By Leah Mann
The lab of Wenbiao Chen, associate professor of molecular physiology and biophysics, identified a signaling pathway for hyperaminoacidemia-induced alpha cell proliferation. Hyperaminoacidemia, or an excess of amino acids in the bloodstream, occurs when the function of glucagon, a pancreatic hormone that raises glucose levels and breaks down amino acids, is disrupted. In turn, the number of glucagon-producing alpha cells increases.
Targeting the glucagon receptor is a promising therapeutic approach for lowering blood glucose in diabetic patients. However, the ensuing hyperaminoacidemia and alpha cell proliferation undermine its viability. The researchers sought to determine the mechanism by which this adaptive propagation transpires.
This work was done in collaboration with the labs of Danielle Dean, assistant professor of diabetes, endocrinology, and metabolism and molecular physiology and biophysics, and Alvin Powers, Joe C. Davis Professor of Biomedical Science and professor of molecular physiology and biophysics. Chen, Dean, and Powers are part of the NIH-funded Vanderbilt Diabetes Research and Training Center. The results were published in Nature Communications.
We sat down with Chen to find out more about this research.
What problem does your research address?
During fasting, pancreatic alpha cells secrete glucagon to promote liver glucose production from noncarbohydrate sources, such as glucogenic amino acids, thereby maintaining blood glucose levels. Insufficient glucagon action increases blood amino acids, which stimulates alpha cell proliferation and function to compensate for the glucagon insufficiency. The way that increased amino acids trigger alpha cell proliferation remains incompletely defined.
What was unique about your approach to the research?
This study used zebrafish, cultured alpha cells, and mouse islets, which are the pancreatic cells. The work employed genetics, pharmacology, and chemical genetics. The research involved two VUMC laboratories, demonstrating the importance of collaboration in producing compelling results.
What were your findings?
We found that CaSR, a cell surface protein sensitive to amino acids, is critical for alpha cell proliferation. We also defined the signal transduction pathway from CaSR to cell proliferation. Importantly, activation of the CaSR pathway and mTORC1, a previously identified intracellular amino acid sensor, causes alpha cell proliferation in the absence of hyperaminoacidemia.
What do you hope will be achieved with the results in the short and long terms?
We will continue to study how the two pathways interact to activate proliferation in alpha cells but not in other cells.
What are the benefits of this research?
Understanding how to control alpha cell proliferation has two potential long-term benefits for diabetes treatment. On the one hand, blocking glucagon function reduces blood glucose in diabetes patients and is thus a potential therapy. However, the consequent alpha cell proliferation is a long-term safety concern. On the other hand, alpha cells are the closest cousins of the insulin-producing beta cells and can be more easily coaxed to become beta cells for treating diabetes. The ability to control alpha cell proliferation may help reap the benefits and mitigate side effects.
Where is this research taking you next?
We are always interested in understanding how the two pathways synergize to drive alpha cell proliferation. Since both mTORC1 and CaSR are well-known drug targets of clinically prescribed drugs, it may be possible to repurpose them for controlling alpha cell mass.
This work was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the Chinese Scholarship Council, and the Vanderbilt Molecular Endocrinology Training Program.