Abstract
Pulsatile insulin secretion into the portal vein from the many pancreatic islets of Langerhans is critical for efficient glucose homeostasis. The islets are themselves endogenous oscillators, but since they are not physically coupled it is not obvious how their oscillations are synchronized across the pancreas. It has been proposed that synchronization of islets is achieved through periodic activity of intrapancreatic ganglia, and indeed there are data supporting this proposal. Postganglionic nerves are cholinergic, and their product, acetylcholine, can influence islet β-cells through actions on M3 muscarinic receptors which are coupled to Gq type G-proteins. In addition, the neurons secrete several peptide hormones that act on β-cell receptors. The data supporting synchronization via intrapancreatic ganglia are, however, limited. In particular, it has not been shown that trains of muscarinic pulses are effective at synchronizing islets in vitro. Also, if as has been suggested, there is a ganglionic pacemaker driving islets to a preferred frequency, no neural circuitry for this pacemaker has been identified. In this study, both points are addressed using a microfluidic system that allows for the pulsed application of the muscarinic agonist carbachol. We find that murine islets are entrained and synchronized over a wide range of frequencies when the carbachol pulsing is periodic, adding support to the hypothesis that ganglia can synchronize islets in vivo. We also find that islet synchronization is very effective even if the carbachol pulses are applied at random times. This suggests that a neural pacemaker is not needed; all that is required is that islets receive occasional coordinated input from postganglionic neurons. The endogenous rhythmic activity of the islets then sets the frequency of the islet population rhythm, while the input from ganglia acts only to keep the islet oscillators in phase.
Highlights
The rodent endocrine pancreas contains thousands to tens of thousands of islets of Langerhans [1], while a human may have over 3 million [2]
The microfluidic platform employed for this study facilitated precise and automated delivery of glucose and the various CCh profiles to groups of 3–4 islets
We found that this active flow rate control was much better at rapidly generating pulses and maintaining stable flow rates than passive methods
Summary
The rodent endocrine pancreas contains thousands to tens of thousands of islets of Langerhans [1], while a human may have over 3 million [2]. Islets contain 500–2000 cells, with each cell type releasing particular hormones in a glucose-dependent manner [3]. The majority of these cells are insulin-secreting β-cells that, like other cells, metabolize glucose leading to an increase in the ratio of ATP/ADP. Β-cells express KATP ion channels that are inactivated by the increased ATP/ADP ratio, and the resulting decrease in hyperpolarizing K+ current depolarizes the cell membrane [4] This depolarization opens voltage-gated Ca2+ channels allowing for the influx of Ca2+ that triggers insulin secretion into the blood [5,6]. Insulin promotes the absorption of glucose into fat, skeletal muscle, and liver cells [7]
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