Diabetes Volume 67, March 2018 351 Closing in on the Mechanisms of Pulsatile Insulin Secretion Richard Bertram,1 Leslie S. Satin,2 and Arthur S. Sherman3 Diabetes 2018;67:351–359 | https://doi.org/10.2337/dbi17-0004 Insulin secretion from pancreatic islet b-cells occurs in b-cells within islets of Langerhans. Although such rhythms a pulsatile fashion, with a typical period of ∼5min.The are ubiquitous across species, we focus on mice, where most basis of this pulsatility in mouse islets has been inves- of the research on b-cell oscillations has been focused. We tigated for more than four decades, and the various theories anticipate that over the next decade much of what we now have been described as either qualitative or mathematical know about mouse islets will be tested in human islets. models. In many cases the models differ in their mech- Pulsatility in insulin secretion reflects oscillations in the anisms for rhythmogenesis, as well as other less important intracellular Ca2+ concentration of islet b-cells, which in PERSPECTIVES IN DIABETES details. In this Perspective, we describe two main classes of fl 2+ turn re ect bursting electrical activity (5). In intact islets, models: those in which oscillations in the intracellular Ca several types of oscillations are commonly observed. Slow concentration drive oscillations in metabolism, and those oscillations have periods typically between 4 and 6 min (Fig. in which intrinsic metabolic oscillations drive oscillations 1A). Fast oscillations are observed in other islets, with peri- in Ca2+ concentration and electrical activity. We then dis- ods typically less than 1 min (Fig. 1B). Fast oscillations can cuss nine canonical experimental findings that provide key also be packaged into episodes to form “compound oscilla- insights into the mechanism of islet oscillations and list the ” models that can account for each finding. Finally, we de- tions, and the episodes repeat with the same range of C scribe a new model that integrates features from multiple periods as the pure slow oscillations (Fig. 1 ). The com- 2+ fl earlier models and is thus called the Integrated Oscillator pound Ca oscillations re ect a type of electrical activity “ ” Model. In this model, intracellular Ca2+ acts on the gly- called compound bursting (6,7). Both slow and compound 2+ colytic pathway in the generation of oscillations, and it Ca oscillations have periods consistent with measure- is thus a hybrid of the two main classes of models. It alone ments of plasma insulin in mice (8). In human islet among models proposed to date can explain all nine key b-cells, most electrical oscillations reported thus far are of experimental findings, and it serves as a good starting the fast type, but slow oscillations in the Ca2+ concentration point for future studies of pulsatile insulin secretion from have been observed (Fig. 2) and have similar periodicity to human islets. pulsatile insulin secretion (4). Human islets tend to have larger action potentials than rodent islets owing to the prominent Na+ currents, but the similarity of the slow os- Insulin secretion in healthy rodents, dogs, and humans is cillation periods suggests that the underlying mechanisms pulsatile, with mean period of ;5 min (1). This pulsatility are similar in rodents and humans. has been reported to enhance insulin action at the liver (2), In the search for the biophysical mechanisms of oscil- although not all studies have shown this (3). The conse- lations in b-cell activity, several classes of models (both quences of pulsatile insulin secretion and its dysfunction in qualitative and mathematical) have emerged. We describe people with or at risk for type 2 diabetes has been recently the key elements of these models, along with experimental reviewed (4). The focus of this Perspective, rather, is the findings that should be explainable by any proposed model. mechanism of insulin pulsatility, in particular the rhythmo- We conclude with a description of one recent model, the genesis of ;5-min oscillations in activity of pancreatic Integrated Oscillator Model (IOM), which combines features 1Department of Mathematics and Programs in Neuroscience and Molecular Bio- Received 2 August 2017 and accepted 30 November 2017. physics, Florida State University, Tallahassee, FL © 2018 by the American Diabetes Association. Readers may use this article as 2 Department of Pharmacology and Brehm Center for Diabetes Research, Univer- long as the work is properly cited, the use is educational and not for profit, and the sity of Michigan Medical School, Ann Arbor, MI work is not altered. More information is available at http://www.diabetesjournals 3 Laboratory of Biological Modeling, National Institute of Diabetes and Digestive .org/content/license. and Kidney Diseases, National Institutes of Health, Bethesda, MD Corresponding author: Richard Bertram, [email protected]. 352 Mechanisms of Pulsatile Insulin Secretion Diabetes Volume 67, March 2018 Figure 1—Intracellular electrical recordings from islet b-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. of prior models and satisfies all the experimental tests de- a continuous train of impulses. Within the bursting regi- scribed herein. men, increases in the glucose level increase the active phase We focus on the interactions of Ca2+ and metabolism in duration relative to the silent phase duration, known as the generating slow oscillations, omitting discussion of other “plateau fraction.” interesting areas that have been the subject of mathemat- Shortly after the publication of this model, ATP-sensitive + fi b ical modeling (as in Fridlyand et al. [9]), such as cAMP K channels (KATP channels) were rst reported in -cells oscillations, synchronization within and among islets, and (11). The importance of these channels in setting insulin exocytosis. Some have suggested that other factors, such as secretion to a level appropriate for the prevailing blood cAMP, islet paracrine factors, and insulin itself may play glucose concentration was immediately recognized, but roles in b-cell oscillations, but because of space restrictions their existence also raised the possibility that oscillations in we do not discuss these hypotheses. metabolism could underlie oscillations in the cells’ electrical activity, Ca2+ level, and insulin secretion. Indeed, there HYPOTHESES FOR ISLET OSCILLATIONS have been numerous subsequent measurements of meta- In 1983 Chay and Keizer (10) published a pioneering b-cell bolic oscillations in islets, including oscillations in oxygen model that spawned many subsequent models. At its core consumption, NAD(P)H, and mitochondrial membrane po- was slow negative feedback, a ubiquitous mechanism for tential, as reviewed in Bertram et al. (12). oscillations, whereby a rise in intracellular free Ca2+ acti- The two main classes of models for b-cell oscillations can 2+ + 2+ vates Ca -activated K channels (KCa channels). According be categorized into those in which oscillations in Ca drive to this model, the rise of intracellular Ca2+ during a burst oscillations in metabolism (Ca2+-driven oscillations) and active phase and its decline during a silent phase drives those in which oscillations in metabolism drive oscillations 2+ bursting through its action on KCa channels. This model in Ca (metabolism-driven oscillations). The many models was successful at reproducing the fast (i.e., 15-s period) constituting the first class differ in the specificbiophysical burst pattern predominantly reported in the literature at components most important for electrical activity and Ca2+ thetime,aswellastheresponseofthecelltochangesin oscillations. In all cases, however, bursting electrical activity glucose. That is, at low glucose levels the cell is silent, at (Fig. 3A)reflects slow negative feedback through one or higher levels it bursts, and at the highest levels it produces more slow processes that we represent by a single slow diabetes.diabetesjournals.org Bertram, Satin, and Sherman 353 Figure 3—Computer simulations of a model in which bursting elec- trical activity is driven by activity-dependent variation in a slow pro- cess s. A: Electrical bursting, characterized by periodic active phases of spiking and silent phases of membrane hyperpolarization. B:Saw- tooth time course of s. PFK isoform (22). The hypothesis is that glycolytic oscil- lations occur in glucose-stimulated b-cells and that these lead to oscillations in ATP production, which modulates 2+ KATP channels, driving electrical bursting and Ca oscilla- Figure 2—Oscillations in intracellular Ca2+ concentration in five differ- tions. This is the template for the second general class of ent human islets loaded with the ratiometric dye Fura-PE3 AM. All models. show slow oscillations, similar to what is often observed in mouse The Dual Oscillator Model (DOM) combines elements of islets. the two major classes and postulates that Ca2+ oscillations drive the fast electrical bursting in b-cells, while glycolytic oscillations, when active, drive slow bursting (12). Com- variable s. During the active phase, s slowly rises and ulti- pound bursting is driven by both processes, the fast bursts 2+ mately terminates spiking, while during the silent phase it within an episode being driven by Ca feedback onto KCa slowly declines, eventually