There is a gap in understanding how the numerous islets in the pancreas synchronize to produce oscillatory insulin secretion. Continued existence of this gap represents an important problem because these oscillations are essential for proper glucose uptake by the liver and peripheral tissues and type II diabetics have perturbed oscillations. The long-term goal of the Roper laboratory is to decipher islet communication by developing new analytical techniques. The objective of this proposal is to identify the mechanism of islet synchronization, and identify the effects it has on islet physiology. The central hypothesis is that a feedback loop between the pancreas and peripheral tissues result in oscillatory glucose levels that synchronize islets, and that these oscillatory glucose levels are essential to islet function by limiting the generation of reactive oxygen species (ROS) within islets. This hypothesis was formulated on the basis of preliminary data formulated in the applicants' laboratories. The rationale behind this proposal is that a better mechanistic understanding of islet synchronization and protection from ROS damage will guide the development of new treatments for type II diabetes. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Determine the mechanism of islet synchronization; 2) Identify the effects of synchronized islet behavior on ROS production; 3) Determine the effect of oscillatory glucose levels on protein modification by O-linked N- acetylglucosamine (O-GlcNAc). Under the first aim, a closed-loop microfluidic system will be used where secretory levels of peptides from islets will be used in a model of glucose uptake to calculate the extracellular glucose concentration to be delivered to the islets. Under the second aim, the amplitude and frequency dependence of glucose waveforms on ROS generation will be measured using a microfluidic device that allows simultaneous testing of a range of waveform amplitudes while measuring intraislet ROS levels. Under the third aim, the amount of O-GlcNAc-modified proteins produced under oscillatory and static glucose levels will be compared using a chemoenzymatic detection method. The approach is innovative because it utilizes novel microfluidic systems for determining the mechanism of islet synchronization while also testing a new paradigm in islet physiology, namely the protective role of oscillatory dynamics in islet physiology. The proposed research is significant because type II diabetics have perturbed insulin oscillations, making it critical to understand the mechanism of islet synchronization and protection for proper glucose homeostasis. Ultimately, such knowledge has the potential to guide the development of therapeutics for reducing the problems associated with glucose toxicity in type II diabetics.
The proposed research is relevant to public health because the discovery of the mechanism responsible for islet synchronization and the protective effects it has on islet physiology is ultimately expected to increase understanding of the pathogenesis of perturbed insulin oscillations in type II diabetics. The proposed research is relevant to the part f NIH's mission that pertains to developing fundamental knowledge that enhances human health.
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