Over the last few years we developed a comprehensive model for oscillations of membrane potential and calcium on time scales ranging from seconds to minutes. These lead to corresponding oscillations of insulin secretion. The basic hypothesis of the model is that the faster (tens of seconds) oscillations stem from feedback of calcium onto ion channels, likely calcium-activated potassium (K(Ca)) channels and ATP-dependent potassium (K(ATP)) channels, whereas the slower (five minutes) oscillations stem from oscillations in metabolism. The metabolic oscillations are transduced into electrical oscillations via the K(ATP) channels. The latter, notably, are a first-line target of insulin-stimulating drugs, such as the sulfonylureas (tolbutamide, glyburide) used in the treatment of Type 2 Diabetes. The model is thus referred to as the Dual Oscillator Model (DOM).? ? In the current year, the model has been applied to understanding how the hundreds of islets in a mouse and the hundreds of thousands of islets in a human synchronize their activity so as to produce pulsatile appearance of insulin in the general circulation. A reduced in vitro experimental preparation was developed comprised of several islets in a chamber. It was found that the islets could be synchronized by brief pulses of acetylcholine (ACh). Synchrony could be maintained for tens of minutes following a single pulse of ACh. As the data were very noisy, an algorithm had to be developed, based on an algorithm used by others to study synchrony of chaotic oscillators, to quantify the degree of synchrony for statistical analysis. In addition, simulations were carried out using the DOM, which showed that the release of calcium from internal stores mediated by the brief pulses of ACh were sufficient to synchronize model islets through indirect effects of calcium on ATP consumption (the elevated calcium has to be pumped out of the cell or back into the endoplasmic reticulum in order to maintain cytosolic calcium at homeostatic levels). The experimental and theoretical results are reported in Ref. # 2.? ? In addition to the dynamics of calcium, secretion of insulin depends on the dynamics of the insulin-containing granule themselves. The latter are found in several distinct pools within the beta-cell, including a very large reserve pool in the cytosol (more than 10,000 granules), a pool of granules docked at the plasma membrane but not release ready (about 600 granules), a primed pool that is available for release whenever elevated calcium is encountered (about 50 granules), and a pool that is tethered in close proximity to calcium channels and hence the most strongly affected by calcium channel openings (about 10 granules). A comprehensive model was developed, combining elements of the classic, phenomenological Grodsky model, dating from the 1960's, with recent data tracking the movements of granules via capacitance or imaging techniques. The Grodsky model was very successful in accounting for the time course of first and second phase insulin release (over 10 minute and 60 minute time scales, respectively), whereas the granule measurements have looked at secretion on time scale of milliseconds and seconds. Moreover, the Grodsky model was developed before much was known about the role of calcium rise in response to glucose-induced closure of K(ATP) channels, and glucose was therefore the only input to the model. Thus, it was unable to account for later experiments in which the effects of glucose metabolism and calcium rise were dissociated. Our new model (Ref. # 1) provides a view of the main phenomena on the full range of time scales from less than one second to one hour. The Grodsky paradigm of a labile pool that accounts for first phase secretion and a latent pool that accounts for the second phase has held up well, but much more can be said with the more comprehensive model. For example, the differences between rat, mice, and humans can be accounted for at least in part by differences in the rate of vesicle progression from the docked pool to the primed pool.
| Pedersen, Morten Gram; Sherman, Arthur (2009) Newcomer insulin secretory granules as a highly calcium-sensitive pool. Proc Natl Acad Sci U S A 106:7432-6 |
| Chen, Yi-der; Wang, Shaokun; Sherman, Arthur (2008) Identifying the targets of the amplifying pathway for insulin secretion in pancreatic beta-cells by kinetic modeling of granule exocytosis. Biophys J 95:2226-41 |
| Zhang, Min; Fendler, Bernard; Peercy, Bradford et al. (2008) Long lasting synchronization of calcium oscillations by cholinergic stimulation in isolated pancreatic islets. Biophys J 95:4676-88 |
| Bertram, Richard; Satin, Leslie S; Pedersen, Morten Gram et al. (2007) Interaction of glycolysis and mitochondrial respiration in metabolic oscillations of pancreatic islets. Biophys J 92:1544-55 |
| Bertram, Richard; Sherman, Arthur; Satin, Leslie S (2007) Metabolic and electrical oscillations: partners in controlling pulsatile insulin secretion. Am J Physiol Endocrinol Metab 293:E890-900 |
