Abstract
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 {text {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 {text {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 text {K}^{+} channels modifies oscillatory activity patterns of beta -cell population lacking intercellular coupling, which significantly affect {text {Ca}}^{2+} concentration and insulin secretion.
Highlights
-cell mass and alteration of β-cell function in the islets of Langerhans, disrupting insulin secretion and glucose homeostasis
Changes in β-cell mass caused the functional alterations in single β-cell, leading to changes in insulin concentration and secretion dynamics
[Ca2+]c level of single β-cell decreased substantially faster after a greater (> 50% ) loss of cells compared with the loss of < 50%. These results indicate that a massive decline in the islet gap junction coupling, resulting in disruption of synchrony in human β-cell islet, plays a key role in more fast decrease in the average [Ca2+]c, poorly coordinated calcium dynamics, and plausibly, impairment of pulsatile insulin release and development of diabetes
Summary
-cell mass and alteration of β-cell function in the islets of Langerhans, disrupting insulin secretion and glucose homeostasis. The human pancreatic β-cells placed in islets of Langerhans organize a complex functional network[1,2,3,4], and ensure blood glucose h omeostasis[5] through a pulsatile, well-regulated insulin secretion[6,7,8] Like their rodent counterparts[9,10,11], human β-cells respond to increasing plasma glucose concentrations with acceleration of metabolism and elevation in ATP levels, which in turn inhibits ATP-sensitive potassium ( KATP ) channels, leading to membrane depolarization, activation of voltage-dependent calcium channels (VDCCs), a rise in the cytosolic calcium concentration ([ Ca2+]c ), and triggering exocytosis of insulin g ranules[12,13,14,15]
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