Abstract:  Pancreatic beta cells are the only cell type in our body capable of producing and secreting the insulin necessary to absorb nutrients after a meal. Accurate control of insulin release is of critical importance; too little insulin leads to diabetes, while an excess of insulin causes potentially fatal hypoglycemia. Because we only become aware of the important contributions of the pancreas when it fails to maintain nutrient homeostasis, it is easy to forget just how well insulin release from a healthy pancreas is matched to insulin need. Beta cells achieve this feat in part by extensive crosstalk with the rest of the endocrine cell types in the islet, notably the glucagon-producing alpha cells and somatostatin-producing delta cells. The complex and dynamic intra-islet crosstalk that shapes insulin release is therefore best understood by quantifying the dynamic changes in calcium and cAMP across all three major islet cell types simultaneously. Incretins and other pro-glucagon-derived peptides released by pancreatic alpha cells promote insulin secretion in the prandial phase. This same mechanism has been targeted for the development of multiple incretin-based drugs including Semaglutide, Ozempic, and Tirzepatide. Exactly how these drugs help millions attain relief from diabetes complications is not understood. By studying dynamic signaling in primary beta cells in response to incretin stimulation, we demonstrate that differences in the efficacy of current incretin therapeutics may be partially explained by the kinetics of cAMP generation that determine insulin secretion in response to GLP-1 receptors on beta cells.

Profile

Mark Huising earned his PhD degree from the Universities of Wageningen and Nijmegen in his native The Netherlands on the topic of the evolution of immune and endocrine systems in vertebrates. His work in this area – and a serendipitous encounter with his future mentor Dr. Wylie Vale led to an invitation to conduct postdoctoral research at the Salk Institute for Biological Studies, near San Diego, CA, USA. It is here that he laid the foundation for his research program in islet biology. He has moved and expanded his research program to the University of California Davis in 2014, where he is now a full Professor in the department of Neurobiology, Physiology and Behavior. He mentors a talented group of half a dozen graduate students, supported by a number of undergraduate research volunteers. He also teaches human physiology to 500 pre-medical students each year. Mark has received a number of honors and awards, including a Graduate Mentoring Award and the 2021 UC Davis Faculty Sustainability Champion. He is an elected fellow of the American Association for the Advancement of Science (AAAS).