Limits...
Investigating the role of islet cytoarchitecture in its oscillation using a new beta-cell cluster model.

Nittala A, Ghosh S, Wang X - PLoS ONE (2007)

Bottom Line: In addition, normal beta-cell clusters are robust against significant perturbation to their architecture, including the presence of non-beta cells or dead beta cells.Our results suggest that the bursting characteristics of a beta-cell cluster depend quantitatively on its architecture in a non-linear fashion.These findings are important to understand the islet bursting phenomenon and the regulation of insulin secretion, under both physiological and pathological conditions.

View Article: PubMed Central - PubMed

Affiliation: Max McGee National Research Center for Juvenile Diabetes, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.

ABSTRACT
The oscillatory insulin release is fundamental to normal glycemic control. The basis of the oscillation is the intercellular coupling and bursting synchronization of beta cells in each islet. The functional role of islet beta cell mass organization with respect to its oscillatory bursting is not well understood. This is of special interest in view of the recent finding of islet cytoarchitectural differences between human and animal models. In this study we developed a new hexagonal closest packing (HCP) cell cluster model. The model captures more accurately the real islet cell organization than the simple cubic packing (SCP) cluster that is conventionally used. Using our new model we investigated the functional characteristics of beta-cell clusters, including the fraction of cells able to burst f(b), the synchronization index lambda of the bursting beta cells, the bursting period T(b), the plateau fraction p(f), and the amplitude of intracellular calcium oscillation [Ca]. We determined their dependence on cluster architectural parameters including number of cells n(beta), number of inter-beta cell couplings of each beta cell n(c), and the coupling strength g(c). We found that at low values of n(beta), n(c) and g(c), the oscillation regularity improves with their increasing values. This functional gain plateaus around their physiological values in real islets, at n(beta) approximately 100, n(c) approximately 6 and g(c) approximately 200 pS. In addition, normal beta-cell clusters are robust against significant perturbation to their architecture, including the presence of non-beta cells or dead beta cells. In clusters with n(beta)> approximately 100, coordinated beta-cell bursting can be maintained at up to 70% of beta-cell loss, which is consistent with laboratory and clinical findings of islets. Our results suggest that the bursting characteristics of a beta-cell cluster depend quantitatively on its architecture in a non-linear fashion. These findings are important to understand the islet bursting phenomenon and the regulation of insulin secretion, under both physiological and pathological conditions.

Show MeSH

Related in: MedlinePlus

Threshold of β-cell loss that would lead to complete loss of bursting synchronization.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC1991600&req=5

pone-0000983-g008: Threshold of β-cell loss that would lead to complete loss of bursting synchronization.

Mentions: During the disease progression for all major forms of diabetes loss of β-cell mass has been observed [46]. The alteration sometimes could be merely a reduction in islet size nβ, but more often more profound changes to the islet cytoarchitecture occur. For example, in type 1 diabetes the infiltrating immune cells spread from peripheral islet vessels to the centre of a given islet, causing β-cell apoptosis across the islet [50], [51]. In this situation both nβ and nc are reduced, more significantly so for nc. For this reason we have examined the impact to the cluster bursting pattern when there is random β-cell loss across the cluster. Both fb and λ fall with increasing loss of β cells (data not shown). The results are similar to that presented in figure 3, where we compared the SCP and HCP cluster at 0% of non-β cells. We are specifically interested in the threshold loss of β-cell mass that would lead to functional failure. As the coordination and synchronization of the β-cell bursting within an islet is fundamental to regulated, glucose dose-dependent insulin release, we investigated this problem from the perspective of β-cell bursting synchronization. We first simulated and determined the degree of synchronization that would be expected by chance for a cluster of uncoupled β cells. We then assumed that a β-cell cluster would not be able to function normally if its λ falls below 2 SD of this basal level. Using this criterion, we investigated the threshold loss of β-cell mass that would result in functional failure, under varying values of gc. Around physiological values of gc (150–250 pS), at 30% non-β cells, we found that HCP β-cell clusters can function with majority, up to 70%, of its β-cell mass lost. The result of gc = 200 pS is given in figure 8. This is consistent with the laboratory and clinical findings. Laboratory studies have shown that islets are tolerant of substantial β-cell loss, and can function normally with majority of β cells either dead or non-functioning [48]. Clinically it is believed that in type 1 diabetes disease onset occurs with up to 70–90% of β cells are destroyed [52]. In contrast, the SCP clusters do not have such robustness, the threshold loss is only 40% at gc = 200 pS (figure 8). If the intercellular coupling is impaired with a low gc value, the function of the β-cell cluster is much less robust against β-cell damages. At gc∼25 pS, a 30% of β-cell loss would completely disrupt the bursting coordination of a HCP β-cell cluster.


Investigating the role of islet cytoarchitecture in its oscillation using a new beta-cell cluster model.

Nittala A, Ghosh S, Wang X - PLoS ONE (2007)

Threshold of β-cell loss that would lead to complete loss of bursting synchronization.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1991600&req=5

pone-0000983-g008: Threshold of β-cell loss that would lead to complete loss of bursting synchronization.
Mentions: During the disease progression for all major forms of diabetes loss of β-cell mass has been observed [46]. The alteration sometimes could be merely a reduction in islet size nβ, but more often more profound changes to the islet cytoarchitecture occur. For example, in type 1 diabetes the infiltrating immune cells spread from peripheral islet vessels to the centre of a given islet, causing β-cell apoptosis across the islet [50], [51]. In this situation both nβ and nc are reduced, more significantly so for nc. For this reason we have examined the impact to the cluster bursting pattern when there is random β-cell loss across the cluster. Both fb and λ fall with increasing loss of β cells (data not shown). The results are similar to that presented in figure 3, where we compared the SCP and HCP cluster at 0% of non-β cells. We are specifically interested in the threshold loss of β-cell mass that would lead to functional failure. As the coordination and synchronization of the β-cell bursting within an islet is fundamental to regulated, glucose dose-dependent insulin release, we investigated this problem from the perspective of β-cell bursting synchronization. We first simulated and determined the degree of synchronization that would be expected by chance for a cluster of uncoupled β cells. We then assumed that a β-cell cluster would not be able to function normally if its λ falls below 2 SD of this basal level. Using this criterion, we investigated the threshold loss of β-cell mass that would result in functional failure, under varying values of gc. Around physiological values of gc (150–250 pS), at 30% non-β cells, we found that HCP β-cell clusters can function with majority, up to 70%, of its β-cell mass lost. The result of gc = 200 pS is given in figure 8. This is consistent with the laboratory and clinical findings. Laboratory studies have shown that islets are tolerant of substantial β-cell loss, and can function normally with majority of β cells either dead or non-functioning [48]. Clinically it is believed that in type 1 diabetes disease onset occurs with up to 70–90% of β cells are destroyed [52]. In contrast, the SCP clusters do not have such robustness, the threshold loss is only 40% at gc = 200 pS (figure 8). If the intercellular coupling is impaired with a low gc value, the function of the β-cell cluster is much less robust against β-cell damages. At gc∼25 pS, a 30% of β-cell loss would completely disrupt the bursting coordination of a HCP β-cell cluster.

Bottom Line: In addition, normal beta-cell clusters are robust against significant perturbation to their architecture, including the presence of non-beta cells or dead beta cells.Our results suggest that the bursting characteristics of a beta-cell cluster depend quantitatively on its architecture in a non-linear fashion.These findings are important to understand the islet bursting phenomenon and the regulation of insulin secretion, under both physiological and pathological conditions.

View Article: PubMed Central - PubMed

Affiliation: Max McGee National Research Center for Juvenile Diabetes, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.

ABSTRACT
The oscillatory insulin release is fundamental to normal glycemic control. The basis of the oscillation is the intercellular coupling and bursting synchronization of beta cells in each islet. The functional role of islet beta cell mass organization with respect to its oscillatory bursting is not well understood. This is of special interest in view of the recent finding of islet cytoarchitectural differences between human and animal models. In this study we developed a new hexagonal closest packing (HCP) cell cluster model. The model captures more accurately the real islet cell organization than the simple cubic packing (SCP) cluster that is conventionally used. Using our new model we investigated the functional characteristics of beta-cell clusters, including the fraction of cells able to burst f(b), the synchronization index lambda of the bursting beta cells, the bursting period T(b), the plateau fraction p(f), and the amplitude of intracellular calcium oscillation [Ca]. We determined their dependence on cluster architectural parameters including number of cells n(beta), number of inter-beta cell couplings of each beta cell n(c), and the coupling strength g(c). We found that at low values of n(beta), n(c) and g(c), the oscillation regularity improves with their increasing values. This functional gain plateaus around their physiological values in real islets, at n(beta) approximately 100, n(c) approximately 6 and g(c) approximately 200 pS. In addition, normal beta-cell clusters are robust against significant perturbation to their architecture, including the presence of non-beta cells or dead beta cells. In clusters with n(beta)> approximately 100, coordinated beta-cell bursting can be maintained at up to 70% of beta-cell loss, which is consistent with laboratory and clinical findings of islets. Our results suggest that the bursting characteristics of a beta-cell cluster depend quantitatively on its architecture in a non-linear fashion. These findings are important to understand the islet bursting phenomenon and the regulation of insulin secretion, under both physiological and pathological conditions.

Show MeSH
Related in: MedlinePlus