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 (IGS) by multiple approaches leads to ?-cell proliferation and hyperplasia. Using a multidisciplinary approach, we recently discovered that the accumulation of blood amino acids (hyperaminoacidemia or AAHi), particularly glutamine and arginine, due to decreased amino acid catabolism in the liver drives ?-cell proliferation. These studies also revealed a previously unappreciated and conserved (fish to man) hepatic-? 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. However, mTORC1 activation alone is insufficient. We hypothesize that hyperaminoacidemia activates both mammalian target of rapamycin complex 1 (mTORC1) and Calcium Sensing Receptor (CaSR) to cause ?-cell specific proliferation due to its high expression of a unique set of AA transporters and catalytic enzymes. In collaborative efforts in this multi-PI proposal, our groups will pursue an experimental strategy that leverages the advantages of zebrafish and mouse models for rapidly identifying pathways and defining mechanisms while in parallel testing the application and translation of our findings into primary human islets. Plus, we will utilize a new in vitro assay for islet ?-cell proliferation to complement in vivo studies in fish, mouse, and transplanted human islets. We will test the hypotheses in fish, mouse, and human islets that 1) high expression of specific plasma membrane AA transporters in ? cells drives mTORC1 activation by allowing efficient AA uptake; 2) glutaminase is required for hyperaminoacidemia activation of mTORC1 through glutaminolysis; and 3) hyperaminoacidemia also activates CaSR, which synergizes with mTORC1 to induce ?-cell proliferation. Furthermore, since hyperaminoacidemia stimulates both ?-cell proliferation and glucagon secretion, these studies should also provide new information about how amino acids regulate glucagon secretion. These studies will expand our understanding of the molecular mechanisms controlling ?-cell biology, function, proliferation and mass and provide insight into how the ?-cell dysfunction in T2D could be mitigated.
Interrupted glucagon signaling is an effective preclinical treatment for diabetes but its clinical application is hindered partially by the concern of ?-cell hyperplasia. We have found that hyperaminoacidemia from impaired glucagon-dependent hepatic amino acid catabolism leads to hyperplasia and elevated glucagon levels. This application will examine the role of amino acid transport, signaling, and metabolism in ?-cell function and proliferation.
