Glucose Oscillations Can Activate an Endogenous Oscillator in Pancreatic Islets

Joseph P McKenna, Raghuram Dhumpa, Nikita Mukhitov, Michael G Roper and Richard Bertram

PLOS Computational Biology, 2016, vol. 12, issue 10, 1-19

Abstract: Pancreatic islets manage elevations in blood glucose level by secreting insulin into the bloodstream in a pulsatile manner. Pulsatile insulin secretion is governed by islet oscillations such as bursting electrical activity and periodic Ca2+ entry in β-cells. In this report, we demonstrate that although islet oscillations are lost by fixing a glucose stimulus at a high concentration, they may be recovered by subsequently converting the glucose stimulus to a sinusoidal wave. We predict with mathematical modeling that the sinusoidal glucose signal’s ability to recover islet oscillations depends on its amplitude and period, and we confirm our predictions by conducting experiments with islets using a microfluidics platform. Our results suggest a mechanism whereby oscillatory blood glucose levels recruit non-oscillating islets to enhance pulsatile insulin output from the pancreas. Our results also provide support for the main hypothesis of the Dual Oscillator Model, that a glycolytic oscillator endogenous to islet β-cells drives pulsatile insulin secretion.Author Summary: A global shift throughout the last century toward excessive nutrient intake relative to energy expenditure has fueled a dramatic increase in the incidence of diabetes in humans. The epidemic is primarily of type 2 diabetes, a disease characterized by the inability of the body to effectively control blood glucose levels. Insulin plays a key role in regulating blood glucose levels by restraining endogenous glucose output from the liver and promoting blood glucose uptake by tissue throughout the body. It is secreted in pulses by islets of Langerhans, endocrine cell aggregates dispersed throughout the pancreas. Loss of insulin pulsatility is an early event in the development of type 2 diabetes. Here, we demonstrate, with a combined modeling and experimental approach, that the loss of pulsatile insulin release that results from elevated glucose may be recovered by an oscillatory glucose stimulus. Our results have potential implications for enhancing insulin pulsatility and therefore mitigating the development of type 2 diabetes.

Date: 2016
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1005143

DOI: 10.1371/journal.pcbi.1005143

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