Electrical bursting, calcium oscillations, and synchronization of pancreatic islets

Abstract

Oscillations are an integral part of insulin secretion and are ultimately due to oscillations in the electrical activity of pancreatic beta-cells, called bursting. In this chapter we discuss islet bursting oscillations and a unified biophysical model for this multi-scale behavior. We describe how electrical bursting is related to oscillations in the intracellular Ca(2+) concentration within beta-cells and the role played by metabolic oscillations. Finally, we discuss two potential mechanisms for the synchronization of islets within the pancreas. Some degree of synchronization must occur, since distinct oscillations in insulin levels have been observed in hepatic portal blood and in peripheral blood sampling of rats, dogs, and humans. Our central hypothesis, supported by several lines of evidence, is that insulin oscillations are crucial to normal glucose homeostasis. Disturbance of oscillations, either at the level of the individual islet or at the level of islet synchronization, is detrimental and can play a major role in type 2 diabetes.

Figure 1

Slow electrical bursting recorded from a mouse islet. Provided by J. Ren and L.S. Satin.

Figure 2

Model simulation of bursting, illustrating the dynamics of membrane potential (V), free cytosolic Ca²⁺ concentration (Ca_c), free ER Ca²⁺ concentration (Ca_ER), and the ATP/ADP concentration ratio. The model is described in (42) and the computer code can be downloaded from www.math.fsu.edu/~bertram/software/islet.

Figure 3

(A) Compound islet Ca²⁺ oscillations measured using fura-2/AM. The oscillations consist of slow episodes of fast oscillations. Reprinted with permission from (79). (B) Slow oxygen oscillations with superimposed fast “teeth”. Reprinted with permission from (76).

Figure 4

Three types of oscillations typically observed in islets. Top row of panels is from islet measurements of Ca²⁺ using fura-2/AM. Middle row shows simulations of Ca²⁺ oscillations using the dual oscillator model. Bottom row shows simulations of the glycolytic intermediate fructose 1,6-bisphosphate (FBP), indicating that glycolysis is either stationary (C) or oscillatory (F, I). Reprinted with permission from (24; 51; 79).

Figure 5

Schematic diagram illustrating the central hypothesis of the dual oscillator model. In this hypothesis, there is an electrical subsystem that may be oscillatory (osc), or in a low (off) or high activity state. There is also a glycolytic subsystem that may be in a low or high stationary state or an oscillatory state. The glucose thresholds for the two subsystems need not be aligned, and different alignments can lead to different sequences of behaviors as the glucose concentration is increased. Reprinted with permission from (51; 85).

Figure 6

A 15-sec pulse of the muscarinic agonist carbachol (25 μM) synchronizes Ca²⁺ oscillations in islets maintained in 11.1 mM glucose. The two panels correspond to different groups of islets. Within each panel, different colors correspond to different islets. Reprinted with permission from (91).

Figure 7

Mathematical simulation showing that the interaction between a population of model islets and the liver can lead to islet synchronization, and large insulin oscillations. Both panels show results for a population of 20 heterogeneous model islets. The glucose concentration (red) is held constant until t=20 min, after which it varies according to the mean insulin level (dashed black curve). A smoothed version of the mean insulin level (blue) is also shown. (A) 20 oscillatory islets with different periods. (B) 20 non-oscillatory islets that begin to oscillate once the “liver” is turned on. Reprinted with permission from (105).