Center | Vanderbilt University |
Award Year | 2020 |
Pilot Study | Glucagon Resistance in Obesity |
Awardee | Danielle Dean PhD |
Abstract |
Glucagon and its partner insulin are dually linked in both their secretion from islet cells and action in the liver. Glucagon signaling increases hepatic glucose output, and hyperglucagonemia is partly responsible for the hyperglycemia in diabetes making glucagon an attractive target for therapeutic intervention. Interrupting glucagon signaling lowers blood glucose, but also results hyperglucagonemia and alpha cell hyperplasia. Our investigation of the mechanism for alpha cell proliferation led to the description describe a conserved liver- alpha cell axis where glucagon is a critical regulator of amino acid homeostasis. In return, amino acids regulate alpha cell function and proliferation. New evidence suggests that dysfunction of the axis in humans may result in the hyperglucagonemia observed in diabetes. This proposal outlines important but often overlooked roles for glucagon that extend beyond glycemia and investigating its role in ureagenesis/amino acid homeostasis. We propose that hyperaminoacidemia observed in the obese and diabetic states are due to dysregulation of the liver-alpha cell axis. We will leverage transcriptomics from liver of obese mice with mouse clamping studies to understand if glucagon resistance is a feature of the obese liver and will form the basis for future funding applications. |
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