Synchronization of Pancreatic Islets

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. We use a semi-empirical mathematical model to 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 on our 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. Further results, due to topological implications of metabolism, strongly suggest innovative experiments which may aid in the verification of the biophysical model.