How synchronization occur between liver and pancrese?
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Abstract
Plasma insulin measurements from mice, rats, dogs, and humans indicate that insulin levels are oscillatory, reflecting pulsatile insulin secretion from individual islets. An unanswered question, however, is how the activity of a population of islets is coordinated to yield coherent oscillations in plasma insulin. Here, using mathematical modeling, we investigate the feasibility of a potential islet synchronization mechanism, cholinergic signaling. This hypothesis is based on well-established experimental evidence demonstrating intrapancreatic parasympathetic (cholinergic) ganglia and recent in vitro evidence that a brief application of a muscarinic agonist can transiently synchronize islets. We demonstrate using mathematical modeling that periodic pulses of acetylcholine released from cholinergic neurons is indeed able to coordinate the activity of a population of simulated islets, even if only a fraction of these are innervated. The role of islet-to-islet heterogeneity is also considered. The results suggest that the existence of cholinergic input to the pancreas may serve as a regulator of endogenous insulin pulsatility in vivo.
Introduction
Plasma insulin levels are pulsatile in normal mice, rats, dogs, and humans (1–4) and this pulsatility is impaired in humans with diabetes (5). In addition, relatives of type II diabetics (6,7) and animal models of human diabetes such as ob/ob mice (8) also show impaired pulsatility. Combined with data showing that pulses of insulin are more efficacious than constant insulin secretion (9–12), this suggests that type II diabetes may be caused, at least in part, by either a loss or irregularity of plasma insulin oscillations.
Insulin secretion from isolated islets is pulsatile because of electrical bursting oscillations. In an islet, the individual insulin-secreting β-cells coordinate their bursting activity primarily through gap junctions. During a burst of electrical impulses the Ca2+ concentration in the cytosol rises, evoking insulin secretion (13). The period of the slow electrical and Ca2+ oscillations in the islet, which is 5–7 min (14–18), is similar to the period of insulin oscillations measured in plasma in vivo (2,3,17,19). Since the insulin in plasma is oscillatory and the islets produce insulin oscillations of a similar frequency, a substantial fraction of the islets must therefore be synchronized, otherwise no oscillation in the blood insulin level would be observed (15,21).
To mediate this synchronization, a number of potential mechanisms have been proposed. One is mutual feedback between the pancreas and liver. Insulin secretion from islets promotes glucose absorption by the liver, affecting all islets. This has a synchronizing effect on the islet population, as was demonstrated in a recent computational study (22). However, this mechanism cannot explain results from in vitro experiments showing that insulin released from perifused pancreas also oscillates (23,24). Another potential synchronizing mechanism is neural input from intrapancreatic ganglia (25). There is a rich innervation of the pancreas by preganglionic vagal neurons (26–29). These autonomic nerves synapse onto intrapancreatic ganglia—clusters of neurons that are spread in a connective plexus throughout the pancreas in rat, cat, rabbit, guinea pig, and mouse (30–33). The ganglia have been shown to be electrically excitable when autonomic nerve trunks are stimulated in cat (31). Furthermore, in vitro and in vivo vagal stimulation promotes glucose-dependent insulin release from the pancreas (28,34–36). Ganglia are often found in the proximity of islets and provide innervation (30,37,38). On the receiving end, β-cells express muscarinic receptors (39,40) and neurons in the pancreatic ganglia of rat, cat, rabbit, and guinea pigs express choline acetyltransferase (30,41). In addition, intrahepatic transplantation of islets to diabetic rats only results in peripheral insulin pulsatility after a 200-day lag (42). This delay may reflect the time required for reinnervation of the islets and thus the synchronization of their activity.
Our goal in this computational study was to investigate the feasibility of the hypothesis that cholinergic neural ganglia can serve as an islet-synchronizing agent and to assess the consequences of periodic neuronal activity on endogenous islet insulin pulsatility.
To this end, we used a mathematical model of the β-cell, the dual oscillator model (DOM), which has been shown to reproduce many of the essential behaviors of the pancreatic islet (43,44). The model is composed of two oscillatory subsystems. The first is an electrical subsystem, which produces fast bursts of action potentials and also accounts
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Abstract
Plasma insulin measurements from mice, rats, dogs, and humans indicate that insulin levels are oscillatory, reflecting pulsatile insulin secretion from individual islets. An unanswered question, however, is how the activity of a population of islets is coordinated to yield coherent oscillations in plasma insulin. Here, using mathematical modeling, we investigate the feasibility of a potential islet synchronization mechanism, cholinergic signaling. This hypothesis is based on well-established experimental evidence demonstrating intrapancreatic parasympathetic (cholinergic) ganglia and recent in vitro evidence that a brief application of a muscarinic agonist can transiently synchronize islets. We demonstrate using mathematical modeling that periodic pulses of acetylcholine released from cholinergic neurons is indeed able to coordinate the activity of a population of simulated islets, even if only a fraction of these are innervated. The role of islet-to-islet heterogeneity is also considered. The results suggest that the existence of cholinergic input to the pancreas may serve as a regulator of endogenous insulin pulsatility in vivo.
Introduction
Plasma insulin levels are pulsatile in normal mice, rats, dogs, and humans (1–4) and this pulsatility is impaired in humans with diabetes (5). In addition, relatives of type II diabetics (6,7) and animal models of human diabetes such as ob/ob mice (8) also show impaired pulsatility. Combined with data showing that pulses of insulin are more efficacious than constant insulin secretion (9–12), this suggests that type II diabetes may be caused, at least in part, by either a loss or irregularity of plasma insulin oscillations.
Insulin secretion from isolated islets is pulsatile because of electrical bursting oscillations. In an islet, the individual insulin-secreting β-cells coordinate their bursting activity primarily through gap junctions. During a burst of electrical impulses the Ca2+ concentration in the cytosol rises, evoking insulin secretion (13). The period of the slow electrical and Ca2+ oscillations in the islet, which is 5–7 min (14–18), is similar to the period of insulin oscillations measured in plasma in vivo (2,3,17,19). Since the insulin in plasma is oscillatory and the islets produce insulin oscillations of a similar frequency, a substantial fraction of the islets must therefore be synchronized, otherwise no oscillation in the blood insulin level would be observed (15,21).
To mediate this synchronization, a number of potential mechanisms have been proposed. One is mutual feedback between the pancreas and liver. Insulin secretion from islets promotes glucose absorption by the liver, affecting all islets. This has a synchronizing effect on the islet population, as was demonstrated in a recent computational study (22). However, this mechanism cannot explain results from in vitro experiments showing that insulin released from perifused pancreas also oscillates (23,24). Another potential synchronizing mechanism is neural input from intrapancreatic ganglia (25). There is a rich innervation of the pancreas by preganglionic vagal neurons (26–29). These autonomic nerves synapse onto intrapancreatic ganglia—clusters of neurons that are spread in a connective plexus throughout the pancreas in rat, cat, rabbit, guinea pig, and mouse (30–33). The ganglia have been shown to be electrically excitable when autonomic nerve trunks are stimulated in cat (31). Furthermore, in vitro and in vivo vagal stimulation promotes glucose-dependent insulin release from the pancreas (28,34–36). Ganglia are often found in the proximity of islets and provide innervation (30,37,38). On the receiving end, β-cells express muscarinic receptors (39,40) and neurons in the pancreatic ganglia of rat, cat, rabbit, and guinea pigs express choline acetyltransferase (30,41). In addition, intrahepatic transplantation of islets to diabetic rats only results in peripheral insulin pulsatility after a 200-day lag (42). This delay may reflect the time required for reinnervation of the islets and thus the synchronization of their activity.
Our goal in this computational study was to investigate the feasibility of the hypothesis that cholinergic neural ganglia can serve as an islet-synchronizing agent and to assess the consequences of periodic neuronal activity on endogenous islet insulin pulsatility.
To this end, we used a mathematical model of the β-cell, the dual oscillator model (DOM), which has been shown to reproduce many of the essential behaviors of the pancreatic islet (43,44). The model is composed of two oscillatory subsystems. The first is an electrical subsystem, which produces fast bursts of action potentials and also accounts
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