Type 2 diabetes (T2D) is a challenging metabolic disorder characterized by a substantial loss of \beta-cell mass via progressive programmed cell death 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 from 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 Ca^{2+} concentration, which can lead to changes in insulin secretion dynamics and in insulin levels. The model demonstrates  good correspondence between suppression of synchronizing electrical activity and pulsatile insulin release, 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 Ca^{2+} 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 conductance gating of delayed rectifier K^{+} channels modifies oscillatory activity patterns of \beta-cell population lacking intercellular coupling, which significantly affect Ca^{2+} concentration and insulin secretion.
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 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 \beta-cell synchronization and metabolic coupling in the behavior of Ca^{2+} 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 Ca^{2+} concentration and insulin secretion.
D
via progressive programmed cell death
R
from
of
A
a
D
pulsatile insulin release, and
R
conductance gating
whole-cell conductance