Kinetics of insulin secretion from MIN6 pseudoislets after encapsulation in a prototype device of a bioartificial pancreas.

摘要

Xenotransplantation of insulin-secreting cells from nonhuman sources is an alternative therapeutic approach to bypass the shortage of human pancreatic islet tissue for transplantation in order to treat insulin deficiency in type 1 diabetes mellitus. Therefore, we studied the suitability of pseudoislets generated from insulin-secreting MIN6 tissue culture cells to serve as a surrogate for replacement of pancreatic islets after encapsulation in a minicell, representing a prototype of a new bioartificial pancreas device. MIN6 pseudoislets showed an excellent insulin secretory responsiveness with a typical biphasic secretory pattern to glucose stimulation. When encapsulated in the minicell, insulin release from the pseudoislets in response to glucose stimulation was reduced. The initial first phase insulin secretory response was greatly attenuated. In contrast, the first phase insulin secretory response of the encapsulated pseudoislets was restored on stimulation with the sulfonylurea drug tolbutamide. Ourresults indicate that the reason for the attenuated first phase of release is the restricted permeability of the pores in the separating membrane in the minicell for the hydrophilic glucose molecule rather than a limited permeability for the secretion product insulin. The reduced release of insulin from the encapsulated pseudoislets could be compensated by overexpression of glucokinase in MIN6 cells, which resulted in an increased glucose responsiveness of the pseudoislets for stimulation with glucose. Thus, this minicell is a well-suited miniature test system for the evaluation of the feasibility of encapsulation of insulin-secreting cells and allows the testing of permeability properties of separating membranes in bioartificial pancreas devices.