Closing in on the Mechanisms of Pulsatile Insulin Secretion

Abstract

Insulin secretion from pancreatic islet β-cells occurs in a pulsatile fashion, with a typical period of ∼5 min. The basis of this pulsatility in mouse islets has been investigated for more than four decades, and the various theories have been described as either qualitative or mathematical models. In many cases the models differ in their mechanisms for rhythmogenesis, as well as other less important details. In this Perspective, we describe two main classes of models: those in which oscillations in the intracellular Ca²⁺ concentration drive oscillations in metabolism, and those in which intrinsic metabolic oscillations drive oscillations in Ca²⁺ concentration and electrical activity. We then discuss nine canonical experimental findings that provide key insights into the mechanism of islet oscillations and list the models that can account for each finding. Finally, we describe a new model that integrates features from multiple earlier models and is thus called the Integrated Oscillator Model. In this model, intracellular Ca²⁺ acts on the glycolytic pathway in the generation of oscillations, and it is thus a hybrid of the two main classes of models. It alone among models proposed to date can explain all nine key experimental findings, and it serves as a good starting point for future studies of pulsatile insulin secretion from human islets.

Figure 1

Intracellular electrical recordings from islet β-cells exhibiting three types of oscillations. A: Example of islet with slow oscillations. B: An islet exhibiting fast oscillations. C: An islet with compound oscillations composed of episodes of fast oscillations. Recordings were made using perforated patch and amphotericin B. Ren and Satin, unpublished data.

Figure 2

Oscillations in intracellular Ca²⁺ concentration in five different human islets loaded with the ratiometric dye Fura-PE3 AM. All show slow oscillations, similar to what is often observed in mouse islets.

Figure 3

Computer simulations of a model in which bursting electrical activity is driven by activity-dependent variation in a slow process s. A: Electrical bursting, characterized by periodic active phases of spiking and silent phases of membrane hyperpolarization. B: Sawtooth time course of s.

Figure 4

Measurement of PKAR, which reflects dynamics in the FBP concentration. The islet is initially exposed to 10 mmol/L glucose (G), then 0.2 mmol/L Dz is added, and finally KCl (K) is added. Oscillations that are eliminated by the Dz are rescued by depolarization when the KCl concentration is increased from 15 to 30 mmol/L. Reprinted with permission from Merrins et al. (35).

Figure 5

Measurement of the K_ATP channel conductance made from a patched cell in an islet exposed to 11.1 mmol/L glucose. A: Slow bursting produced when the patch electrode is in current clamp mode. B: K_ATP channel conductance when the patch electrode is in voltage clamp mode with the application of rapid voltage ramps (2-s ramps from −120 mV to −50 mV). Red symbols identify the conductance during the active phases of two bursts; there are clear pulses of reduced conductance during the bursts. Panels A and B are sequential, not aligned. Protocol similar to that used in Ren et al. (29). nS, nanosiemens.

Figure 6

PKAR measurements from two bursting islets with very different time courses. A: Sawtooth PKAR time course, measured simultaneously with the membrane potential from a patched cell. B: Pulsatile PKAR time course.

Figure 7

Effects of glycolytic input and output on FBP and ATP. A–F: DOM; G–I: IOM. In each panel, the box represents the core glycolytic oscillator, in which positive feedback of FBP on PFK supplies the drive. A: With low glucose influx, both FBP and ATP levels are low and steady. B: With intermediate glucose influx, pulsatile oscillations of FBP result. C: With high glucose influx, both FBP and ATP levels are high and steady. D: With moderate glucose influx and low glycolytic efflux, the FBP level will be high but the ATP level will be low. E: Glycolytic oscillations can occur with moderate glucose influx and moderate glycolytic efflux, resulting in pulses of FBP and ATP, as in panel B. F: With moderate glucose influx and high glycolytic efflux, FBP is low but ATP level is high. G: In the IOM, Ca²⁺ modulates the glycolytic efflux through stimulation of PDH. With low Ca²⁺ glycolytic efflux is low (black output channel), and with high Ca²⁺ it is high (gray output channel). This results in sawtooth-shaped FBP and ATP time courses. H: The IOM can produce pulsatile FBP oscillations if the basal efflux is in the permissive intermediate range. I: The fuel KIC enters metabolism in the citric acid cycle, downstream of glycolysis. Oscillations in ATP and Ca²⁺ can occur due to the hydrolysis of ATP that powers Ca²⁺ pumps. Other models in which Ca²⁺ drives metabolic oscillations can account for this, but not for any of the other panels. Thicker arrows indicate greater flux.