Dr. Clayton Mathews is the IDI Chair, Director of the Center for Cellular Reprogramming, and a professor at the University of Florida with over 30 grants and 150 publications. His research focuses on diabetes, energy metabolism, and the genetic and cellular drivers of beta cell failure and autoimmunity. His lab uses approaches such as live imaging, spatial metabolomics, and CRISPR-edited stem cells to better understand how genes and metabolic pathways influence diabetes risk and progression.
Read the full interview here:
Can you provide a brief introduction about yourself and your academic background?
I’ve always been interested in energy metabolism. I grew up as an endurance athlete, a runner, which probably sparked that interest. As an undergraduate at North Carolina State University, I worked with Evan “Swede” Jones, studying nutritional biochemistry.. When I began thinking about pursuing metabolism in the context of disease, diabetes stood out as energy metabolism is critical in cells that are essential in disease progression. That led me to graduate school, where I joined Carolyn Berdanier’s lab at the University of Georgia. I completed my doctorate there in 1997 in the field of foods and nutrition. After receiving my doctorate, I performed a postdoctoral fellowship at The Jackson Laboratory in Bar Harbor, Maine. I’ve been involved in energy metabolism research since 1990.
What is the primary focus of your research?
My work focuses on diabetes, genetics, inflammation, and energy metabolism, which are deeply connected. Diabetes has often been described as “starvation in the land of plenty”, where nutrients are abundant, but the body can’t use them properly. In type 2 diabetes, excess nutrients overstimulate insulin production, leading to dysfunction, resistance to insulin, and then disease onset.
In type 1 diabetes, the immune system fails to regulate itself, and it mistakenly attacks insulin-producing beta cells in the pancreas . Our goal is to understand the genetic factors behind the immune failure, both those that amplify immune signals, sometimes in response to viruses, and those that fail to dampen inflammation. We are also seeking to define
To prevent or cure diabetes, we need to stop the immune system from damaging beta cells and figure out why beta cells themselves fail. Even when we replace beta cells through transplant or islet replacement, the immune system rejects them. We want to understand how to protect new or existing beta cells from dysfunction and destruction.
Why is your research important? What impact does it have on the field or society?
For beta cells to secrete insulin, they must generate energy in the form of ATP, usually from glucose metabolism. In healthy cells, glucose enters, is metabolized to pyruvate through glycolysis, and then goes into the mitochondria to fuel the TCA cycle and electron transport chain, producing ATP. The increase in ATP triggers insulin secretion through potassium channel closure and calcium signaling.
Recently, we’ve published findings showing that in people at risk for diabetes, or in people newly diagnosed with type 1 diabetes, there’s a significant decline in enzymes involved in glucose metabolism and ATP production. Clinically, type 1 diabetes patients often become “blind” to glucose; their beta cells fail to secrete insulin in response to glucose alone, though they may still respond to glucose combined with amino acids or lipids. This inability to sense glucose is a major risk factor.
What’s especially novel about our findings is that this failure in metabolic pathways appears to occur in the absence of acute inflammation at the site. That challenges the traditional view that inflammation is the main driver of dysfunction.
By studying human tissue directly, we can separate what is truly happening from what older models predicted. This has clear translational impact: we can identify real therapeutic targets to reverse beta cell failure. I have a family history of autoimmunity and diabetes, so this work is both scientifically and personally meaningful.
Can you describe any current research projects you are working on?
In addition to the project to understand why the beta cells lose glucose metabolic pathway we are also currently focused on studying how specific genes regulate diabetes risk. Genetic variation can affect a disease in different ways: sometimes it changes the coding sequence of a protein, altering its structure; other times it influences gene expression, splicing, or protein levels. For example, in someone with a common allele, form A might dominate, while in someone with a risk allele, form B could be more prevalent. That shift in balance can have consequences: form B might function poorly, or even trigger excess inflammation.
Of the 150 genes linked to type 1 diabetes, about 7–10 involve nonsynonymous mutations that directly change protein structure. These are somewhat simpler to study, and over the past decade we’ve published on four of them. All of these genes are associated with inflammation or immune response.The other projects we’re working on examine why beta cells fail, and what are the changes in beta cells during disease progression.
What methodologies or approaches do you use in your research?
We use a wide range of methodologies, many of which are designed to let us study human beta cells as directly and accurately as possible.
One of our core approaches is live imaging of pancreas tissue obtained from organ donors whose organs are not suitable for transplantation. Pancreas transplants are relatively rare, but when tissue becomes available, we can process it to study beta cell function in real time. This allows us to observe how cells respond to glucose uptake, calcium flux, and ATP production, all of which are key to insulin secretion.
We’ve also developed techniques to trace nutrient metabolism inside these cells. For example, by using labeled glucose, we can follow the carbons as they move through glycolysis and into the TCA cycle, mapping exactly where the metabolic process may stall. This lets us create a kind of “spatial map” of beta cell function. We combine that with advanced technologies such as spatial metabolomics, transcriptomics, and proteomics, which allow us to measure changes in metabolites, gene expression, and protein content across individual cells. By layering these data, we can pinpoint how and why specific cells become dysfunctional.
On the genetic side, we rely heavily on induced pluripotent stem cells (iPSCs) derived from patients and their relatives. These cells can be genetically edited using CRISPR-Cas9, allowing us to switch alleles between risk and common variants. For example, if a patient has a risk allele, we can edit it to the common form, and vice versa. We also create a cell where the gene is entirely removed. This results in a collection of 4 cells: the original patient cell, a risk-edited cell, a common-edited cell, and the gene-less cell. By comparing these side by side, we can directly test how genetic variation affects beta cell behavior.
Are you collaborating with any other researchers or institutions? If so, how do these collaborations enhance your work?
Yes, collaboration is essential. At UF, we’re part of the Diabetes Institute and have joint grants and projects with Martha Campbell-Thompson, Jing Chen, Ed Phelps, Todd Brusko, Des Schatz, Clive Wasserfall, Matthew Merritt, Ramon Sun, Holger Russ, and Mark Atkinson. I study immune cell metabolism with Phil Efron, Rob Maile, and Linc Moldawer in UF-Surgery and work with Tommy Angelini and Xing Pan in mechanical and aerospace engineering on building bone marrow organoids, which may help us understand how infection and autoimmunity affect immune cell production.
I also collaborate with David Ostroff and Danmeng Li on protein structures as well as islet stress responses, which may reveal how new autoimmune targets emerge. Outside UF, I currently have projects with Weijun Qian (Pacific Northwest National Lab), Rohir Kulkarni (Harvard), Hubert Tse (University of Kansas Medical Center), and Jeff Millman (Washington University). You can’t do everything alone. Having people that are interested in the same idea but do unique things allows us to get more done and understand the processes that occur in a more rigorous way.
Have you received any notable awards or recognitions for your research?
I am currently the Chair of the Infectious Diseases and Immunology Department at UF, and the director of the Center for Cellular Reprogramming. Before becoming IDI Chair, I was the Sebastian Family Professor for Diabetes Research. I was also named a UF Research Foundation Professor in recognition of my research contributions. I’ve received over 30 grants and have over 150 peer-reviewed publications.
Outside of your research, what other interests or hobbies do you have?
I enjoy traveling, both for conferences and personal trips. Last year I visited Italy and Switzerland, and next year I’ll be in Australia for a meeting and plan to take time off to explore. I also enjoy reading, cycling, and spending time with my family. My daughter is an athlete, so we often travel around the country for her competitions.
How can others learn more about your work or get in touch with you?
Email: cxm@ufl.edu
Phone Number: (352) 273-9269
What is your general advice for anyone who wants to do what you do?
For anyone interested in becoming a scientist, the most important thing is to find something you’re passionate about, something you want to wake up every day and study to make positive progress. Science comes with a lot of failure. Many ideas don’t work out, not because they were bad, but because we didn’t yet know enough to understand why they failed. If you love what you’re doing, you’ll keep pushing until you find answers.
You also need to be persistent and committed to learning. Read constantly, keep up with what others are publishing, and stay engaged with the field. If you want to be in academia, you need to enjoy mentoring and training people, and you should do everything you can to help your students and colleagues succeed. Writing strong, smart, and innovative grant applications is another essential skill, funding keeps research alive.
If you want to move into leadership roles, like department chair, there are additional responsibilities. You need to understand finances and know how to manage budgets without letting labs run deficits. You have to keep track of personnel, make adjustments when needed, and anticipate problems before they arise. While financial management may not be what excites me most, it’s necessary to set everything else up for success.
Finally, it’s critical to increase the visibility of your work. Learn how to communicate what you do and why it matters. Be proactive about sharing your research, engage with different audiences, and make sure your science has a presence.
Interviewer: Julia Martin, UF Undergraduate
Interview with Clayton Mathews
Transcribed: 9/3/2025
