title: Investigating the role of islet cytoarchitecture in its oscillation using a new beta-cell cluster model.
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.
authors.affiliation: Max McGee National Research Center for Juvenile Diabetes, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors.forename: Aparna
authors.initials: A
authors.lastname: Nittala
authors.forename: Soumitra
authors.initials: S
authors.lastname: Ghosh
authors.forename: Xujing
authors.initials: X
authors.lastname: Wang
mesh_terms: D001703:Biophysics / Q000379:methods; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D016000:Cluster Analysis; D005947:Glucose; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007515:Islets of Langerhans / Q000378:metabolism*; D008954:Models, Biological; D015233:Models, Statistical; D008962:Models, Theoretical; D009991:Oscillometry / Q000379:methods
chemical_list: D007328:Insulin; D005947:Glucose; D002118:Calcium