Calcium and Glycolysis Mediate Multiple Bursting Modes in Pancreatic Islets

Abstract

Pancreatic islets of Langerhans produce bursts of electrical activity when exposed to stimulatory glucose levels. These bursts often have a regular repeating pattern, with a period of 10-60 s. In some cases, however, the bursts are episodic, clustered into bursts of bursts, which we call compound bursting. Consistent with this are recordings of free Ca2+ concentration, oxygen consumption, mitochondrial membrane potential, and intraislet glucose levels that exhibit very slow oscillations, with faster oscillations superimposed. We describe a new mathematical model of the pancreatic beta-cell that can account for these multimodal patterns. The model includes the feedback of cytosolic Ca2+ onto ion channels that can account for bursting, and a metabolic subsystem that is capable of producing slow oscillations driven by oscillations in glycolysis. This slow rhythm is responsible for the slow mode of compound bursting in the model. We also show that it is possible for glycolytic oscillations alone to drive a very slow form of bursting, which we call "glycolytic bursting." Finally, the model predicts that there is bistability between stationary and oscillatory glycolysis for a range of parameter values. We provide experimental support for this model prediction. Overall, the model can account for a diversity of islet behaviors described in the literature over the past 20 years.

A novel fluorescence imaging approach for comparative measurements of pancreatic islet function in vitro

“…This observation supports our previous findings regarding the importance of oscillations to normal islet health, 8,10 however, it should be noted that ideally oscillations should be recorded in steady-state glucose to prevent transient states in their oscillatory periods. 18,19 Two separate trials were conducted, one with untreated islets labeled with CTR and another with cytokine-treated islets labeled with CTR. In each trial, the cytokine-treated islets showed a substantially reduced GSCa regardless of labeling.…”

Mathematical model for glucose regulation in the whole-body system

“…Accordingly, a number of researchers have proposed mathematical models for the β-cell electrical activity or the insulin secretion mechanism in the β-cell. 23,[46][47][48]52 Further, there have appeared a couple of studies tests have demonstrated such increased durations of activated membrane potentials as the glucose input rate is increased. In addition, slow oscillation behaviors of the insulin secretion are also observed under the indirect insulin inhibition effects on the β-cell bursting activity, which suggests that the secreted insulin inhibits the electrical activity of the β-cell by decreasing the GLUT2 transport rate.…”

“…6 It was also checked that the glucose concentration would maintain given external conditions, e.g., a constant extracellular glucose concentration. 46,48 On the other hand, there have also been suggested a few models, combine the β-cell electrical activity model with the whole-body glucose regulation model. For example, Chew et al have introduced the mathematical model for the β-cell electrical activity at varying glucose concentrations in the whole body.…”

“…45 In order to describe the insulin secretion pattern precisely, many researchers have investigated the microscopic behavior of the β-cell electrical activity with calcium dynamics. [46][47][48] Most of those studies focused on experimental results or mathematical modeling for the β-cell electrical activity under 200 mg/min, the ultradian oscillation period becomes shortened to 100 min, and the membrane potential is activated in longer time (see Fig. 9A and B).…”

The Interaction of Calcium and Metabolic Oscillations in Pancreatic Beta-cells

“…The K(Ca) conductance in (4a) is given by an increasing sigmoidal function of the Ca 2`c oncentration and the K(ATP) conductance in (4b) is dependent on the ADP and ATP concentrations, where the conductance function O 8 is given by the Magnus-Keizer expression [3], as shown by…”