Experimental evaluation and computational modeling of the effects of encapsulation on the time-profile of glucose-stimulated insulin release of pancreatic islets

Abstract

BackgroundIn type 1 diabetic patients, who have lost their ability to produce insulin, transplantation of pancreatic islet cells can normalize metabolic control in a manner that is not achievable with exogenous insulin. To be successful, this procedure has to address the problems caused by the immune and autoimmune responses to the graft. Islet encapsulation using various techniques and materials has been and is being extensively explored as a possible approach. Within this framework, it is of considerable interest to characterize the effect encapsulation has on the insulin response of pancreatic islets.MethodsTo improve our ability to quantitatively describe the glucose-stimulated insulin release (GSIR) of pancreatic islets in general and of micro-encapsulated islets in particular, we performed dynamic perifusion experiments with frequent sampling. We used unencapsulated and microencapsulated murine islets in parallel and fitted the results with a complex local concentration-based finite element method (FEM) computational model.ResultsThe high-resolution dynamic perifusion experiments allowed good characterization of the first-phase and second-phase insulin secretion, and we observed a slightly delayed and blunted first-phase insulin response for microencapsulated islets when compared to free islets. Insulin secretion profiles of both free and encapsulated islets could be fitted well by a COMSOL Multiphysics model that couples hormone secretion and nutrient consumption kinetics with diffusive and convective transport. This model, which was further validated and calibrated here, can be used for arbitrary geometries and glucose stimulation sequences and is well suited for the quantitative characterization of the insulin response of cultured, perifused, transplanted, or encapsulated islets.ConclusionsThe present high-resolution GSIR experiments allowed for direct characterization of the effect microencapsulation has on the time-profile of insulin secretion. The multiphysics model, further validated here with the help of these experimental results, can be used to increase our understanding of the challenges that have to be faced in the design of bioartificial pancreas-type devices and to advance their further optimization.Electronic supplementary materialThe online version of this article (doi:10.1186/s12938-015-0021-9) contains supplementary material, which is available to authorized users.

Metabolomics Study of the Effects of Inflammation, Hypoxia, and High Glucose on Isolated Human Pancreatic Islets

“…This is well-illustrated by our model 15, 39 calculated values shown in Supplementary Figure S8. While tissue oxygen concentrations are around 5% 21, 22 , most of the islet tissue will be exposed to lower oxygen concentrations, hence 3% is a reasonable choice and one that has been used by others 33, 34 .…”

“…With the improvement in equipment and analytical techniques, GSIR studies, which were introduced in the early 1970s 50 , can now provide robust quantitative characterization of insulin release kinetics, including both first- and second-phase response, under fully controllable experimental conditions of varying external concentrations of glucose and other segretagogues 39, 51–54 . GSIR is routinely used to assess islet quality and function 55 .…”

“…GSIR is routinely used to assess islet quality and function 55 . In this study, perifusions were performed using an automated perifusion machine (PERI4-02, Biorep) that allows parallel assays for up to eight chambers and our standard protocol of low-high-low (3 → 11 → 3 mM) glucose 39, 56 . As shown in Figure 8, hypoxia severely depressed the ability of islets to secrete insulin in response to a HG challenge, whereas the inflammatory conditions used elevated both baseline and stimulated insulin secretions (per unit islet volume; i.e., islet equivalent, IEQ), indicating stressed islets.…”

Resealable, optically accessible, PDMS-free fluidic platform for ex vivo interrogation of pancreatic islets

“…The influx of glucose and oxygen was set to be transported with the inlet velocity. Islet nutrient consumption and hormone secretion was modeled with a Hill-type sigmoid dependence on local concentration, while insulin release was modeled in a first and second phase, depending on the glucose time-gradient and its concentration, respectively 26 . At the outlet, insulin, glucose and oxygen were allowed to freely flow outward.…”

Transplantable bioartificial pancreas devices: current status and future prospects

“…Maintaining this subtle regulation within an encapsulated islet is one of the major challenges in this field. The production, secretion, and diffusion of insulin through a capsule/chamber system depend on a variety of biological and physico-chemical factors [75,84]. Extensive research has been done to identify the most optimal conditions and select appropriate capsule components [75,79] with reasonable success in insulin release upon glucose in vitro and in vivo.…”