A local glucose-and oxygen concentration-based insulin secretion model for pancreatic islets

Abstract

BackgroundBecause insulin is the main regulator of glucose homeostasis, quantitative models describing the dynamics of glucose-induced insulin secretion are of obvious interest. Here, a computational model is introduced that focuses not on organism-level concentrations, but on the quantitative modeling of local, cellular-level glucose-insulin dynamics by incorporating the detailed spatial distribution of the concentrations of interest within isolated avascular pancreatic islets.MethodsAll nutrient consumption and hormone release rates were assumed to follow Hill-type sigmoid dependences on local concentrations. Insulin secretion rates depend on both the glucose concentration and its time-gradient, resulting in second-and first-phase responses, respectively. Since hypoxia may also be an important limiting factor in avascular islets, oxygen and cell viability considerations were also built in by incorporating and extending our previous islet cell oxygen consumption model. A finite element method (FEM) framework is used to combine reactive rates with mass transport by convection and diffusion as well as fluid-mechanics.ResultsThe model was calibrated using experimental results from dynamic glucose-stimulated insulin release (GSIR) perifusion studies with isolated islets. Further optimization is still needed, but calculated insulin responses to stepwise increments in the incoming glucose concentration are in good agreement with existing experimental insulin release data characterizing glucose and oxygen dependence. The model makes possible the detailed description of the intraislet spatial distributions of insulin, glucose, and oxygen levels. In agreement with recent observations, modeling also suggests that smaller islets perform better when transplanted and/or encapsulated.ConclusionsAn insulin secretion model was implemented by coupling local consumption and release rates to calculations of the spatial distributions of all species of interest. The resulting glucose-insulin control system fits in the general framework of a sigmoid proportional-integral-derivative controller, a generalized PID controller, more suitable for biological systems, which are always nonlinear due to the maximum response being limited. Because of the general framework of the implementation, simulations can be carried out for arbitrary geometries including cultured, perifused, transplanted, and encapsulated islets.

Angiogenesis revisited – role and therapeutic potential of targeting endothelial metabolism

“…Their reliance on anaerobic generation of ATP enables endothelial cells to proliferate, and to migrate in hypoxic environments where angiogenesis is stimulated and oxidative metabolism would be impaired. Accordingly, glucose availability is not a rate-limiting factor because its concentrations are sufficient in interstitial tissue whereas those of oxygen drop away from blood vessels (Buchwald, 2011;Gatenby and Gillies, 2004). Although lack of glucose enhances endothelial cell vulnerability to hypoxia, when sufficiently high concentrations of glucose are present, glycolysis can generate as much ATP as glucose oxidation because glycolysis rapidly produces ATP (Locasale and Cantley, 2011;Mertens et al, 1990).…”

Survival of encapsulated islets: More than a membrane story

“…A BAP device should continuously sense ambient glucose concentrations and respond to a glucose concentration change by releasing adequate amounts of insulin. This process is also PO2dependent [146,147] . Fractional secretion of islets decreases at PO2 below 60 Torr and reaches 50% efficiency at 27 Torr.…”

Human islet preparations distributed for research exhibit a variety of insulin-secretory profiles

“…4, H and I) indicate that stimulation of insulin secretion in static islet culture does not correlate with stimulated insulin secretion via perifusion. Other approaches used to assess islet health have included glucose-induced changes in oxygen consumption rate (7,31,34,35), glucose-induced preproinsulin mRNA expression (30), and mitochondrial integrity (16). Given that these approaches, including islet perifusion, are not widely available and preexperimental human islet assessment is critical, a new approach for islet distribution programs is necessary.…”

“…Furthermore, how or whether to assess the health and function of health of islet preparations prior to study is not standardized. Some laboratories assess human islet health and/or function using methods such as measurement of oxygen consumption (7,35) or insulin release in response to stimuli (3,10), among others (15,16). Although studies have examined the relationship between donor attributes and insulin release in the context of a single isolation center (9), little is known about insulin secretion compared among islet preparations from different isolation centers, which reflects how human islet research is currently being conducted in most research laboratories.…”