Measurement of the entrainment window of islets of Langerhans by microfluidic delivery of a chirped glucose waveform

Abstract

Within single islets of Langerhans, the endocrine portion of the pancreas, intracellular metabolites, as well as insulin secretion, oscillate with a period of ∼5 min. In vivo, pulsatile insulin oscillations are also observed with periods ranging from 5–15 minutes. In order for oscillations of insulin to be observed in vivo, the majority of islets in the pancreas must synchronize their output. It is known that populations of islets can be synchronized via entrainment of the individual islets to low amplitude glucose oscillations that have periods close to islets' natural period. However, the range of glucose periods and amplitudes that can entrain islets has not been rigorously examined. To find the range of glucose periods that can entrain islets, a microfluidic system was utilized to produce and deliver a chirped glucose waveform to populations of islets while their individual intracellular [Ca²⁺] ([Ca²⁺]_i) oscillations were imaged. Waveforms with amplitudes of 0.5, 1, and 1.5 mM above a median value of 11 mM were applied while the period was swept from 20–2 min. Oscillations of [Ca²⁺]_i resonated the strongest when the period of the glucose wave was within 2 min of the natural period of the islets, typically close to 5 min. Some examples of 1 : 2 and 2 : 1 entrainment were observed during exposure to long and short glucose periods, respectively. These results shed light on the dynamic nature of islet behavior and may help to understand dynamics observed in vivo.