Research Description
Type 1 diabetes (T1D) and Type 2 diabetes (T2D) are devastating diseases caused by distinct and poorly understood mechanisms. Pancreatic islets play critical roles in both diseases, and recent findings demonstrate that chemical heterogeneity exists within the classic islet endocrine cell types (e.g., there are subtypes of beta cells with distinct transcriptomes that respond differently to chemical signals). One critical scientific question is how does this cellular heterogeneity influence chemical signaling in T1D and T2D? The hypothesis here is that characteristic changes in chemical cellular heterogeneity within human islet cell types during diabetes progression alter the signaling pathways inside and outside of the pancreatic islets. Determining the dynamics of these changes will provide insight into chemical mechanisms that can be exploited for the prevention, treatment, and ultimately the cure of diabetes. The current lack of chemical detail for islet cells is partially due to the unmet need for high-throughput and highly sensitive technologies that are capable of probing a sufficient number of chemical constituents in single cells. This deficiency in knowledge will be addressed using three unique measurement platforms that implement advanced single cell mass spectrometry and analyte separation techniques to characterize the peptide and small-molecule content in individual human islet cells affected by T1D and T2D, information that cannot be obtained by other approaches. This research will improve the understanding of the cellular mechanisms of both T1D and T2D, and elucidate new chemical parameters characteristic of each disease, helping to identify novel pathways for therapeutic intervention.Research Profile
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?My group has pioneered novel technologies to measure the chemical content of individual cells, and we have unique abilities to uncover unexpected compounds that act as key players in both Type 1 diabetes and Type 2 diabetes. When combined with the recent ability to obtain transplant-quality human pancreatic specimens/islets from individuals at various stages of health and disease, our research strategy provides a unique opportunity to understand how the molecules of life, both known and previously unknown, change during diabetes progression at the cellular scale without requiring prior knowledge of the specific molecules of interest. We will fill critical information gaps regarding the roles of important cellular communication molecules (e.g., serotonin, dopamine, D-serine) that are known to be present within islets but poorly characterized. Such broad-based discovery science can open up new therapeutic targets and novel avenues for exploration.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?I find it particularly intriguing that within the islets, almost all categories of transmitters and modulators found in the brain are present, including the well-known peptide hormones, such as glucagon and insulin. Also present are glutamate, GABA, dopamine, and serotonin, and the D-amino acids, molecules that likely play important roles in human health but have yet to be thoroughly explored outside of the brain. Our unique measurement toolsets are particularly well-suited to the study of islet cells, and I am excited about using them to advance diabetes research and understand human islet biology. For the long term, I am committed to integrating our measurement techniques into projects with established diabetes investigators to make significant advancements towards the prevention and cure of diabetes.
Why important for you, personally, to become involved in diabetes research? What role will this award play?Throughout my career, I have directed my group’s research toward two synergistic foci: the development of new chemical measurement approaches and their application to understanding cell-to-cell signaling. We have created the most comprehensive chemical characterization toolsets available and are confident in our ability to probe the chemical contents (peptides, hormones, metabolites) within individual islet cells. I am eager to combine these tools with my passion for collaborations towards advancing the field of diabetes research, a research direction enabled by receiving the ADA Visionary Award.
In what direction do you see the future of diabetes research going?While the mechanisms of Type 1 diabetes (T1D) and Type 2 (T2D) diabetes differ, both diseases present changes in the biochemistry and morphology of pancreatic islets during disease progression that remain poorly understood. Therefore, it is important to enhance our understanding of the molecular mechanisms of autoimmune destruction of beta cells in T1D, as well as insulin resistance and subsequent loss of beta cell mass in T2D. More research is needed to understand novel and cell-specific biochemical pathways in order to identify novel therapeutic targets to prevent, and ultimately, cure these diseases.