beta -cell, impairment in intra-islet synchrony, and changes in the form of oscillatory patterns of membrane potential and intracellular Ca2+ 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 beta -cell synchronization and metabolic coupling in the behavior of Ca2+ concentration dynamics within human islets. Our results indicate that inter-beta -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 beta -cell population lacking intercellular coupling, which significantly affect Ca2+ concentration and insulin secretion.

Automated summary

The study demonstrates that defects in beta-cell mass can lead to functional decline in individual beta-cells, impairment in intra-islet synchrony, and changes in oscillatory patterns of membrane potential and intracellular Ca2+ concentration, thereby affecting insulin secretion dynamics and levels. Additionally, inter-beta-cellular electrical coupling is shown to play a more important role in regulating islet function and in the development of human T2D.