Symbiosis of Electrical and Metabolic Oscillations in Pancreatic β-Cells (original) (raw)
Related papers
Metabolic and electrical oscillations: partners in controlling pulsatile insulin secretion
AJP: Endocrinology and Metabolism, 2007
Impairment of insulin secretion from the β-cells of the pancreatic islets of Langerhans is central to the development of type 2 diabetes mellitus and has therefore been the subject of much investigation. Great advances have been made in this area, but the mechanisms underlying the pulsatility of insulin secretion remain controversial. The period of these pulses is 4–6 min and reflects oscillations in islet membrane potential and intracellular free Ca2+. Pulsatile blood insulin levels appear to play an important physiological role in insulin action and are lost in patients with type 2 diabetes and their near relatives. We present evidence for a recently developed β-cell model, the “dual oscillator model,” in which oscillations in activity are due to both electrical and metabolic mechanisms. This model is capable of explaining much of the available data on islet activity and offers possible resolutions of a number of longstanding issues. The model, however, still lacks direct confirma...
Electrical, Calcium, and Metabolic Oscillations in Pancreatic Islets
Oscillations are an integral part of insulin secretion, and are due ultimately to oscillations in the electrical activity of pancreatic β-cells, called bursting. We discuss the underlying mechanisms for bursting oscillations in mouse islets and the parallel oscillations in intracellular calcium and metabolism. We present a unified biophysical model, called the Dual Oscillator Model, in which fast electrical oscillations are due to the feedback of Ca 2+ onto K + ion channels, and the slow component is due to oscillations in glycolysis. The combination of these mechanisms can produce the wide variety of bursting and Ca 2+ oscillations observed in islets, including fast, slow, compound, and accordion bursting. We close with a description of recent experimental studies that have tested unintuitive predictions of the model and have thereby provided the best evidence to date that oscillations in glycolysis underlie the slow (~5 min) component of electrical, calcium, and metabolic oscillations in mouse islets.
Phase Analysis of Metabolic Oscillations and Membrane Potential in Pancreatic Islet β-Cells
Biophysical Journal, 2016
Metabolism in islet b-cells displays oscillations that can trigger pulses of electrical activity and insulin secretion. There has been a decades-long debate among islet biologists about whether metabolic oscillations are intrinsic or occur in response to oscillations in intracellular Ca 2þ that result from bursting electrical activity. In this article, the dynamics of oscillatory metabolism were investigated using five different optical reporters. Reporter activity was measured simultaneously with membrane potential bursting to determine the phase relationships between the metabolic oscillations and electrical activity. Our experimental findings suggest that Ca 2þ entry into b-cells stimulates the rate of mitochondrial metabolism, accounting for the depletion of glycolytic intermediates during each oscillatory burst. We also performed Ca 2þ clamp tests in which we clamped membrane potential with the K ATP channel-opener diazoxide and KCl to fix Ca 2þ at an elevated level. These tests confirm that metabolic oscillations do not require Ca 2þ oscillations, but show that Ca 2þ plays a larger role in shaping metabolic oscillations than previously suspected. A dynamical picture of the mechanisms of oscillations emerged that requires the restructuring of contemporary mathematical b-cell models, including our own dual oscillator model. In the companion article, we modified our model to account for these new data.
2016
Diabetes is a disease characterized by an excessive level of glucose in the bloodstream, which may be a result of improper insulin secretion. Insulin is secreted in a bursting behavior of pancreatic β-cells in the islets of Langerhans, which is affected by oscillations of cytosolic calcium concentration. We used the Dual Oscillator Model to explore the role of calcium in calcium oscillation independent and calcium oscillation dependent (CaD) modes as well as the synchronization of metabolic oscillations in electrically coupled β-cells. We also implemented a synchronization index in order to better measure the synchronization of the β-cells within an islet. We observed that voltage or calcium coupling result in increased synchronization and are more effective in CaD modes. Furthermore, we studied heterogeneous modes of coupled β-cells, their arrangements in the islets, and their synchronization. We saw that increasing calcium coupling or increasing voltage coupling in heterogeneous c...
The Interaction of Calcium and Metabolic Oscillations in Pancreatic Beta-cells
SPORA: A Journal of Biomathematics, 2017
Diabetes is a disease characterized by an excessive level of glucose in the bloodstream, which may be a result of improper insulin secretion. Insulin is secreted in a bursting behavior of pancreatic β-cells in islets, which is affected by oscillations of cytosolic calcium concentration. We used the Dual Oscillator Model to explore the role of calcium in calcium oscillation independent and calcium oscillation dependent modes and the synchronization of metabolic oscillations in electrically coupled β-cells. We implemented a synchronization index in order to better measure the synchronization of the β-cells within an islet, and we studied heterogeneous modes of coupled β-cells. We saw that increasing calcium coupling or voltage coupling in heterogeneous cases increases synchronization; however, in certain cases increasing both voltage and calcium coupling causes desynchronization. To better represent an islet, we altered previous code to allow for a greater number of cells to be simulated.
Diabetes, 1999
Normal mouse islets were used to determine whether oscillations of these three signals are able and necessary to trigger oscillations of insulin secretion. The approach was to minimize or abolish spontaneous oscillations and to compare the impact of forced oscillations of each signal on insulin secretion. In a control medium, repetitive increases in the glucose concentration triggered oscillations in metabolism [NAD(P)H fluorescence], [Ca 2+ ] i (fura-PE3 method), and insulin secretion. In the presence of diazoxide, metabolic oscillations persisted, but [Ca 2 + ] i and insulin oscillations were abolished. When the islets were depolarized with high K + with or without diazoxide, [ C a 2 + ] i was elevated, and insulin secretion was stimulated. Forced metabolic oscillations transiently decreased or did not affect [Ca 2 + ] i and potentiated insulin secretion with oscillations of small amplitude. These oscillations of secretion followed metabolic oscillations only when [Ca 2+ ] i did not change. When [Ca 2+ ] i fluctuated, these changes prevailed over those of metabolism for timing secretion.
Physics Letters A, 2012
A theoretical approach to the glucose-insulin regulatory system is presented. By means of integrated mathematical modeling and extensive numerical simulations, we probe the cell-level dynamics of the membrane potential, intracellular Ca 2+ concentration, and insulin secretion in pancreatic β-cells, together with the whole-body level glucose-insulin dynamics in the liver, brain, muscle, and adipose tissues. In particular, the three oscillatory modes of insulin secretion are reproduced successfully. Such comprehensive mathematical modeling may provide a theoretical basis for the simultaneous assessment of the β-cell function and insulin resistance in clinical examination.
Journal of Biological Chemistry, 2001
Insulin secretion from glucose-stimulated pancreatic -cells is oscillatory, and this is thought to result from oscillations in glucose metabolism. One of the primary metabolic stimulus-secretion coupling factors is the ATP/ADP ratio, which can oscillate as a result of oscillations in glycolysis. Using a novel multiwell culture plate system, we examined oscillations in insulin release and the ATP/ADP ratio in the clonal insulin-secreting cell lines HIT T-15 and INS-1. Insulin secretion from HIT cells grown in multiwell plates oscillated with a period of 4 min, similar to that seen previously in perifusion experiments. Oscillations in the ATP/ADP ratio in cells grown under the same conditions also occurred with a period of 4 min, as did oscillations in [Ca 2؉ ] i monitored by fluorescence microscopy. In INS-1 cells oscillations in insulin secretion, the ATP/ADP ratio, and [Ca 2؉ ] i were also seen, but with a shorter period of about 1.5 min. These observations of oscillations in the ATP/ADP ratio are consistent with their proposed role in driving the oscillations in [Ca 2؉ ] i and insulin secretion. Furthermore, these data show that, at least in the clonal -cell lines, cell contact or even circulatory connection is not necessary for synchronous oscillations induced by a rise in glucose.
Biophysical journal, 2015
Recent advances in imaging technology have revealed oscillations of cyclic adenosine monophosphate (cAMP) in insulin-secreting cells. These oscillations may be in phase with cytosolic calcium oscillations or out of phase. cAMP oscillations have previously been modeled as driven by oscillations in calcium, based on the known dependence of the enzymes that generate cAMP (adenylyl cyclase) and degrade it (phosphodiesterase). However, cAMP oscillations have also been reported to occur in the absence of calcium oscillations. Motivated by similarities between the properties of cAMP and metabolic oscillations in pancreatic β cells, we propose here that in addition to direct control by calcium, cAMP is controlled by metabolism. Specifically, we hypothesize that AMP inhibits adenylyl cyclase. We incorporate this hypothesis into the dual oscillator model for β cells, in which metabolic (glycolytic) oscillations cooperate with modulation of ion channels and metabolism by calcium. We show that ...
IEEE Transactions on Biomedical Engineering, 2000
The role of pancreatic -cells is fundamental in the control endocrine system, maintaining the blood glucose homeostasis in a physiological regime, via the glucose-induced release of insulin. An increasing amount of detailed experimental evidences at the cellular and molecular biology levels have been collected on the key factors determining the insulin release by the pancreatic -cells. The direct transposition of such experimental data into accurate mathematical descriptions might contribute to considerably clarify the impact of each cellular component on the global glucose metabolism. Under these perspectives, we model and computer-simulate the stimulus-secretion coupling in -cells by describing four interacting cellular subsystems, consisting in the glucose transport and metabolism, the excitable electrophysiological behavior, the dynamics of the intracellular calcium ions, and the exocytosis of granules containing insulin. We explicit the molecular nature of each subsystem, expressing the mutual relationships and the feedbacks that determine the metabolic-electrophysiological behavior of an isolated -cell. Finally, we discuss the simulation results of the behavior of isolated -cells as well as of population of electrically coupled -cells in Langerhans islets, under physiological and pathological conditions, including noninsulin-dependent diabetes mellitus (NIDDM) and hyperinsulinemic hypoglycaemia (PHHI).