Hyperglucagonemia contributes to the hyperglycemia of type 2 diabetes (T2D). As such, antagonism of glucagon action has great promise as a therapeutic intervention for T2D. However, interrupted glucagon signaling by multiple approaches leads to ?-cell proliferation and hyperplasia. Using a multidisciplinary approach we recently discovered when glucagon signaling is interrupted in the liver, the accumulation of blood amino acids (hyperaminoacidemia or AAHi), particularly glutamine and arginine, drive ?-cell proliferation. These studies also revealed a previously unappreciated and conserved (fish to man) hepatic-islet ?-cell axis where hepatic glucagon signaling regulates serum amino acid levels and increased AA, especially glutamine (Q), regulate glucagon secretion and ?-cell proliferation and mass. AAHi is necessary and sufficient to cause ?-cell proliferation in an mTORC1-dependent manner. We hypothesize that AAHi exerts the effect specifically in ?- cells because of the high expression of a unique set of AA transporters and catalytic enzymes, leading to mTORC1 activation, glucagon secretion and ?-cell proliferation. I will pursue an experimental strategy that leverages the advantages of mouse models for identifying pathways and defining mechanisms while in parallel testing the translation my findings into primary human islets. Plus, I will utilize a new in vitro assay for islet ?- cell proliferation to complement in vivo studies in mouse with transplanted human islets. These studies will expand our understanding of the molecular mechanisms controlling ?-cell biology, function, proliferation, and mass and provide insight into pathways for controlled and safe expansion of islet cell mass. These studies should also provide new insights into normal ?-cell function and how the ?-cell dysfunction in T2D could be mitigated.
The goal of this project is to provide the training and skills necessary to launch the independent phase of my career as research scientist at the nexus of nutrient signaling, islet biology, and disease. I will expand my current research program to define the molecular mechanism by which amino acids stimulate glucagon secretion and ?-cell proliferation. I have assembled a talented team of investigators, including my mentor Dr. Alvin Powers, to provide career mentorship and scientific training towards my efforts to become an R01-funded independent investigator.
