Glucose-stimulated insulin secretion in isolated pancreatic islets: Multiphysics FEM model calculations compared to results of perifusion experiments with human islets

Abstract

<span style="font-size:10.0pt;font-family:;" "=""><span style="font-family:Verdana;font-size:12px;">Because insulin released by the </span><i><span style="font-family:Verdana;font-size:12px;">β</span></i><span style="font-family:Verdana;font-size:12px;">-cells of pancreatic islets is the main regulator of glucose levels, the quantitative modeling of their glucose-stimulated insulin secretion is of obvious interest not only to improve our understanding of the processes involved, but also to allow better assessment of </span><i><span style="font-family:Verdana;font-size:12px;">β</span></i><span style="font-family:Verdana;font-size:12px;"> -cell function in diabetic patients or islet transplant recipients as well as the development of improved artificial or bioartificial pancreas devices. We have recently developed a general, local concentrations-based multiphysics computational model of insulin secretion in avascular pancreatic islets that can be used to calculate insulin secretion for arbitrary geometries of cultured, perifused, transplanted, or encapsulated islets in response to various glucose profiles. Here, experimental results obtained from two different dynamic glucose-stimulated insulin release (GSIR) perifusion studies performed by us following standard procedures are compared to those calculated by the model. Such perifusion studies allow the quantitative assessment of insulin release kinetics under fully controllable experimental conditions of varying external concentrations of glucose, oxygen, or other compounds of interest, and can provide an informative assessment of islet quality and function. The time-profile of the insulin secretion calculated by the model was in good agree- ment with the experimental results obtained with isolated human islets. Detailed spatial distributions of glucose, oxygen, and insulin were calculated and are presented to provide a quantitative visualization of various important aspects of the insulin secretion dynamics in perifused islets.</span></span

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

“…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.…”

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

“…Perifusion was performed with four channels in parallel and using a low (3 mM), high (11 mM), low (3 mM) glucose step with frequent sample collection (every minute); the insulin response obtained is shown in Figure 2 . To allow a clear delineation of the first-phase response, the high glucose step (G11) was maintained for 20 min, which is longer than in our previously used standard protocols [ 34 – 36 ]. Unencapsulated islets demonstrated a well-defined first-phase peak, followed by a second-phase plateau, with possibly a slightly rising tendency (Figure 2 ).…”

“…Finally, all the local (cellular-level) oxygen, glucose, and insulin concentrations are combined together with solute transfer equations to calculate observable, external concentrations as a function of time and incoming glucose and oxygen concentrations (see Computational methods and Additional file 1 : Appendix 1 for further details). Calculations were done using the same model parameterized originally based on perifusion data from human islets [ 21 ], except the kinetics of insulin release was increased slightly ( k insL = 0.006 s −1 vs. the original 0.003 s −1 ) to account for the somewhat sharper first phase response of murine islets observed here as compared to human islets [ 34 , 43 ]. The effect of this change on the predicted insulin release profile of free islets is shown in Figure 4 .…”

“…Mesh and boundary conditions used were also as described before [ 21 ] (see also Additional file 1 : Appendix 1, Additional files for further details). Similar to our previous models of human islet perifusions [ 21 , 34 ], here, we also used two spherical islets of 100 and 150 μm diameter placed in a 2D cross-section of a cylindrical tube with fluid flowing from left to right. Islets were considered homogeneous inside; individual cells (e.g., α- or β-cells) were not considered separately.…”

Visible light-initiated interfacial thiol-norbornene photopolymerization for forming an islet surface conformal coating

“…The diffusivities of insulin in the swollen hydrogel were slightly lower than that in aqueous buffer solution (D 0 : ~1500 μm 2 /sec). 50 These estimations suggest that the diffusion of insulin from the highly swollen thiol-norbornene hydrogels will be affected only minimally.…”