The secretory dynamics of insulin and glucagon from individual pancreatic islets of Langerhans and the roles that these dynamics play in hepatic glucose regulation 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 control mechanisms that regulate dynamic hormone release from islets and how dynamic hormone input to the liver optimizes net hepatic glucose control by the liver. The central hypothesis is that insulin and glucagon released from islets of Langerhans interact with the liver to generate a feedback loop that synchronizes islet behavior, sets the phase of the insulin and glucagon oscillations, and promotes optimal hepatic metabolism. The rationale for performing this work is that a thorough understanding of the dynamics of glucose-regulatory hormone secretion and glucose handling by the liver may 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 three specific aims: 1) Determine the dynamics of glucose-regulatory hormone release from islets, 2) Identify the dynamics of small molecule secretion from islets that shape hormonal response, and 3) Identify the metabolic response of hepatocytes to dynamic hormonal profiles. Under the first aim, a novel approach to measure glucagon secretion from single islets with high temporal resolution will be utilized. This method will be incorporated with our assay for insulin release to enable hormone oscillation amplitudes, frequencies, and phase relationships to be identified. In the second aim, ?-aminobutyric acid and glutamate secretion will be monitored from islets simultaneously with insulin and glucagon secretion. This will enable the determination of the roles that these small molecules play in oscillatory hormone release. In the third aim, pulsatile hormone profiles will be delivered to hepatocytes while monitoring glucose output. This method will facilitate the understanding of how dynamic hormone profiles control hepatic behavior. The proposed research is innovative because the microfluidic systems and measurement approaches developed in this proposal will allow dynamics of islet and hepatocyte behavior to be observed for the first time. These results will provide a significant increase in the knowledge of the interplay between the pancreas and liver, 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 diabetics.
The proposed research is relevant to public health because the identification of the secretory dynamics of insulin and glucagon, the mechanisms that control these dynamics, and the roles that they play in hepatic regulation is ultimately expected to increase understanding of the pathogenesis of perturbed hormone oscillations observed in type II diabetics. The proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that enhances human health.
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