Saturday, April 20, 2024
4/20/2024
The mechanisms that synchronize hormone secretion across millions of islets of Langerhans in the pancreas are unknown. The long-term goal of the Roper laboratory is to decode cellular communication to enable understanding of normal biological function and disease progression. The objective of this proposal is to identify the mechanisms that generate synchronized rapid and ultradian insulin and glucagon oscillations from multiple islets. The central hypothesis is that multiple mechanisms working in concert produce both rapid and ultradian oscillations of hormone release. The rationale for performing this work is that a thorough understanding of the dynamics of glucose-regulatory hormone secretion will lead to the design of therapeutic approaches that alleviate the complications associated with diabetes and other metabolic diseases. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Determine the effect of time delays and dual entrainment on insulin synchronization, and 2) identify glucagon secretion and synchronization dynamics. Under the first aim, two methods for inducing islet synchronization will be used together, one a negative insulin/glucose feedback loop with time delays, and the other, pulsatile activation of M3 receptors. To accomplish this aim, a high-speed method for insulin measurement will be developed using droplet microfluidics and will be used for testing a range of time delays and the ability to perfuse multiple secretagogues in parallel. In the second aim, glucagon secretion will be measured for the first time from single islets of Langerhans using a homogeneous time resolved fluorescence assay using a microfluidic system. With this method, we anticipate observing single islet glucagon secretion dynamics and will parallelize the method to discern how glucagon pulses are synchronized across multiple islets. The proposed research is innovative because the microfluidic systems and measurement approaches developed in this proposal will allow rapid and ultradian oscillations of islet secretion to be observed for the first time. These results will provide a significant increase in the knowledge of islet regulation, which is crucial for fully understanding the mechanism of glucose homeostasis and how it goes awry in metabolic diseases. Ultimately, this knowledge has the potential to guide therapeutic development for reducing the problems associated with unregulated glucose levels in type II diabetes.
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